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Evaluation of a computer-assisted technique for distal locking of femoral intramedullary nails Beadon, Katherine E. 2007

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E V A L U A T I O N OF A COMPUTER-ASSISTED TECHNIQUE FOR DISTAL LOCKING OF F E M O R A L I N T R A M E D U L L A R Y NAILS by KATHERINE E. B E A D O N B.Sc.(Physics), The University of British Columbia, 2005 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF M A S T E R OF APPLIED SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES (Mechanical Engineering) THE UNIVERSITY OF BRITISH C O L U M B I A July 2007 © Katherine E. Beadon, 2007 Abstract The objective of this work was to design the devices and methods necessary for a computer-assisted distal locking technique for intramedullary nailing of the femur using an electromagnetic tracking system. The long-term goal of this work is to increase the efficiency and decrease the radiation exposure to the surgical team during the intramedullary nailing procedure. The accuracy of the electromagnetic system was determined to be acceptable for our application, even in the presence of the titanium implant. A distal locking tool was designed that locks into the distal locking holes from within the intramedullary nail with high repeatability. The stresses predicted from a finite element analysis of the removal process predict maximum stresses of l/500 t h of the yield stress of the material. The use of this tool produces wear particles too few in number and too small in size to induce osteolysis in a patient. We conclude that the distal locking device is very likely to be successful in a surgical setting. A clinical trial was designed in order to test this hypothesis. The clinical trial has been delayed due to the establishment of new requirements at our hospital governing the introduction of custom-made research devices into a surgical setting. As a result, we have developed a set of guidelines for future researchers to facilitate completing all the required testing to obtain approval to perform a clinical trial. We are currently in the final stages of satisfying these requirements and anticipate that our clinical trial will begin in early fall. Table of Contents Abstract i i Table of Contents . i i i List of Tables v List of Figures vi List of Abbreviations x Acknowledgments x i 1 Introduction and Literature Review 1 1.0 History of Intramedullary Nailing of the Femur 3 1.1 Intramedullary Nailing Technique 4 1.1.1 Nail Insertion 4 1.1.2 Proximal Locking 5 1.1.3 Distal Locking 6 1.2 Disadvantages of the Current Technique 7 1.3 Alternative Techniques for Distal Locking 7 1.4 Purpose of This Study 12 2 Materials and Methods 14 2.1 Aurora Electromagnetic Tracking System 14 2.2 Synthes Universal Femoral Intramedullary Nail 16 2.3 Effect of the Intramedullary Nail 17 2.4 Distal Locking Tool 20 2.4.1 Design 20 2.4.2 Insertion Repeatability 23 2.5 Mechanical Testing 27 2.5.1 Experimental Moment to Remove DLT 28 2.5.2 Maximum Moment 29 2.5.3 Stress Analysis 29 2.5.4 Particulate Formation 30 3 Results 33 3.1 Effect of the Intramedullary Nail 33 3.2 Insertion Repeatability 36 3.3 Mechanical Testing 37 3.3.1 DLT Removal Moment 37 3.3.2 Stress Analysis 38 3.3.3 Particulate Formation 39 4 Discussion 42 4.1 Effects of the Intramedullary Nail 43 4.2 Distal Locking Tool Accuracy 46 4.3 Ease and Safety of Distal Locking Tool Design 52 4.4 Optimizing the Design 52 4.5 Particulate Formation 54 5 Implementation of a Clinical Trial for the D L I M N project 57 5.1 Materials and Methods 58 ii i 5.1.1 Required Instrumentation 59 5.1.2 Data Collection 61 5.1.3 Data Analysis 62 5.2 Current Status 63 5.2.1 Safety Testing for the D L I M N trial 63 5.2.2 Sterilization Method and Validation for the D L I M N Trial 64 5.2.3 Final Approval 67 5.3 Expected Contributions : 67 6 Conclusion 69 6.1 Design and Testing of the Distal Locking Tool 69 6.2 Evaluation of the Method and Apparatus 70 References 71 Appendix 1: Design Evolution of the Distal Locking Tool 77 Appendix 2: ABS Material Specifications 80 Appendix 3: Theoretical Force to Remove DLT and Factor of Safety Calculations 81 Appendix 4: Planning and Implementation of a Clinical Trial in a Research Setting 83 Appendix 5: Clinical Research Ethics Board Application: Protocol for D L I M N Trial 107 Appendix 6: Clinical Research Ethics Board Application: Consent Form for D L I M N Trial 113 Appendix 7: Clinical Research Ethics Board Application: Online Application Form 117 Appendix 8: Approval to Conduct Research at Vancouver Coastal Health 134 Appendix 9: Guideline for Obtaining Approval to Conduct Research at Vancouver Acute 137 Appendix 10: Radiation Stability of Polymer Materials 148 Appendix 11: Aurora Approvals and Classifications 150 Appendix 12: Cleaning and Sterilization Protocol for MIS Study 151 Appendix 13: Results for Sterility Testing of the Reference Clip 154 iv List of Tables Table 3.1: Summary of Results for Accuracy Testing 34 Table 3.2: Moment Required to Remove the Distal Locking Tool 37 Table 4.1: Standard Deviations for Sensor Accuracy and Insertion Repeatability for all 6 DOF 46 Table 5.1: Radiation Doses Applied to the DLTs. Four tools were radiated at each radiation dose tested. The doses tested were 25, 35, and 45 kGy 67 List of Figures Figure 1.1 Rigidly Locked Femoral Intramedullary Nail. Proximal and distal locking of intramedullary nails allows for early mobilization without the risk of angular or femoral length malalignment, (source: Trigen® IM Nail System Surgical Technique) 4 Figure 1.2: Nail Insertion. Once the intramedullary canal has been opened, a small guide wire is fed down the canal through all bone fragments under fluoroscopic guidance, (source: Synthes® Universal Nail System Technique Guide) 5 Figure 1.3: Proximal Locking. The insertion handle attached to the proximal end of the IMN is fitted with an alignment guide for proximal locking (left). Both the drilling and screw insertion are done by placing the screw through the alignment guide and into the bone (right), (source: Synthes® Universal Nail System Technique Guide) 6 Figure 1.4: Distal Locking Under Fluoroscopic Guidance. The fluoroscope must first be positioned such that the locking holes appear as perfect circles (B) and not ellipses (A). The drill bit is then aligned such that its tip appears in the centre of the circle (C) and then so that the drill bit appears only in the centre of the circle, (source: Synthes® Universal Nail System Technique Guide) 6 Figure 1.5: Mechanical Guide for Distal Locking. The use of this mechanical guide requires the surgeon to drill a 6-10 mm working channel in order to palpate the distal holes using a guide hook. This method has not come into widespread use due to the potential for complications associated with the creation of a working channel, (source: Krettek 1998) 8 Figure 1.6: Inflatable Nail. Insertion of the Fixion Inflatable Nail obviates the need for distal locking and therefore reduces surgical time and radiation exposure. This nail has not come into widespread use due to complications associated with inflation and potential lack of torsional stability, (source: www.disc-o-tech.com) 9 Figure 1.7: Virtual Fluoroscopy Setup. In order to reduce radiation exposure during D L I M N , the fluoroscope (A) and surgical tools (B) are tracked using an optical tracking system (not shown). This allows the D L I M N procedure to be accomplished with as few as two fluoroscopic shots that are approximately perpendicular, (source: Suhm 2004) 10 Figure 1.8: Magnetic Probe System. A permanent magnet is inserted into the central canal of an IMN. Local changes in magnetic field in the area of the locking holes are sensed by an external magnetic sensor fitted with an L E D display and a drill sleeve, (source: Szakelyhidi 2002) 11 Figure 1.9: Testing of a Novel Surgical Method: After design and lab-based testing is complete, it is necessary to test the method and apparatus against the current surgical approach and to complete a surgical task simulation to ensure that the method is accurate enough to be tested in a clinical setting using a randomized controlled trial 12 Figure 2.1: Aurora Electromagnetic Tracking System. The system is made up of a control unit, a field generator, a sensor interface unit and a 6 DOF sensor with a diameter of 2.5 mm. The sensor is attached to lead wires and a connector vi plug which mates with the system interface unit.(source: Northern Digital, www.ndigital.com) 15 Figure 2.2: Aurora Measurement Volume. The measurement volume of the Aurora system is a cube with side lengths of 500 mm. The origin of the system lies on the front face of the field generator with the measurement volume projecting outwards, (source: Aurora User Manual 2005) 15 Figure 2.3. Synthes Universal Femoral Nail. A l l of the testing was performed using Synthes Universal Femoral Nails 16 Figure 2.4: Calibration Phantom. The calibration phantom was placed approximately 250 mm in front of the Field Generator. Data was collected while the calibration plug was in each of the alignment holes. The distance between the calibration plug and the reference plug was calculated and compared to the known locations of alignment holes, (source: Kirsch 2005) 17 Figure 2.5: Calibration Plug. The sensor was fixed within the IMN using set screws (C). The IMN was rigidly fixed in the calibration plug by press fitting it into a cylinder attached to the calibration plug (B) and inserting a rod through the distal locking hole (A) 19 Figure 2.6: Distal Locking Tool. The custom designed Distal Locking Tool is placed inside of the IMN once the nail has been inserted into the femur, (source: modified from Trigen® IM Nail System Surgical Technique) 21 Figure 2.7: Design of the Distal Locking Tool. The locking arms are designed to expand when the distal locking tool is inserted and lock into the distal locking holes. The diameter of the distal locking tool is 3.4 mm. The sensor is offset from the locking plugs by 50 mm 22 Figure 2.8: Distal Locking Tool Plug. The distal ends (left) of the DLT are designed with plugs to engage the locking holes of the IMN. The distal surface of the plugs are cylindrically shaped so that they do not slide past the locking holes. The proximal (right) surface of the plugs are spherically shaped in order to facilitate removal of the DLT 22 Figure 2.9: C-shaped canal. The DLT is fitted with a C-shaped canal to allow the 6DOF sensor to be sealed within the DLT 23 Figure 2.10: Digitizing Probe. The probe reports the tip location in 6 DOF. The tip of the probe is chamfered 24 Figure 2.11: Digitizing the Locking Holes. The locking holes were digitized by placing the chamfered tip of the probe into the holes until the probe made contact with the rim of the locking hole 24 Figure 2.12: Nail Frame Construction 1. Four points on the IMN were digitized in order to create the nail frame, the medial and lateral surfaces of the most distal locking hole (pi and p2) and the medial and lateral surfaces of the more proximal distal locking hole (p3 and p4) 25 Figure 2.13: Nail Frame Construction 2. The centers of the locking holes were defined as the midpoints between the two sides of the locking holes 25 Figure 2.14: Torque Necessary to Remove DLT. The IMN was fixed in the calibration box and the DLT was inserted. The proximal end of the DLT was threaded through a cylindrical attachment and supported at the proximal end. A rope was wrapped around the cylinder and threaded through the base of the calibration box. Weights with increasing mass were attached to the rope until the DLT was released from the locking holes 28 vn Figure 2.15: F E M mesh for the distal locking tool. The DLT was meshed with 289,540 tetrahedral elements and 279,954 degrees of freedom 30 Figure 3.1: Accuracy of the Aurora sensor with and without the IMN. The accuracy of the Aurora sensor in standard conditions was 0.41± 0.12 mm and 0.38± 0.28°. With the IMN, the accuracy was 0.52 ± 0.16 mm and 0.43 ± 0.20°. Precision error of the readings increased in the presence of the IMN 33 Figure 3.2: Cumulative Distribution of Accuracy Errors. Results for positional readings (left) taken without the IMN (-) and with the IMN (--) show that a distortion of approximately 0.1 mm in induced by the presence of the nail. This difference is statistically significant (p = 0.006) but not clinically relevant. Orientation errors (right) were not significantly different ( p = 0.41) 34 Figure 3.3: Probability Distribution for Accuracy Errors. Positional errors (left) without the IMN (-) and with the IMN (--) show very small 95% confidence intervals (0.06 and 0.05 respectively). Orientation errors (right) have 95% confidence intervals of 0.12° and 0.16° without and with the IMN 34 Figure 3.4: Position Accuracy Error does not change as a function of distance from the sensor to the field generator 35 Figure 3.5: Position precision error increases with increasing sensor distance from the field generator 35 Figure 3.6: Mean Deviations for Translations. Boxplots showing the mean, +/- standard deviation, min and max for each of the cardinal directions. Translational errors were very low with standard deviations of 0.03, 0.12 and 0.20 mm in the x (longitudinal axis of the nail), y (anteroposterior axis), and z (mediolateral axis) directions 36 Figure 3.7: Mean Deviations for Rotations. Boxplots showing the mean, +/- standard deviation, min and max for rotations about each of the cardinal directions. Rotational errors were low with standard deviations of 1.59°, 0.13° and 0.08° about the x (longitudinal axis of the nail), y (anteroposterior axis), and z (mediolateral axis) axes respectively 36 Figure 3.8: Finite Element Model of the Distal Locking Tool. The maximum von Mises stress reported from the model was 8.5-104 Pa and was located at the junction of the locking arms and the locking plugs 38 Figure 3.9: Number of Particles Produced. The number of particles produced was reduced by 77% for devices that were filed (trials 3-4) compared to devices that were not filed (trials 1-2) 39 Figure 3.10: Particulate Samples. Very small (A), small (B), medium (C), and large (D) particles had maximum edge lengths of <10 urn, 10-20 um, 20-50 um and >50 urn respectively 40 Figure 4.1: Maximum Error Tolerance for Distal Hole Targeting. The maximum error tolerance for targeting distal locking holes has been previously reported as 0.75 mm and 8°. (source Szakelyhidi 2002) 42 Figure 4.2: Orthopaedic Fracture Table. Surgical tables designed for orthopaedic fracture fixation are designed to be radiolucent. The composite table top and abductor bars decrease the amount of steel near the sensing area thereby decreasing the interference for electromagnetic tracking, (source: www.steris.com) 44 Figure 4.3: Accuracy (shown here as Trueness) of the Aurora 2 system is optimal at d < 400mm. Precision of the Aurora readings also decreases for distances over 400 mm. (source: Kirsch 2005-1) 45 vm Figure 4.4: The total distance between the sensor and locking plugs is 50mm. This distance is made up of the locking arms (shown above) and the transition zone. Decreasing this total distance may decrease the error associated with predicting the locking hole axis from the sensor location 48 Figure 4.5 Tracking accuracy decreases with decreased distance between the sensor and a CT table (source: Krucker 2006) 51 Figure 5.1: Testing Involved in Proof of Concept for Electromagnetic Targeting in D L I M N . Accuracy has been demonstrated in a lab-based setting. It is now necessary to test the systems performance in a simulated surgical task and compared to the conventional technique. When this is complete, the system can be used for targeting in the OR 57 Figure 5.2: Reference Clip. The reference clip will be attached to the drill bit during alignment for distal hole targeting using a fluoroscope 59 Figure 5.3: Distal Targeting Device. The drill bit is fastened into the radiolucent targeting device using a set screw (A). The distal holes are the located by aligning the drill bit to the centre of the locking hole under fluoroscopic guidance, (source: Zimmer M / D N ® Femoral Interlocking and Recon Nail Intramedullary Fixation Surgical Technique) 60 Figure 5.4: Reference Clip. The reference clip contains a small channel (A) into which the drill bit (E) is placed. The clip is then tightened down by turning a lever (B). The clip is also fitted with screw holes (C). These holes are used to attach the sensor (D) to the clip 61 IX List of Abbreviations ABS Acrylonitrile Butadiene Styrene B M E Biomedical Engineering CAOS Computer Assisted Orthopaedic Surgery CAS Computer Assisted Surgery CREB Clinical Research Ethics Board DLIMN Distal Locking for Intramedullary Nailing DLT Distal Locking Tool DOF Degree of Freedom EMTS Electromagnetic Tracking System FG Field Generator IMN Intramedullary Nail MDDSC Medical Device Development Safety Committee M D R Medical Devices Regulations M o H (British Columbia) Ministry of Health P M M A Polymethyl methacrylate, Bone cement RMS Root Mean Square SPD Sterile Processing Department THA Total Hip Arthroplasty U B C University of British Columbia U H M W P E Ultra High Molecular Weight Polyethylene VCHRI Vancouver Coastal Health Research Institute Acknowledgments I would like to thank all those who have supported me throughout this project. Thank you to my supervisor, Dr. Antony Hodgson for sharing his knowledge and providing encouragement. Thanks to Drs. Pierre Guy and Peter O'Brien for the idea that lead to this thesis topic and for providing valuable insight into all things surgical. Special thanks to Dr. Guy for making time in his busy schedule to coach me through the M D interview process. Many thanks to Jeff Stanley, Saibal Chakraburtty and their colleagues at Northern Digital Inc. for their financial support, guidance with the Aurora system and for agreeing to allow me to work with them in Waterloo, despite my being a security risk... I would also like to thank everyone at VCHRI who took part in the development of the new hospital guidelines. Thank you to Dr. Elizabeth Bryce, Darren Kopetsky, Stephania Manusha, Mona Sharman, Gord McConnell, Debbie Hendricks and Murray Dore for working tirelessly to arrive at a solution that worked for everyone instead of simply not allowing my work. Thank you to Alex English and Andrea Geere for initiating me into the world of sterilization of medical devices and for fielding my innumerable questions about processes and procedures. Thanks to Caron Fournier, Perri Berthelet and Nancy Henderson for their technical assistance in various aspects of the project. Special thanks to all my colleagues at the Neuromotor Control Lab. Sayra, Jill , Jeremy and all the others who have passed through here in the last several years, you have made our lab a productive and enjoyable place to work. Thanks for the random discussions about nearly everything, helping me with my project, listening to me rant and for escaping the lab for much needed breaks! Thank you also to team spondy for teaching me the skills necessary to be an effective researcher and for keeping me company throughout all the long hours spent watching the Instron. Thank you to Matt and Josh for making Friday afternoon anatomy labs something to look forward to! Many thanks to all of my friends who were so supportive throughout my degree and especially in the last several weeks. Thanks for the late night sushi deliveries, the last minute editing, and for listening to me whine on occasion. Thanks to all the brostellers for an incredible community in which to live and play; the weekends in the mountains and on the water have made these last few years some of my best. Thank you to my family for teaching me to work hard and play hard, for instilling in me the self-confidence and self-reliance that have guided me through my choices so far, and for your support as I begin my next challenge. Lastly, thanks to Brad for being here for the last six years despite my neuroses and indecision. Thanks for understanding me. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC). xi 1 Introduction and Literature Review Over the past two decades, computer-assisted orthopaedic surgical (CAOS) techniques have been developed for a variety of traditional orthopaedic procedures. Incorporating real-time feedback during surgery can allow for better precision, better limb and implant alignment, better fracture reduction and less radiation exposure (Kanlic 2006). New surgical tools and techniques have also allowed many traditionally open procedures to be completed less invasively allowing for faster recovery, decreased post-operative pain, and improved functional outcomes (Kanlic 2006). This general approach of combining intra-operative tracking of surgical tools with pre or intra-operative images has been successfully used in a wide variety of applications ranging from neurosurgery to gynecology. One of the most common procedures performed by orthopaedic surgeons is fracture treatment. A British study spanning ten years found that long bone fractures (eg, of the femur, tibia/fibula and humerus) are very common: the femur is the fifth most common fracture site, fractures of the tibia and fibula ranked third most common and those of the humerus ranked seventh (van Staa 2001). Fractures of the shaft of long bones are often treated by insertion of an intramedullary nail which has been shown to be an extremely successful procedure(Winquist 1984). Nonetheless, femur fracture cases represent the single most prevalent and the third most expensive type of malpractice suit brought against orthopaedic surgeons. Tibial and humeral fractures rank second and tenth respectively on the list of most common malpractice suits (AAOS 2001). It is therefore not surprising that a wide variety of surgical improvements have been proposed for safe and accurate intramedullary nailing (Pennig 1997, Krettek 1999, Slomczykowski 2001, Szakelyhidi 2002, Hazan 2003, Suhm 2004, Ozturk 2005, Hollstein 2006). 1 During intramedullary nailing of the femur, the items of interest are the bone fragments, the surgical tools, and the intramedullary nail (IMN) itself. Some researchers have used optical systems to track bone fragments during fracture reduction (Hart 2007, Khoury 2007, Weil 2007) but optical systems cannot accurately track the position of the intramedullary nail due to the deformation associated with nail insertion (Pennig 1997, Slomczykowski 1998, Krettek 1998). This makes distal locking of intramedullary nails a time consuming and technically demanding procedure. The traditional approach relies on fluoroscopic guidance. This method exposes the surgical team to a significant amount of cumulative radiation over the course of their careers. In the last several decades, surgeons have become increasingly specialized and consequently perform procedures that expose them to potentially harmful radiation more often. The accumulation of radiation exposure over the course of an orthopaedic surgeon's career is a rising concern and has received significant attention in the literature of late (Mehlman 1997, Herscovici 2000, Madan 2002, Hafez 2005, Singer 2005). A l l of these studies emphasize the need to minimize fluoroscopic time and to avoid being in the direct path of the x-ray beam. Hafez argues that previous studies have significantly underestimated the actual radiation exposure received at surgeons' fingertips. The authors found that radiation doses recorded at the fingertips were as much as 75 times higher than doses recorded at the base of the fingers. This is likely due to the fingers being positioned directly in the x-ray beam during screening. This conflicts with the conclusions drawn in older studies (Miller 1983, Levin 1987, Riley 1989, Goldstone 1993, Noordeen 1993, Sanders 1993, Smith 1996, Jones 1998, Muller 1998) that the radiation exposure to the hands of orthopaedic surgeons is below acceptable limits. The risks of ionizing radiation in relation to initiating cancers are well known and the incidence of such cases is rising 2 (Gundestrup 1999). It is therefore pertinent to explore surgical solutions that minimize the use of ionizing radiation. The long-term goals of this research are to develop the tools and methodology necessary to accomplish distal locking of intramedullary nails (DLIMN) with a more time-efficient, accurate and radiation-free technique. The scope of this project was the development and evaluation of the tools necessary for targeting distal locking holes from within the intramedullary nail (IMN) using an electromagnetic-based tracking system. 1.0 History of Intramedullary Nailing of the Femur Beginning as early as the 16 th century, intramedullary fixation for the treatment of long bone fractures has been explored (Farill 1952). Modern intramedullary nailing was spearheaded by a 1931 report by Smith-Petersen on the use of stainless-steel nails in femoral neck fracture treatment. This technique was adapted by Kutscher in the early 1940's for the treatment of femoral shaft fractures (Bong 2007). These early surgeries involved the use of head-worn fluoroscopy to visualize the bone. The advent of penicillin in the late 40's led to a resurgence of an open surgical technique in order to avoid the detrimental effects of the high levels of the radiation emitted by the radiographic techniques of the time. With the development of better radiological image intensification in the 60's and 70's, closed intramedullary procedures could once again be performed with reduced risks to patients and surgeons (Bong 2007). Winquist (1984) reviewed 520 intramedullary nailing procedures performed between 1968 and 1979 and found union rates of over 99% with very few complications. Intramedullary nailing remains the standard of care for the treatment of femoral fractures today. 3 1.1 Intramedullary Nailing Technique Modern treatment of femoral fractures involves the insertion of a metal nail into the intramedullary canal (Figure 1.1). The implant used is usually a hollow tube, 10-15 mm in diameter that is placed into the central canal of the bone and locked into place with screws drilled through the bone and implant at both the proximal and distal ends. The surgical procedure can be divided into three main steps: nail insertion, distal locking, and proximal locking. Locking the IMN both proximally and distally allows for early mobilization without the risk of limb length discrepancies or angular malalignment (Dobbs 2006). Figure 1.1 Rigidly Locked Femoral Intramedullary Nail. Proximal and distal locking of intramedullary nails allows for early mobilization without the risk of angular or femoral length malalignment, (source: Tr igen® IM Na i l System Surgical Technique) The order in which locking is performed is at the discretion of the surgeon. Once the nail is locked distally, the distal femoral bone fragment can be manipulated to obtain optimum alignment before locking the IMN proximally. Distal locking is therefore often completed prior to proximal locking. 1.1.1 Nail Insertion After the correct entry point is identified, the intramedullary canal is opened and a guide wire is inserted through the femur to the distal metaphysis (Figure 1.2). 4 Figure 1.2: Nail Insertion. Once the intramedullary canal has been opened, a small guide wire is fed down the canal through all bone fragments under fluoroscopic guidance, (source: Synthes® Universal Nail System Technique Guide) Both entry point localization and guide wire insertion are done under fluoroscopic guidance. The hollow implant is then threaded onto the guide wire and hammered into place inside the femur assisted by the use of an insertion handle. Once the IMN is in place, final placement is verified using the fluoroscope. 1.1.2 Proximal Locking In order to insert the proximal locking screws into the IMN, a mechanical guide is fixed to the insertion handle. Both the drill and the locking screws are placed through the guide and into the bone and implant (Figure 1.3). 5 Figure 1.3: Proximal Locking. The insertion handle attached to the proximal end o f the I M N is fitted with an alignment guide for proximal locking (left). Both the dri l l ing and screw insertion are done by placing the screw through the alignment guide and into the bone (right), (source: Synthes® Universal N a i l System Technique Guide) 1.1.3 Distal Locking Inserting the IMN often leads to unpredictable deformation of the implant (Pennig 1997, Krettek 1998). This makes it difficult for surgeons to identify the position of the distal locking holes externally and has led to the abandonment of proximally mounted distal aiming jigs (Whatling 2005). The conventional solution involves the use of a fluoroscope to visualize the holes. The surgeon must adjust the positioning of the fluoroscope until the holes appear as perfect circles (Figure 1.4). Figure 1.4: Distal Locking Under Fluoroscopic Guidance. The fluoroscope must first be positioned such that the locking holes appear as perfect circles (B) and not ellipses (A). The dril l bit is then aligned such that its tip appears in the centre of the circle (C) and then so that the dr i l l bit appears only in the centre o f the circle, (source: Syn thes® Universal Na i l System Technique Guide) 6 Then a radiolucent drill guide must be placed in the correct orientation and drilled under x-ray guidance. Once the first screw is in place, the alignment method must be repeated for the second locking screw. 1.2 Disadvantages of the Current Technique This method has two major disadvantages: it is not time efficient and it exposes the surgical team to a significant amount of radiation. In an ex vivo study, Krettek found that distal locking of the implant took 4.8 minutes and accounted for over 23% of the total surgical time (Krettek 1999). A study by Suhm revealed that distal locking in vivo was accomplished in a mean time of 27.4 minutes (Suhm 2004). Okcu reported a total surgical time of 141.6± 20.2 minutes for intramedullary nailing of the femur in vivo (Okcu 2003). Distal locking in vivo may therefore account for approximately 20 % of total surgical time. Distal locking ex vivo required 0.62 minutes of fluoroscopic screening time and accounted for over 53% of the total fluoroscopic screening time of 1.15 minutes for one senior orthopaedic surgeon (Krettek 1999). In vivo total fluoroscopic screening times as low as 0.52 minutes have been reported for senior orthopaedic surgeons (Madan 2002) but are more commonly reported to be in the range of 4 to 7 minutes (Blattert 2004, Mueller 1998). The wide range of screening times is likely due to the complexity of reducing comminuted fractures and the range of experience of orthopaedic surgeons (Blattert 2004, Madan 2002, Hafez 2005). 1.3 Alternative Techniques for Distal Locking Several alternative locking techniques have been developed in order to address the aforementioned problems. These alternatives include nail mounted mechanical guides, self-7 locking nails, computer-assisted fluoroscope navigation and magnetic-based targeting systems. Unfortunately, none of these methods have come into widespread use. First generation nail-mounted mechanical guides were unsuccessful due to the difficulty of quantifying nail deformation as it enters the intramedullary canal (Pennig 1997, Krettek 1998, Slomczykowski 1998). Krettek found mean mediolateral and anteroposterior translations of 18.1 and 3.1 mm respectively after insertion of intramedullary nails into cadaveric femora. They also found nail deformations of up to 10° about the longitudinal axis (Krettek 1998). A more recent mechanical guide requires surgeons to drill a 6-10 mm working channel into the cortex of the bone near the screw hole so that screw holes may be palpated and located directly using a guide-hook (Figure 1.5) (Krettek 1999). This method is unpopular due to the additional time required and the risks associated with drilling a working channel, which can cause stress concentrations that weaken the bone (Whatling 2005). Figure 1.5: Mechanical Guide for Distal Locking. The use of this mechanical guide requires the surgeon to dri l l a 6-10 mm working channel in order to palpate the distal holes using a guide hook. This method has not come into widespread use due to the potential for complications associated with the creation o f a working channel, (source: Krettek 1998) Self-locking nails have obvious advantages in decreasing both surgery time and radiation exposure. However, the two different types of self-locking nails proposed to date - self-engaging guide hook bolts and inflatable nails - have been criticized for their lack of torsional stability and their potential to induce fracture in compromised bone (Ozturk 2005). These implants are still in the prototype stage but researchers and surgeons have not expressed confidence that this solution will be widely accepted (Whatling 2005). During Fix ion" Nail Insertion . 1 Bone Afte *r Pixjori* N a i l Expans ion *— ^ » •»-— *~imcraan Handle Pump 1 i \ l >h' Nail Figure 1.6: Inflatable Nail. Insertion o f the Fixion Inflatable Na i l obviates the need for distal locking and therefore reduces surgical time and radiation exposure. This nail has not come into widespread use due to complications associated with inflation and potential lack o f torsional stability, (source: www.disc-o-tech.com) More recently, virtual fluoroscopy has been developed in which two or more fluoroscopic images are acquired while the position of the patient and C-arm are tracked, typically with an optical position measurement system. The optical tracker also measures the position of surgical tools such as a drill which allows current position of the drill to be displayed on the previously-acquired x-ray images without requiring additional exposures. This enables distal nail locking to be accomplished with as few as two single-shot x-ray exposures. On the positive side, this method has succeeded in reducing both x-ray exposure time (7.3 vs 108 seconds) and the time necessary for distal locking (13.7 vs 19.9 minutes) (Suhm 2004). However, using the system generally increases overall surgical duration due to the time required for equipment setup (approximately 40 minutes) and tool registration processes (Suhm 2004). Although there are over 500 hospitals worldwide currently using virtual fluoroscopy for intramedullary nailing or other orthopaedic procedures, the relatively high equipment costs ($100,000-250,000) and the additional overall surgical time have limited their widespread use (Hazan 2003). 9 Figure 1.7: Virtual Fluoroscopy Setup. In order to reduce radiation exposure during D L I M N , the fluoroscope (A) and surgical tools (B) are tracked using an optical tracking system (not shown). This allows the D L I M N procedure to be accomplished with as few as two fluoroscopic shots that are approximately perpendicular, (source: Suhm 2004) More recently, a novel approach has been proposed which involves the use of a magnet and magnetic field sensor. This radiation-free technique relies on the fact that the implants used for tibial and femoral fracture contain a small open space within the centre of the nail. A permanent magnet on a probe is inserted into this space and is sensed by a magnetic sensor integrated into a drill-mounted guiding system. This system allows the drill to be aligned with the axis of the locking holes by sensing local changes in the magnetic field (Hollstien 2006). A prototype system has recently been licensed to DePuy (Depuy Orthopaedics Inc., Warsaw IN) but has not been marketed commercially. We believe that this concept is promising, but largely limited to this single procedure. It would therefore be difficult to promote this approach to hospitals and surgeons alike. Figure 1.8: Magnetic Probe System. A permanent magnet is inserted into the central canal of an IMN. Local changes in magnetic field in the area of the locking holes are sensed by an external magnetic sensor fitted with an LED display and a drill sleeve, (source: Szakelyhidi 2002) In contrast, navigation equipment for a wide variety of computer-assisted orthopaedic procedures is becoming relatively common and its market share will likely continue to increase. We therefore propose to develop a radiation-free targeting process based on a more general-purpose measurement tool that can be used in a variety of surgical procedures. In order to determine the location and orientation of the holes for the distal locking of an intramedullary nail, we require a sensor which can be placed within the nail itself and be detected with sufficient accuracy by an instrument outside the bone. The use of the Aurora Electromagnetic Tracking System (Northern Digital Inc, Waterloo, ON) has been explored for a variety of surgical procedures including biopsy, radiotherapy, spinal injections, shunt placement and angiography (Krucker 2006, Kirchstein 2005, Wood 2005, Glossop 2002, Levy 2007). Numerous studies examining the distortions caused by common operating room (OR) equipment have been completed with varying results (Schicho 2005, Glossop 2002, Elfring 2007, Wood 2005). The release of a second generation Aurora system designed to minimize the error associated with distortion from metallic objects and the recent development of six degree of freedom sensors with diameters of less than 2.5 mm make this system a likely candidate for intramedullary nail distal locking. A system that can be used for a wide variety of computer-assisted surgical procedures has distinct economic advantages over a system developed solely for the distal locking procedure. 1.4 Purpose of This Study The long term goal of this research is to develop and evaluate a computer-assisted technique to achieve distal locking of intramedullary nails using an electromagnetic tracking system. The first step in this research is to design the method and apparatus necessary to complete our technique. A series of evaluation steps must then be completed before the proposed technique can be used to complete distal locking in a clinical setting (Figure 1.9). Design of the Method and Apparatus Accurate in Lab-based Testing Accurate Compared to Conventional Technique Accurate in Surgical Task Simulation Randomized Control Trial Figure 1.9: Testing of a Novel Surgical Method: After design and lab-based testing is complete, it is necessary to test the method and apparatus against the current surgical approach and to complete a surgical task simulation to ensure that the method is accurate enough to be tested in a clinical setting using a randomized controlled trial. Lab-based testing of the apparatus includes evaluation of the accuracy and repeatability of the tracking method, the ease of use of the apparatus and all safety concerns surrounding the necessary apparatus. Once this has been completed, the proposed technique must be introduced into a surgical setting to evaluate its performance with all the complications that may present in such a setting. Our targeting approach will not be used to complete distal locking at this stage, but data will be collected and compared to the data from the traditional fluoroscopic technique. This will allow the accuracy of our proposed technique to be compared to that of the traditional fluoroscopic method. Once this has been established, surgeons will use the proposed method and apparatus to complete distal locking ex vivo. This surgical task simulation will familiarize the 12 surgeons with all aspects of the method and give a further measure of the accuracy of the technique in a risk-free setting. The final evaluation of the proposed method will be to compare our method to the standard fluoroscopic method using a randomized control trial. In this project, we have completed the design of the method and apparatus. We have also completed the lab-based testing and have designed the study that will be used in the following step to compare the accuracy of the two distal locking methods. The main research questions for the lab-based evaluation of the apparatus were: 1. Is the Aurora prototype six degree of freedom (6DOF) sensor accurate and repeatable enough to be used in distal locking of intramedullary nails? Does the presence of a titanium intramedullary nail adversely affect the readings of the 6DOF sensor? 2. Can the Distal Locking Tool accurately and reproducibly locate the distal locking holes of the intramedullary nail? 3. Can the distal locking tool be removed from the intramedullary nail easily and without damaging the tool or producing any unwanted debris? Chapters 5 summarizes the next step in the testing of our device and protocol: the planning of a clinical trial to test the performance of our approach to intramedullary nailing compared to the current technique. The planned apparatus, method, and data analysis for our initial clinical trial are presented in this chapter. 13 2 Materials and Methods In order to complete distal locking of intramedullary nails without the use of fluoroscopy, a navigation technique must be developed that does not require line of sight, can predict the position and orientation of the locking hole axis with high accuracy and repeatability, and can function well in the OR environment. Most surgical navigation is optically-based (Elfring 2007, Ewers 2005) and is not suitable for techniques where line of sight is not available. Magnetic-based systems have been developed for use in the OR, but traditionally these systems have had sensors that are too large for our purposes or that could only measure five degrees of freedom (DOF). Recently, Northern Digital (Northern Digital Inc, Waterloo, ON) has developed a prototype 6 DOF miniature electromagnetic sensor for their Aurora Electromagnetic Tracking System. The development of this sensor allows us to incorporate it into the IMN to track the location of the implant in real-time following implantation into the femur. In order to locate the distal locking holes from within the IMN using the 6DOF mini sensors, we designed a device known as a Distal Locking Tool (DLT) to engage with the locking holes and hold the sensor in a fixed position relative to these holes. After calibration, we can then track the position of the locking holes. In this chapter, I describe the testing of the 6 DOF mini-sensors and the design and subsequent testing of the Distal Locking Tool (DLT). 2.1 Aurora Electromagnetic Tracking System The Aurora Electromagnetic Tracking System (EMTS) was used in this study. This commercially available system consists of a field generator, system control unit, a sensor interface unit and sensors. (Figure 2.1) This system calculates the position of a sensor that measures a magnetic alternating field. Fields arising due to eddy currents created in electrically 14 conductive materials (interference currents) are calculated based on the alternating field and accounted for in the reported readings. (Seiler 2004). Figure 2.1: Aurora Electromagnetic Tracking System. The system is made up of a control unit, a field generator, a sensor interface unit and a 6 DOF sensor with a diameter of 2.5 mm. The sensor is attached to lead wires and a connector plug which mates with the system interface unit.(source: Northern Digital, www.ndigital.com) The Aurora system calculates the position and orientation of a tool and returns a transformation containing three rotations (in Euler xyz format) and three translations as well as an indicator value. The indicator value is a dimensionless number which measures the quality of the reading; it ranges from 0 (excellent) to 9.9 (poor). The measurements from the two magnetic coils within the sensor are compared to the known positions of the coils relative to each other and deviations from the expected values are assigned increased indicator values. Large indicator values can indicate magnetic field disturbances or faulty tool definition files. Generally a value of less than 1 is considered acceptable (Aurora User Manual 2005). Figure 2.2: Aurora Measurement Volume. The measurement volume of the Aurora system is a cube with side lengths of 500 mm. The origin of the system lies on the front face of the field generator with the measurement volume projecting outwards, (source: Aurora User Manual 2005) 15 The measurement volume of the Aurora system is a cube 500 mm on edge (Figure 2.2). The measurement rate of the system when five or fewer sensor coils are being tracked is 45 Hertz (Hz). If six or more sensor coils are simultaneously tracked, the measurement rate is 20 Hz. Electromagnetic tracking systems allow for navigation without line-of-sight (Kirsch 2005). The first generation Aurora EMTS has been used for several medical applications including biopsy, angiography and radiotherapy (Krucker 2006, Wood 2005, Kirchstein 2005). In 2007, the first commercial system combining the Aurora EMTS with pre or intra-operative CT and ultrasound images was released (PercuNav System, Traxtal Inc., Toronto, Ontario). The development of prototype 6 DOF miniature sensors make the Aurora a plausible candidate for our envisioned computer-assisted distal locking technique. 2.2 Synthes Universal Femoral Intramedullary Nail The implant used in this study is a Synthes Universal Femoral IMN (Figure 2.3). This implant is primarily made of titanium (87%) with small amounts of niobium (7%) and aluminum (6%) (Synthes ® Universal Nail System Technique Guide). Figure 2.3. Synthes Universal Femoral Nail. All of the testing was performed using Synthes Universal Femoral Nails. The Synthes IMN is a cylinder with an inner diameter of 4.5mm. The outer diameter ranges from 10-15 mm. The implant has a slight bow with a radius of curvature of 1.5 m in order to match the natural anatomy of the human femur. Over 50% of femoral shaft fracture fixations completed at Vancouver General Hospital use Synthes nails or other IMNs with the very similar designs (IM 16 Nails by Year and Diagnosis- 2003-2005, correspondence with Raman Johal, Orthopaedic Trauma Research Coordinator, VCHRI). The similarities in inner diameter, shape and location of the locking holes of all of the commonly used nails (M/DN Femoral Nails, Zimmer and Gamma Femoral Nails, Stryker) will allow us to generalize the technique and testing described for this particular nail to many other manufacturers' products. 2.3 Effect of the Intramedullary Nail In order to determine the exact effects on sensor accuracy of enclosing the Aurora sensor in a titanium rod, a standard characterization method used at Northern Digital (Kirsch 2005-1) was completed using a bare sensor and then while the sensor was enclosed in an IMN. A l l testing was completed at Northern Digital Inc. (Waterloo, ON). The sensor was affixed to a calibration plug and data was collected from the sensor while it was in each of the alignment holes in a calibration phantom. The calibration phantom is a hemisphere of radius 85 mm with 50 alignment holes designed to cover the sensors workspace. The calibration phantom was placed approximately 250 mm from the field generator. Sensor in Calibration Plug Figure 2.4: Calibration Phantom. The calibration phantom was placed approximately 250 mm in front of the Field Generator. Data was collected while the calibration plug was in each of the alignment holes. The distance between the calibration plug and the reference plug was calculated and compared to the known locations of alignment holes, (source: Kirsch 2005) In order to determine the accuracy and precision of the sensor, the calibration plug was placed within each of the 50 alignment holes. Throughout the calibration procedure, readings were also 17 collected from a reference plug which remained stationary in a single alignment hole. In order to determine the accuracy of the sensor, the transformation from the calibration plug to the reference plug was calculated and compared to the known locations of the alignment holes. The absolute locations of the alignment holes were defined using a coordinate measurement machine (CMM) which is accurate to less than 10 microns. The accuracy error is reported for both position and orientation. Position accuracy error was defined as the difference between the radial position vector measured by the sensor and the radial position vector that was pre-registered from the C M M . The consolidated rms position accuracy error value was then determined. * " . R M S = J2. 0 i - € i ) / N s N - 1 Orientation accuracy error was defined as the angle between the orientation vectors measured by the sensor and pre-registered using the C M M . Si = arccos(nr. •«,„.) The consolidated rms orientation accuracy error was then determined. <5RMS = A', During the characterization procedure, 30 frames of data were collected in each of the alignment holes. The precision of the sensor was calculated by determining the jitter of the 30 frames of data collected for each hole. The mean position and orientation of each alignment hole was determined and the deviations from the mean locations were calculated. The mean position 18 precision and orientation precision was then determined from the 1500 values calculated (50 holes x 30 frames in each hole). This characterization procedure was then repeated with the sensor enclosed in the intramedullary nail. The sensor was rigidly fixed in the intramedullary nail using set screws (Figure 2.5). A custom calibration plug was made with a cylinder to house the intramedullary nail. The nail was press fit into the cylinder and then held in place by inserting a small plastic rod through the locking hole (Figure 2.5). Figure 2.5: Calibration Plug. The sensor was fixed within the IMN using set screws (C). The IMN was rigidly fixed in the calibration plug by press fitting it into a cylinder attached to the calibration plug (B) and inserting a rod through the distal locking hole (A). The previously described characterization was then completed to determine the accuracy and precision of the sensor when inside an intramedullary nail. In order to determine the offset of the sensor from the calibration plug, data was collected in 43 of the 50 alignment holes and a best-fit was performed using the known locations of the alignment holes (as determined using the C M M ) . The offset was then applied to the readings prior to determining the vector between the calibration plug and the reference plug. Data could not be collected from the remaining seven alignment holes because the proximal end of the intramedullary nail interfered with the field generator. 19 The probability distribution of position accuracy error and orientation accuracy error were plotted in order to confirm a normal distribution. A t-test was then performed to determine whether there was any significant difference between the errors reported with and without the IMN present. Because the alignment holes closest to the field generator could not be targeted due to IMN making contact with the filed generator and because the sensor was offset from the calibration plug by several centimeters while inside the IMN, the mean distance between the field generator and the sensor was different with and without the IMN. To determine whether the increased distance between the field generator and the sensor was responsible for any decrease in accuracy or precision, the accuracy error and precision error were plotted as a function of distance between the sensor and the field generator. 2.4 Distal Locking Tool 2.4.1 Design In order to orient the E M sensor within the IMN, the DLT was developed. The DLT is designed to slip into the IMN after it has been inserted into the IM canal. 20 Femoral Intramedullary Nail Figure 2.6: Distal Locking Tool. The custom designed Distal Locking Tool is placed inside of the IMN once the nail has been inserted into the femur, (source: modified from Trigen® IM Nail System Surgical Technique) The DLT must be placed in the IMN after it has been inserted into the bone because during IMN insertion the implant follows a pre-inserted guide wire to ensure that it remains centered in the IM canal. The guide wire's diameter is approximately equal to the inner diameter of the insertion handle (which is attached to the proximal end of the IMN and removed after the distal locking process is complete) and it is therefore impossible to insert a tool into the IMN while the guide wire is inserted. In order to be inserted after the removal of the guide wire, the DLT must be small enough to fit through the IMN insertion handle. This device has an inner diameter of 3.5 mm. Once through the insertion handle, the DLT must expand to the inner diameter of the IMN (4.5 mm) so that as soon as it encounters the transverse locking holes of the IMN, it expands even further into the locking holes (Figure 2.7). This allows the DLT to be reliably locked into place relative to the locking holes. In order to achieve this lock, many iterations of the distal locking tool were explored (See Appendix 1: Evolution of Distal Locking Tool Design). In our current design, the distal end of the DLT has an elevated plug that matches the diameter of the locking holes (Figure 2.7). sensor location locking plugs h = 10 mm 0 3.4 mm d = 50 mm + V locking arms = 25 mm Figure 2.7: Design of the Distal Locking Tool. The locking arms are designed to expand when the distal locking tool is inserted and lock into the distal locking holes. The diameter of the distal locking tool is 3.4 mm. The sensor is offset from the locking plugs by 50 mm. The distal ends of the plugs are cylindrically shaped to prevent the tool from slipping past the locking holes. The proximal ends of the plugs are spherical in order to allow the tool to be removed by simultaneously applying tension and torsion to the proximal end of the DLT (Figure Figure 2.8: Distal Locking Tool Plug. The distal ends (left) of the DLT are designed with plugs to engage the locking holes of the IMN. The distal surface of the plugs are cylindrically shaped so that they do not slide past the locking holes. The proximal (right) surface of the plugs are spherically shaped in order to facilitate removal of the 2.8). DLT. 22 Sensor Location Figure 2.9: C-shaped canal. The DLT is fitted with a C-shaped canal to allow the 6DOF sensor to be sealed within the DLT. The DLT is fitted with a c-shaped canal into which the 6 DOF mini sensor is placed (Figure 2.9). The sensor is laid into this C-shaped canal of the DLT and secured using medical grade adhesive silicone (Silastic Type-A, Dow Corning Inc., Midland, MI). In order to achieve the desired geometry and dimensions, the DLT was created by fused deposition modeling on a Stratasys Rapid Prototyping Machine (Stratasys Inc., Eden Prairie, MN) using ABS-P400 (Appendix 2: ABS Material Specifications). This bio-inert (Raya 1993) material is non-magnetic and therefore does not affect the functioning of the sensor. 2.4.2 Insertion Repeatability The repeatability of locking the sensor into the same place within the IMN each time the DLT is inserted was determined by doing multiple insertions while the IMN was rigidly fixed to the benchtop. The DLT was inserted into the distal locking holes and 50 frames of data were collected from the sensor. The DLT was then completely removed from the IMN and reinserted for a total of 50 trials. The data reported from the system includes the position and Euler rotation angles of the sensor relative to the global reference frame. In order to relate these transforms to a more meaningful 23 frame, a nail frame was created. The nail frame was created by digitizing the locations of the distal holes while the IMN was affixed to the tabletop. An Aurora Probe (Traxtal Inc., Toronto, Ontario) (Figure 2.10) was inserted into the locking hole as shown in Figure 2.11. Figure 2.10: Digitizing Probe. The probe reports the tip location in 6 DOF. The tip of the probe is chamfered. Figure 2.11: Digitizing the Locking Holes. The locking holes were digitized by placing the chamfered tip of the probe into the holes until the probe made contact with the rim of the locking hole. The tip of the probe is chamfered and it was inserted until the neck of the probe made contact with the locking holes. The locations of the outer surface of both distal locking holes on both sides of the nail were digitized (Figure 2.12). 24 Figure 2.12: Nail Frame Construction 1. Four points on the IMN were digitized in order to create the nail frame, the medial and lateral surfaces of the most distal locking hole (pi and p2) and the medial and lateral surfaces of the more proximal distal locking hole (p3 and p4). The centre of each locking hole was determined by finding the midpoint between the points collected (Figure 2.13): M i = (p2-pl)/2 M 2 = (p3-p4)/2 Figure 2.13: Nail Frame Construction 2. The centers of the locking holes were defined as the midpoints between the two sides of the locking holes. The origin of the nail frame was defined to be M 2 . The nail frame x-axis was defined on the line between the two midpoints: 25 X = M2-M1 X This vector was then normalized: * = T H r l The z-axis was defined by creating a vector from the midpoint of the more proximal locking hole to p4: z = p4-M2, z = 7^ 7 r l The y-axis was then defined as the cross product of these two unit vectors: A A A In order to ensure that all three axes are orthogonal, the final z-axis was found by taking the cross product of the x and y axes: A A A z = xxy The rotation matrix from the transform from the global frame (O) to the nail frame (N) was then created with the unit vectors of the three axes.: RN0 = The homogeneous Transform was then created: where RNO is the rotation matrix above and d>io is the displacement from ^NO ^NO 0 1 origin of nail frame to origin of the global frame expressed in nail frame coordinates. As previously mentioned, the origin was defined as M2. This origin is reported by the system in global coordinates and must therefore be translated: d N o = - RNO*doi The data reported by the Aurora system during the insertion trials included the positions (Tx, Ty, Tz) and orientations (Rx, Ry, Rz) of the sensor. 50 frames of data were collected for each of the 26 50 insertion trials. This data was imported into Matlab and the 6 variables were translated into a homogenous transform from the global frame (O) to the sensor frame (S). This was defined as Tosi. From this variable, the mean transform from the global frame to the sensor frame was defined (T0$). Both of these variables were transformed into the nail frame by applying the transform from the global frame into the nail frame: TNS = TNO ' Tos TNSJ = TNO ' Tosi In order to determine the deviation of each measurement from the mean location, the transform from the mean location (TNS) to each measurement (TNSD was calculated: TNNJ = TNS ' (TNSO ' The positions (Tx, Ty, Tz) and orientations (Rx, Ry, Rz) of the deviations from the mean were then extracted from the homogeneous transform (TNNJ) and the standard deviations of these deviations were determined. 2.5 Mechanical Testing After the accuracy and repeatability of the Aurora sensor and distal locking tool were verified, several basic mechanical tests were conducted. The purpose of these tests was not to define the actual values of various mechanical properties of our tool, but to gain insight into whether or not any particular responses of the tool should be of concern to us. Our testing was designed to determine whether the distal locking tool could be easily removed from the intramedullary nail, to determine whether the stresses produced during that removal were near the yield stress of the material, and to determine whether distal locking tool insertion and removal would cause particulate formation that may be harmful to patients. 27 2.5.1 Experimental Moment to Remove DLT In order to remove the distal locking tool from the intramedullary nail the proximal end of the distal locking tool must be twisted and pulled away from the proximal end of the nail. We were interested in how difficult this removal process is. In order to quantify ease of removal, a simplified release mechanism which incorporates only twist was modeled. The IMN was fixed to a calibration box to keep it from moving or rotating and the DLT was inserted. The DLT was supported at the proximal end by a support structure and a cylinder was attached to the DLT between the proximal end of the IMN and the support structure. A rope was rigidly fixed to the cylinder and then wrapped around the cylinder multiple times. This rope then descended straight down through a hole in the calibration box (Figure 2.14). A starting mass of 60 g-which was shown in preliminary tests not to release the DLT- was applied and then mass was added in 5 g increments until the DLT released from the locking holes (as evidenced by an audible noise and a large drop of the weight). Figure 2.14: Torque Necessary to Remove DLT. The IMN was fixed in the calibration box and the DLT was inserted. The proximal end of the DLT was threaded through a cylindrical attachment and supported at the proximal end. A rope was wrapped around the cylinder and threaded through the base of the calibration box. Weights with increasing mass were attached to the rope until the DLT was released from the locking holes. The total mass required to release the DLT was recorded. This process was completed three times per distal locking tool and tested on 5 separate tools. 28 The diameter of the cylinder was measured and the moment applied to the distal locking tool was calculated: M = rxF where r is the radius of the cylinder and F is the force produced by the mass shown in 2.14. 2.5.2 Maximum Moment In order to determine how easily the distal locking tool can be removed, we compared the moment required to release the tool to the maximum moment that two researchers could produce. It was determined in preliminary testing that a rotation of the proximal end of the distal locking tool of approximately 360° was necessary in order to cause release from the distal locking holes. Moments were produced by placing the distal locking tool in the set-up shown in Figure 2.14 and then twisting the cylinder 360° using only the thumb and forefinger. Mass was added to the string in 100 g increments until it was no longer possible to move the cylinder 360°. The largest mass that was moved through the required angle was used to determine the maximum moment that can be produced in this set-up. The percentage of the maximum moment that is required to release the distal locking tool was then calculated. 2.5.3 Stress Analysis The actual mechanism of release of the distal locking tool from the distal locking holes likely involves a complex combination of bending and twisting of the locking arms. In order to obtain a simple measure of the stress produced in the distal locking tool during removal, the theoretical force necessary to compress the locking arms was determined and the stress produced in the locking plugs was calculated (See Appendix 3: Theoretical Force to Remove the DLT). This was accomplished by modeling the locking arms as simple beams with constant cross sections. In 29 order to gain some insight into the stress that would be produced in a model with more realistic geometry and determine whether this stress is anywhere near the yield stress of the material, the C A D file used for manufacture of the distal locking tool was imported into finite element analysis software (COMSOL 3.3). The boundary conditions were set such that the distal locking plugs were fixed while the rest of the DLT was free to move. The tool was meshed with 289,540 tetrahedral elements and contained 279,954 degrees of freedom (Figure 2.15). Figure 2.15: F E M mesh for the distal locking tool. The DLT was meshed with 289,540 tetrahedral elements and 279,954 degrees of freedom. The mean moment necessary to release the distal locking tool (as determined in the tests described in section 2.5.1) was applied to the proximal end of the DLT and the resulting von Mises stress was predicted. The maximum von Mises stress was compared to the yield stress of the material to determine whether failure by yielding is likely in this loading scenario. 2.5.4 Particulate Formation It was observed early in testing that the insertion and removal of the DLT, particularly the first few times it is inserted, leaves behind small particles of ABS on the implant. To determine 30 whether or not the quantity and size of these particles were such that there might be a concern about future osteolysis i f some particles remained in the patient, a series of tests were performed. The IMN was thoroughly cleaned, dried, and inserted into the calibration box. A DLT that had never previously been inserted into an IMN was inserted and removed a total of three times. After the third removal, the distal locking hole and distal portion of the IMN inner canal were washed with 1 ml of distilled water using a small pipette. This wash was collected into a small vial held below the locking hole or distal end of the IMN. Any remaining water was forced into the vial using high pressured air. In order to quantify the size and number of particles left on the IMN, the solution was examined microscopically. The vial was vigorously shaken to ensure that there was a good mechanical mixture of the solution and then 0.25 ml was removed using a pipette. This solution was placed on a slide and covered with a coverslip. The slide was observed using the 40x objective lens and lOx ocular lens for a total magnification of 400 times. The slide was positioned such that the leftmost margin of the sample was visible. Both the number and the relative size of particles were recorded as the slide was incrementally advanced to the far sample margin. Particles were classified according to their longest edge length. Very small particles were less than 10 um, small particles were 10-20 um, medium particles were 20-50 um and large particles had edge lengths of over 50 um. This process was repeated for a second row using the same slide. Using the microscope-mounted digital camera and the appropriate software (Fujifilm EXTouch and Fujifilm Photograb-300Z), representative photos were taken of each of the sizes of particles. In order to quantify their size, a micrometer slide was also photographed under the same conditions. The size of representative samples was determined by comparison with the micrometer slides. This method was repeated for a second DLT. 31 In order to test the effect of original surface roughness on particle formation, a second pair of DLTs were filed and sanded using a fine file and sandpaper prior to insertion. They were then washed thoroughly with water, allowed to dry, and the method described above was used to collect particles resulting from three insertions. 32 3 Results 3.1 Effect of the Intramedullary Nail The results of the calibration testing with and without the IMN are shown in Figure 3.1. 0.8 0.7 • • No Nai l • 1 W i t h Nai l 0.6 o- Position Orientation Accuracy Position Orientation Precision Figure 3.1: Accuracy of the Aurora sensor with and without the IMN. The accuracy of the Aurora sensor in standard conditions was 0.41± 0.12 mm and 0.38± 0.28°. With the IMN, the accuracy was 0.52 ± 0.16 mm and 0.43 ± 0.20°. Precision error of the readings increased in the presence of the IMN. The mean position accuracy error with and without the IMN were 0.41± 0.12 mm and 0.52 ± 0.16 mm respectively. This difference was significant (p = 0.006). The orientation accuracy error reported for the two cases were 0.38 ± 0.28° and 0.43 ± 0.20°. The effect of the IMN on screw angle orientation trueness was not significant (p = 0.41). The cumulative error distributions for distance and orientation trueness are shown in Figure 3.2. The probability distributions for the errors are shown in Figure 3.3. 33 / f J f J S -/ / /  J / 1 / c • 45 ion 40 35 30 GO b 25 20 > TO 15 10 E 5 o 0 / ^ f I / / ' / / • • / / 3D Er ro r ( m m ) Screw Angle Error (degrees) Figure 3.2: Cumulative Distribution of Accuracy Errors. Results for positional readings (left) taken without the IMN (-) and with the IMN (--) show that a distortion of approximately 0.1 mm in induced by the presence of the nail. This difference is statistically significant (p = 0.006) but not clinically relevant. Orientation errors (right) were not significantly different (p = 0.41). 3D Error (mm) Screw Angle Error (degrees) Figure 3.3: Probability Distribution for Accuracy Errors. Positional errors (left) without the IMN (-) and with the IMN (--) show 95% confidence intervals or 0.06 and 0.05 respectively. Orientation errors (right) have 95% confidence intervals of 0.12° and 0.16° without and with the IMN. The 95% confidence intervals for position and orientation for the tests with and without the IMN are shown in Table 3.1. With the IMN in place, the 95% confidence levels are 0.57 mm and 0.55°. Table 3.1: Summary of Results for Accuracy Testing. Mean Std 95% C.I. Posit ional 3D Error (mm) Without Nail 0.41 0.12 0.06 With Nail 0.52 0.16 0.05 Screw Axis Angle Error (°) Without Nail 0.39 0.28 0.16 With Nail 0.43 0.20 0.12 The precision reported when no IMN is present (0.072 mm and 0.046°) was significantly different from the reading taken with the IMN (0.192 mm and 0.145°). 34 The position accuracy and precision are shown as a function of distance to the field generator Figures 3.4 and 3.5 respectively. 4 3.5 3-h w 2.5 4 -o n 1.5 i 2 o u < c 5 1 (/> o Q_ 0.5 With IMN No IMN —- -0 100 200 300 400 Radial Distance From Sensor to Field Generator Figure 3.4: Position Accuracy Error does not change as a function of distance from the sensor to the field generator. 0.16 0.14 1 0.12 0.1 c o w § 0.08 I 0 0 6 § 0.04 Q. 0.02 0 With IMN Without IMN 4" ^ Ai 0 100 200 300 400 Radial Distance From Sensor to Field Generator Figure 3.5: Position precision error increases with increasing sensor distance from the field generator. 3.2 Insertion Repeatability Repeatability of distal locking tool insertions was well within the acceptable limits. The largest differences from the mean value were seen in the z-direction, with a standard deviation over 50 trials of 0.20 mm. The standard deviations in x and y directions were 0.03 and 0.12 mm respectively (Figure 3.5). The largest rotational deviations from the mean were in the x direction (1.59°). The rotational deviations in y and z had standard deviations of 0.13° and 0.08° respectively (Figure 3.6). 0.4 0.2 E~ £ 0 c o | - 0 . 2 CD Q -0.4 -0.6 Tx Ty Tz Figure 3.6: Mean Deviations for Translations. Boxplots showing the mean, +/- standard deviation, min and max for each of the cardinal directions. Translational errors were very low with standard deviations of 0.03, 0.12 and 0.20 mm in the x (longitudinal axis of the nail), y (anteroposterior axis), and z (mediolateral axis) directions. ~ 2 O) CD TD | 0 '> CD Q -2 -4 Rx Ry Rz Figure 3.7: Mean Deviations for Rotations. Boxplots showing the mean, +/- standard deviation, min and max for rotations about each of the cardinal directions. Rotational errors had standard deviations of 1.59°, 0.13° and 0.08° about the x (longitudinal axis of the nail), y (anteroposterior axis), and z (mediolateral axis) axes respectively. 36 3.3 Mechanical Testing 3.3.1 DLT Removal Moment The average moment necessary to remove the DLT from the intramedullary nail was 0.011 ± 0.001 Nm (Table 3.2). The first tool tested had several tests applied to it prior to the final protocol being determined. The mean removal moment for this tool was 0.008 Nm. We observed over the course of all testing that the moment required to remove the DLT decreased with increasing numbers of insertions and removals. This DLT was not included in the analysis. Table 3.2: Moment Required to Remove the Moment Tool Trial (Nm) 1 1 0.010 2 0.009 3 0.009 2 1 0.011 2 0.011 3 0.011 3 1 0.011 2 0.011 3 0.010 4 1 0.011 2 0.011 3 0.011 Mean 0.011 The maximum moment that could be produced using the set-up for the removal tests ranged from 0.129 to 0.172 Nm. The moment necessary to remove the distal locking tool is approximately 7.5% of maximum moment that can be applied by the thumb and forefinger. 37 3.3.2 Stress Analysis The maximum Von Mises stress predicted when a moment of 0.011 Nm was applied to the proximal end of the tool was 8.5 x 104 Pa. This was seen at the junction of the locking plugs and the locking arms. Figure 3.8: Finite Element Model of the Distal Locking Tool. The maximum von Mises stress reported from the model was 8.5 TO 4 Pa and was located at the junction of the locking arms and the locking plugs. The yield stress of the ABS plastic used in the construction of the DLT is 41MPa. The stress predicted for the removal of the distal locking tool is approximately 1/500 of the yield stress. 38 3.3.3 Particulate Formation Particles were classified according to their longest edge length. Very small particles were less than 10 um, small particles were 10-20 um, medium particles were 20-50 um and large particles had edge lengths of over 50 p.m (Figure 3.9, 3.10). The smallest particle recorded had an edge length of 1.2 um while the average particle size was 8.2 um. The distal locking tools that were not filed showed a mean of 18 very small, 12.5 small, 5 medium, and 0.25 large particles for a total of 36 ± 19 particles per count. For the devices that were filed prior to insertion, a mean of 3.75 very small, 2.25 small, 2 medium, and 0.25 large particles were observed. The mean total number of particles for a single count was 8.25 ± 2.87. The number of particles produced was reduced by 77% when the device was filed before use. H< 10 (jm • 10-20 0 20-50 pm S >50 pm 1a 1b 2a 2b 3a 3b 4a 4b Trial Figure 3.9: Number of Particles Produced. The number of particles produced was reduced by 77% for devices that were filed (trials 3-4) compared to devices that were not filed (trials 1-2). 39 Figure 3.10: Particulate Samples. Very small (A), small (B), medium (C), and large (D) particles had maximum edge lengths of <10 urn, 10-20 \im, 20-50 um and >50 um respectively. The number of particles for each count was extrapolated to the entire solution collected from each insertion trial. The mean total number of particles seen for three insertions and removals of 40 an unfiled.distal locking tool was 8,580 ± 4,330. For the filed tool the mean total number of particles was 1,980 ±760. 41 4 Discussion In a previous study, the maximum error tolerance for locking screw alignment in intramedullary nailing was defined as 0.75 mm and 8° (Figure 4.1) (Szakelyhidi 2002). IMN 0.75 mm maximum lateral tolerance Screw Figure 4.1: Maximum Error Tolerance for Distal Hole Targeting. The maximum error tolerance for targeting distal locking holes has been previously reported as 0.75 mm and 8°. (source Szakelyhidi 2002) It is the experience of our clinical collaborators that the actual lateral tolerance is significantly larger than this. As long as the drill tip is within the 5 mm diameter locking hole (less then 2.5 mm from the hole centre), the drill bit will be guided into the hole with minimal damage to the nail. During the distal locking of the first hole, the intramedullary nail is still free to move relative to the bone, small shifts of the intramedullary nail are therefore possible. The upper bound of the 95% confidence limit for lateral errors found in our testing (0.57 mm) falls below this stringent cut-off described in this previous study (0.75 mm) and well below the clinically consequential level of 2.5 mm. The equivalent error for orientation was found to be 0.55°, well below the 8° tolerance. 42 4.1 Effects of the Intramedullary Nail Enclosing the prototype 6 DOF sensor in a titanium intramedullary nail changes the accuracy by a detectable amount but likely not by a clinically consequential amount. The difference between radial position (3D rms) and screw angle errors for readings with and without the IMN were only 0.1 mm and 0.05°. In a 2005 study of the susceptibility of the Aurora system to the presence of various metallic objects in the sensing volume, a titanium rod was among the materials tested. For these tests, the rod was placed in different locations relative to the sensor and field generator. The results obtained were very similar to those reported in our testing: the differences in mean error with and without the titanium rod were approximately 0.2 mm and 0.025° (Kirsch 2005-2). This study is consistent with our conclusion that the IMN will not degrade the readings of the Aurora sensor by any clinically significant amount. Although the tracking of the Aurora system is not affected by the intramedullary nail, interactions with other intra-operative equipment such as surgical tables, imaging equipment and surgical tools may also affect the accuracy of the system. A report by the manufacturer of the Aurora system showed that sheets of stainless steel, designed to mimic surgical tables, introduced distortions of up to 5 mm and 5° at distances of 70 mm from the sensor when the first generation Aurora system (Aurora 1) was used (Kirsch 2005-2). However, when the distance between the sensor and the sheet was increased to 270 mm, the distortions decreased to 0.7 mm and 0.5°. Repeating the same test for the Aurora system used in our study (Second generation-Aurora 2) showed distortions of 0.7 mm and 0.8° when the steel sheet was 70 mm from the sensor and 0.3 mm and 0.5° when the sheet to sensor distance was 270 mm (Kirsch 2005-2). The surgical table is therefore unlikely to be a problem using the Aurora 2 system. 43 The use of specialized orthopaedic fracture tables can also reduce the probability of table-related distortion. Orthopaedic fracture tables are designed to be radiolucent and therefore have carbon fiber or composite table tops and radiolucent leg stabilizers (Steris Corporation, vvww.steris.com) (Figure 4.2). These tables further increase the distance between the electromagnetic sensors and the steel table frame, which would decrease the interference felt by the sensor. Figure 4.2: Orthopaedic Fracture Table. Surgical tables designed for orthopaedic fracture fixation are designed to be radiolucent. The composite table top and abductor bars decrease the amount of steel near the sensing area thereby decreasing the interference for electromagnetic tracking, (source: www.steris.com) It is well documented that the Aurora system's performance depends on the distance between the sensor and any sources of distortion, as discussed above and also on the distance between sensors and the field generator (Kirsch 2005-1). The Aurora 2 system has optimal accuracy when sensor-field generator distance is less than 400 mm (Figure 4.3). 44 Ill o CO 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 Trueness Aurora 2 Precision Auroras Trueness Aurora 1 Precision Aurora 1 12? -x-100 200 300 400 500 600 700 Sensor Distance [mm] Figure 4.3: Accuracy (shown here as Trueness) of the Aurora 2 system is optimal at d < 400mm. Precision of the Aurora readings also decreases for distances over 400 mm. (source: Kirsch 2005-1) During surgery we will aim to keep the sensor-field generator distance below 400 mm and the sensor-surgical table distance over 270 mm in order to optimize the accuracy of the sensor. The interference of imaging machines has been explored in several studies. Wood et al found that tracking directly inside a CT gantry caused some distortion but there was no significant distortion (defined as a shift of over 1 mm) if the image intensifier was over 100 mm away from the Aurora sensors (Wood 2005). There was also no significant effect associated with turning the x-ray tube on. This study was performed using an Aurora 1 system and we would therefore expect even better results using the Aurora 2. Schicho et al examined the effect of an ultrasonic scanhead on Aurora 1 readings. In this study, the scanhead was placed at distances of 10-60 mm from the sensor. The maximum distortion was found to be 2.6 mm (Schicho 2005). Schicho et al. also studied the effects of 2 surgical instruments: a dental drill and a steel dental hook. The maximum distortions caused by these instruments at distances of 10-60 mm were 1.2 and 2.1 mm respectively. Results for distances of over 100 mm were not obtained. 45 To simulate surgical tools, Kirsch introduced aluminum and ferromagnetic stainless steel into the sensing volume (Kirsch 2005-2). In this study, distortion increased significantly as the rod was moved closer to the sensor. The aluminum rod showed distortions of up to 2 mm for distances of fewer than 25 mm and distortions of approximately 0.25 mm for distances of 25 to 200 mm. The stainless steel rods caused distortions of up to 10 mm at distances of less than 25 mm and distortions ranging from 1 to 3.5 mm for distances of 25 to 200mm. The rods used in this study were fairly large (200 mm length and 15 mm diameter) and are therefore unlike tools we would expect to encounter in surgery, but the results of the Kirsch study emphasize the need to test our device in a live surgical environment, incorporating all possible sources of distortion, prior to judging the absolute error associated with our distal locking method. 4.2 Distal Locking Tool Accuracy Our custom-built distal locking tool can reproducibly target the distal locking holes from within the IMN. The largest translational standard deviation was 0.20 mm and the largest rotational standard deviation was 1.59°. To estimate the variability associated with identifying the locations of the locking holes we need to combine the variability arising from both the sensor's position in the measurement volume and the variability due to targeting the locking holes using the DLT. Table 4.1: Standard Deviations for Sensor Accuracy and Insertion Repeatability for all 6 DOF Tx Ty Tz Rx Ry Rz (mm) (mm) (mm) O O (°) Sensor Std 0.40 0.37 0.27 0.25 0.25 0.32 Insertion Std 0.03 0.12 0.20 1.59 0.13 0.08 46 It is important to note that the deviations for the sensor accuracy tests are reported in the global reference frame whereas the insertion repeatability deviations are reported in the nail frame. If we consider the worst case scenario for translational error, the nail frame z-axis (std = 0.20 mm) will coincide with the global frame x-axis (std = 0.40 mm). By summing the variances we find that the standard deviation is approximately 0.45 mm in that direction. Similarly, if the nail frame x-axis were aligned with the global z-axis, the standard deviation for the rotation about this axis would be approximately 1.62°. For the clinical trial which will be described in detail in chapter 5, we will be comparing the readings from the distal locking tool to a second Aurora sensor attached to a tool used to determine the drilling axis for distal locking (drilling tool). This second sensor would add an additional error to the overall reading. If we once again assume the worst possible alignment in terms of error, the standard deviation for the combination of these three sources of error in one dimension would be approximately 0.6 mm or 1.65°. If we extend this worst case scenario to three dimensions, rms translational standard deviation would be approximately 0.89 mm and 1.7°. These deviations are still below our clinically consequential tolerances for targeting the distal locking holes. Tracking the DLT relative to the drilling tool is therefore likely to be accurate enough for our purposes. The minimum translational deviation (0.03 mm) that we observed was along the longitudinal (x) axis of the nail (roughly equal to the longitudinal axis of the femur). Due to the design of the DLT, there is very little freedom to move on this axis. The deviations in the y and z axes (0.12 and 0.20 mm) were larger. 47 The DLT was designed to fit through the insertion handle used during surgery (inner diameter 3.5 mm). The inner diameter of the IMN is 4.2 mm, which means that the DLT was not tightly restrained laterally during this test; there was therefore freedom to move along the anteroposterior (y) and mediolateral (z) axes. Although the presence of the insertion handle will largely restrict the possible y and x axis movements of the proximal end of the DLT, there could still be error associated with the bending or twisting of the DLT between the sensor and the locking holes. Currently, the locking arms are 25 mm long, as shown in Figure 4.5. This design was adopted in order to allow for a locking arm that will expand upon intersection with the locking holes but is flexible enough to be compressed easily to facilitate insertion and removal from the implant. There is an additional 25 mm between the end of the locking holes and the beginning of the C-channel where the sensor lies. This transition zone was included in the design in order to ensure adequate torsional strength for transmitting the moment used to remove the DLT. In the current design, the total distance between the locking holes and sensor is 50 mm. Figure 4.4: The total distance between the sensor and locking plugs is 50mm. This distance is made up of the locking arms (shown above) and the transition zone. Decreasing this total distance may decrease the error associated with predicting the locking hole axis from the sensor location. As will be discussed later, the tool design can likely be optimized to reduce the separation between sensor and locking holes; the stresses associated with insertion and removal of the DLT are well below critical failure values. The DLT's design could therefore be altered by decreasing the length of the transition zone and increasing the torsional stiffness of the locking arms. Both 48 of these design changes would serve to limit the errors associated with rotation and deviation of the tool relative to the locking holes. The torsional stiffness could possibly be increased by modifying the geometry of the locking arms or possibly by using a stiffer material. Deflections of the DLT between the sensor and the locking tips could potentially be exacerbated by the presence of debris in the inner canal of the implant. Fluids and bony debris are normally forced up into the IMN during insertion into the femur. We don't anticipate that this will be a major problem because during insertion, a 3.5 mm guide wire is present. When the guide wire is removed, many bony particles are also removed. When the DLT (diameter 3.4 mm) is then inserted, will not fill the inner diameter of the nail (4.5 mm). Fluids and small bone particles will therefore be able to pass around the outside of the tool. If it does become problematic to advance to DLT to the distal locking holes, it might be necessary to clean out the canal prior to DLT insertion by using pressurized water or a probing tool, for example. The difficulties associated with this potential challenge will be evaluated during our preliminary clinical trial, the planning of which will be discussed in Chapter 5. Several other studies using the Aurora system have reported accuracy errors significantly larger than the 0.63 mm error (95% C.L.) found in our study (Levy 2007, Krucker 2006, Wood 2005, Schicho 2005, Glossop 2002, Elfring 2007). Errors reported in these studies range from 1.28 mm to 5.8 mm. However, there are several differences between these previous studies and our own. Firstly, with the exception of Elfring, all the studies mentioned above used the first generation Aurora. The second generation Aurora system was developed in response to the high error associated with distortion from metallic objects and was released in September of 2005. Improved accuracy in a surgical setting could therefore be expected if the other studies were repeated using the Aurora 2. Elfring's results showed mean distortions of 2 mm caused by a 49 surgical environment. However, they did not clarify what type of surgical instruments were introduced into the field nor at what distances the objects were placed relative to the field generator or sensors. Secondly, as previously mentioned, the use of radiolucent surgical tables decreases the interference caused by the surgical table. Wood tested both angiography and CT tables and found mean errors of 1 mm and 2.5 mm respectively (Wood 2005). Intramedullary nailing of the femur is routinely performed on a radiolucent surgical table to allow for fluoroscopic guidance. We can therefore expected results similar to, or better than Wood's study. Thirdly, another key variable between various electromagnetic tracking studies is how errors are reported. FCrucker reports on the accuracy of the Aurora-2 combined with pre-operative CT and intra-operative ultrasound for guidance in soft-tissue biopsy and radio-frequency ablation. The study was designed as a bystander study using CT tracking for intra-operative guidance and comparing it to the electromagnetic/ultrasonic tracking. A l l 20 procedures were carried out successfully and without any clinical complications. The mean tracking accuracy for the Aurora system was found to be 5.8 ± 2.6 mm. The researchers noted a strong correlation between the distance from the CT surgical table and decreased accuracy, (see Figure 4.5) 50 2 I ~M- - j - - j - i Distance from table (mm) Figure 4.5 Tracking accuracy decreases with decreased distance between the sensor and a C T table (source: Krucker 2006) The authors suspect that this distortion may be the largest contributor to error in their clinical evaluation. The use of the second generation Aurora system may therefore lead to significantly better accuracy results. The authors also cite patient motion as another important source of error. In their guidance procedure, a significant difference in tracking accuracy was found between tracking in the lungs and in the liver. Respiratory motion as well as gross patient motion can be compensated for using skin trackers but needs to be further investigated (Krucker 2006). The maximum accuracy errors of 5.8 mm reported in this study are over our suspected clinical tolerance however, the D L I M N procedure does not share the two most significant sources of error in this study since intramedullary nailing would take place on a radiolucent table and patient motion would be irrelevant because the sensor would be located within the patient and not registered to any pre-acquired images. Computer-assisted navigation in D L I M N is therefore very likely to produce acceptable clinical results. 51 4.3 Ease and Safety of Distal Locking Tool Design The moment required to remove the DLT from the nail was 0.011 ± 0.001 Nm, approximately 7% of the maximum moment that can be applied using the thumb and index finger to rotate the DLT. When the moment required to remove the tool was applied to the proximal end of the tool in a finite element analysis, the resulting Von Mises stress was predicted to be highest at the junction of the locking plugs and locking arms, with a value of 8.5 -104 Pa. This is approximately l/500 t h of the yield stress of the ABS used, so we conclude that the moment required to remove the tool from the IMN will not cause the DLT to fail by yielding. It should be noted that the location of maximum stress was predicted to be at the boundary between the portion of the tool that was rigidly fixed (locking plugs) and the portion that was free to move (locking arms). In reality, the locking plugs will not be held rigidly in place. The deformation caused by the applied moment will therefore be distributed throughout the locking plugs and arms. The predicted value of maximum stress from this model is therefore likely to overestimate the actual maximum stress seen during removal. 4.4 Optimizing the Design As previously mentioned, the design could be further optimized by minimizing the separation between the locking plugs and the sensor. Since the stresses induced throughout the DLT are so far below the yield failure values (1/500th), we conclude that much of the solid portion of the transmission zone could be removed without introducing critical stress values. Although it is difficult to determine the actual mechanism involved in releasing the DLT from the locking holes, it is likely that the moment applied induces a lateral force on the locking holes which, through interactions with the side of the holes, likely produces a combination of twisting and 52 bending of the locking arms that results in releasing them from the locking holes. Changing the bending and torsional stiffness of the locking arms would therefore control the moment necessary to release the tool. The theoretical force necessary to bend the locking arms sufficiently is approximately 2.6 N (See Appendix 3: Theoretical Force to Remove DLT). If this stress is applied through the surface of the locking plug, the stress induced would be approximately 15 • 104 Pa. This is similar to the 8.5 • 104 Pa stress predicted by the F E M . As previously discussed, the repeatability error could be further reduced by increasing the torsional stiffness of the locking arms. It is important, however, that we do not compromise the ease of locking the D L T in place in an effort to increase torsional stiffness. Currently, removal of the DLT only requires 7% of the maximum producible moment; it is therefore reasonable to assume that small increases in bending stiffness of the locking arms (through material choice or arm length or cross-sectional geometry changes) would not have an adverse effect on the locking procedure. However, increasing the bending stiffness of the locking arms would increase the friction felt between the IMN and DLT during insertion. This may make it more difficult to target the distal locking holes intra-operatively. We conclude that the 50 mm separation between locking plugs and sensor could be reduced to 20 mm by decreasing the length of the transition zone and reducing the length of the locking arms without affecting the locking procedure but otherwise, we believe that the design is near-optimal. If further design developments are required, all of these parameters must be taken into account. The finite element model created for the evaluation of the D L T may be expanded to allow parametric analysis of any potential design alterations to be accomplished quickly and easily. 53 4.5 Particulate Formation The presence of bio-inert particles in the tissues surrounding implants has long been associated with osteolysis and subsequent implant loosening so we must ensure that any particles left in the patient during use of the DLT are unlikely to cause harm. This phenomenon has been extensively studied in relation to Total Hip Arthroplasty (THA) (Revell 1997, Green 2000, Ingham 1999, Ingham 2005, Howie 1993, Schmalzreid 1994, Nashed 1995). In the presence of wear particles, macrophages will attempt to phagocytose small particles (<10 um) or surround larger particles (>10 um) in order to degrade the foreign object. For bio-inert materials, the macrophages will be unable to degrade the particles (Ingham 1999). As a result, additional macrophages will be recruited, fuse, and create multi-nucleated giant cells. These giant cells form a barrier between the foreign particle and the surrounding tissue to avoid any potential threat (Ingham 1999). These activated macrophages initiate a foreign body reaction that consists of the release of cytokines and other inflammatory mediators which stimulate the recruitment of osteoclasts. This process ultimately leads to osteolysis and eventual loosening of the implant (Ingham 2005). Although bone cement (PMMA) and metal particles (titanium, cobalt-chrome) have been shown to cause inflammatory reaction and osteolysis, the evidence is very strong that osteolysis is primarily related to the Ultra High Molecular Weight Polyethylene (UHMWPE) particle generation in THA (Ingham 2005). The extent of the inflammatory reaction and subsequent osteolysis due to wear particles depends on the number of particles present. Osteolysis is likely to occur in THA when over H O 1 0 particles are present per gram of tissue (Revell 1997). Repeated insertion and removal of the unfiled distal locking tool resulted in a maximum of 11,640 particles, only 0.0001% of this threshold for a single gram of tissue. The filed DLTs produced a maximum of 2,520 particles or 0.00003%) of the critical number. It is therefore be very unlikely that the number of particles associated with the use of the DLT could lead to osteolysis. The size and concentration of particles have also been shown to be determinants in bioreactivity. Micrometer and submicrometer sized particles are stimulatory (Archibeck 2000, Jacobs 2006). In particular, U H M W P E particles with a mean size of 0.24 urn have been shown to stimulate bone resorption in vitro at a concentration of approximately lOpmVcell. Larger particles (0.45 and 1.71 um) required a concentration of 100 um3/cell to induce bone resorption (Green 2000). Particles larger than this did not stimulate macrophage induced bone resorption. It is reasonable to assume that the biological reaction to ABS particles is analogous to that of U H M W P E . In vivo and in vitro testing of A B S biocompatibility has shown the 'best results possible' (Raya 1993). Since both ABS and U H M W P E are bio-inert, the reactions of similar sizes and concentrations of particles are likely comparable. The smallest recorded particle for our testing was 1.2 um but the average was 8.2 urn. There was only a single particle seen that was under 2 urn in largest side length (1.2 um). The surface area of this particle was approximately 1 pm. If we assume the particle was approximately 0.5 um thick, this gives a particle volume of 0.5 um. In order to reach concentrations of 100 um3/cell, 200 such particles would have to be present in one cell. Since we only recorded one particle of this size and the since the particles will likely be dispersed over tens or hundreds of cell, it is unlikely that a concentration of 100 um would be achieved. The large size and small concentrations of particles that are produced 55 with use of the DLT are therefore very unlikely to cause any adverse biological reactions in the patients. If it is necessary to further decrease the number of particles produced, this could be accomplished by modifying the ratio of acrylonitrile, butadiene and styrene in the A B S (Lee 2003) or by increasing the cross-linking of polymer molecules by applying radiation (Hemmerich 2000). In summary, we have shown that our distal locking tool design is near optimal in its targeting of distal holes, ease of insertion and removal, and patient safety. We conclude that our computer-assisted approach to distal locking will likely be successful in a surgical setting. To further validate our method, we will test our approach in a surgical setting in which we compare the targeting of distal holes using the customary fluoroscopic approach and electromagnetic tracking. The details of this trial will be discussed in chapter 5. 56 5 Implementation of a Clinical Trial for the DLIMN project In lab testing, we have demonstrated that the sensor and distal locking tool have sufficient accuracy when inserted down the nail to make our proposed electromagnetic targeting approach feasible. However, in order to move our technique towards clinical deployment, we need to determine whether it can reliably measure the hole locations under clinical conditions. This process involves both showing that our method is accurate compared to the current operative technique in a live surgical setting and determining the system's performance in a simulation of a surgical task (Figure 5.1). Accurate in Lab-based Testing Accurate in Surgical Task Simulation Accurate Compared to Conventional Technique Use in OR Figure 5.1: Testing Involved in Proof of Concept for Electromagnetic Targeting in DLIMN. Accuracy has been demonstrated in a lab-based setting. It is now necessary to test the systems performance in a simulated surgical task and compared to the conventional technique. When this is complete, the system can be used for targeting in the OR. To test the system in a surgical task simulation, further software development is necessary. Our current software allows real-time tracking of the Aurora sensors but does not incorporate a targeting component to allow the alignment of the drill axis and the location of the distal locking holes to be visualized. We have therefore deferred this process until software development is complete. In the meantime, we will complete a bystander clinical study to evaluate the 57 performance of our system relative to the current technique. This trial will also give us preliminary insight into clinical practice issues which may need to be addressed in our final design and into the length of time that might be required for our computer-assisted procedure relative to the conventional technique. We hypothesize that our CAS approach to distal locking is sufficiently accurate to allow for targeting of the distal locking holes without the use of fluroscopy and that it is efficient enough to decrease total surgical time. 5.1 Materials and Methods In order to evaluate our system intraoperatively, the actual drilling path chosen for distal locking under fluoroscopic guidance will be compared to the axis computed using our technique. Using this method, we can quantify the success of our device and approach without putting the patient at any significant risk. In order to complete this comparison, both the locking holes of the intramedullary nail and the drill bit will be tracked during the drill alignment procedure. Tracking will be used solely for evaluation of our technique and will not be visible to the surgeon during surgery and will not be used to determine the drilling axis. This type of study is known as a bystander study. Patients presenting at Vancouver General Hospital with diagnosed femoral shaft fractures will be invited to participate in this study. Consenting patients who meet the inclusion criteria will undergo standard IM Nailing of the femur. Our intent is to enroll approximately 10-15 patients at this stage as the purpose of this study is to obtain some pilot data which will allow us to better 58 estimate the variances needed for computing the number of patients required in a future randomized control trial. 5.1.1 Required Instrumentation Tools will be tracked intraoperatively using the previously described Aurora Electromagnetic Tracking System (see section 2.1). The IMN will be tracked using the distal locking device described in chapters 2 to 4. As previously described, the DLT will be inserted into the central canal of the intramedullary nail after nail insertion until it makes contact with the distal locking holes. Since the repeatability of distal locking is very good (see section 3.2), the DLT will be pre-calibrated so that the transformation between the sensor and the distal locking hole axis is known prior to surgery. The axis of the locking holes can therefore be computed intra-operatively by applying the pre-determined transformation to real-time sensor tracking. The actual drilling axis will be tracked using a drill-bit mounted reference clip. This tool is a 6 DOF Aurora sensor attached to an ABS instrument clip (Figure 5.2). Figure 5.2: Reference Clip. The reference clip will be attached to the drill bit during alignment for distal hole targeting using a fluoroscope. In the conventional IMN technique, the approximate location of the distal locking holes is determined under fluoroscopic guidance (see section 1.1.3) and an incision is made through the 59 soft tissues. The drill bit is then mounted into a radiolucent targeting device and secured into place by tightening a set screw (Figure 5.3). Figure 5.3: Distal Targeting Device. The drill bit is fastened into the radiolucent targeting device using a set screw (A). The distal holes are the located by aligning the drill bit to the centre of the locking hole under fluoroscopic guidance, (source: Zimmer M/DN ® Femoral Interlocking and Recon Nail Intramedullary Fixation Surgical Technique) The drill bit is inserted through the incision to the surface of the bone and alignment is determined using the method described in section 1.1.3. Once alignment is complete, the drill bit is anchored into the cortical bone by tapping it into place. The targeting device is then removed, the chuck and drill are attached, and drilling is completed. The reference clip has a channel into which the drill bit can be inserted. The clip is then screwed down tightly to avoid any motion of the clip relative to the drill bit. Once the clip is attached, the direction of the long axis of the instrument can be defined by completing a pivot calibration before the alignment procedure (Cleary 2005). The intraoperative drilling axis can therefore be defined by applying the transformation determined during calibration to the real-time data from the reference clip (Figure 5.4). 60 A A C Figure 5.4: Reference Clip. The reference clip contains a small channel (A) into which the drill bit (E) is placed. The clip is then tightened down by turning a lever (B). The clip is also fitted with screw holes (C). These holes are used to attach the sensor (D) to the clip. 5.1.2 Data Collection To compare the efficiency of the two methods, the time necessary for insertion and removal of the distal locking tool, the time necessary for attachment, calibration and removal of the reference clip and the time necessary for fluoroscopic alignment will be recorded. Data will be collected from the DLT and reference clip during alignment for both the more distal and more proximal distal locking holes. The more distal locking hole will be targeted first, since the DLT is locked into the more proximal hole. Data will be collected after alignment is complete, the reference clip will be removed from the drill bit and drilling will be completed. The reference clip will then be re-attached to the drill bit, recalibrated, and placed in the drilled hole axis. Distal screw insertion will then proceed in the standard manner. For the more proximal locking hole, data will be collected once alignment is complete. The distal locking tool will then be removed from the IMN, the reference clip will be removed from the drill bit, and drilling and screw insertion will proceed in the standard manner. 61 The surgeon will also be asked to classify the drilling by fluoroscopic guidance (as successful drilling and no contact with the nail, slight nail contact, severe nail contact, or unable to target hole) in order to determine the quality of the fluoroscopic alignment process. 5.1.3 Data Analysis Our primary goal is to measure the difference between the locking hole axis as calculated using our approach and as aligned using the standard fluoroscopic technique. The locking hole axis will be defined as the long axis of the drill bit (z-axis). In order to determine the angular deviation between this axis and the hole axis calculated using the DLT, the angle between the orientation vector (w) for these two axes will be compared. Scr ex Axis Angle = arccos(wDtf • uDIT ) The variations in the rotation and pitch will be determined by projecting the data onto the distal locking hole axis plane (x-y plane of the nail frame) and the transverse plane (x-z plane of the nail frame). This will be accomplished by taking the dot product of the two dimensional orientation vectors that define the drill bit and the 2D unit vectors that define the appropriate plane. Rotation = arccos((w/jWx, umy) • ( /7 V , hv)) In order to compare the lateral deviations, an x-y plane will be defined on the z= 0 plane of the nail frame, the midpoint between the medial and lateral side of the more proximal distal locking 62 hole. The two dimensional radial distance between the pierce point of the hole axis as defined by the DLT and by the drill bit axis will be computed. Our secondary goal is to estimate the amount of time needed to perform targeting using the CAS approach compared with the time needed for the conventional fluoroscopic approach. We propose to use a (non-parametric) ranked pairs Wilcoxon test to test for differences in the mean time needed. 5.2 Current Status After obtaining a Health Canada Exemption for our device (Appendix 4:Planning and Implementation of a Clinical Trial in a Research Setting), our CREB application went before full board review and was approved (approved May 9 t h, 2007 H06-03500). In order to obtain VCHRI approval according to the new guidelines described in Appendix 4, section 3, a medical device development safety validation was conducted. Details of this trial are summarized below. 5.2.1 Safety Testing for the DLIMN trial The equipment involved in our clinical trial includes the two tools described above (DLT and reference clip) as well as the Aurora system itself. The system is comprised of a system control unit, field generator, system interface unit, mounting arm and clamp (see section 2.1). These are commercially available products and all powered components are in compliance with the 63 appropriate electrical standards (See Appendix 11: Aurora Approvals and Classifications). This compliance was verified by the B M E department at V G H . The distal locking tool and reference clip are not independently powered and do not need to be examined for electrical safety. The reference clip was originally designed for use in a study exploring the kinematics of surgical movements during minimally invasive cholecystectomy. The reference clip was tested for mechanical integrity as a part of this study. There are no reprocessing steps involved with the reference clip; it is simply cleaned and then resterilized. We therefore did not complete any mechanical testing of the reference clip for this study. The mechanical safety tests completed for the DLT are described in Chapter 2. The results of these tests were all positive. For our clinical trial, we plan to dispose of the used DLT but retrieve the 6 DOF sensors and re-use them for a maximum of three trials. Mechanical integrity testing of the removal and recalibration process is therefore required. We are currently completing these tests. The sensor can be removed from the DLT with very little difficulty and without using any sharp tools. We therefore do not expect any microscopic damage to the sensor casing. This has not yet been examined under microscope. These examinations will be performed and the results will be included in our report to the B M E department. 5.2.2 Sterilization Method and Validation for the DLIMN Trial 5.2.2.1 Reference Clip An EtO sterilization method and the reference clip's response to EtO sterilization was tested for the previous cholecystectomy study and were therefore not explored in this project. The details 64 of this protocol can be found in Appendix 12: Cleaning and Sterilization Protocol for MIS Study. In order to satisfy the new guidelines, the EtO sterilization technique developed for the cholecystectomy study was applied to two clips and they were then subjected to the sterility test described in Appendix 4, section 3.3.1. The results from the sterility tests were not satisfactory, one of the tools was sterile but the second showed growth (See Appendix 13: Results of Sterility Testing for Reference Clip). The director of the third party microbiology lab that completed the sterility testing (Dr. Ian Geere, I.G. Micromed Environmental Inc.) expressed his concern that the contamination arose from their handling of the tool prior to sterility testing due to difficulties in placing the sensor leads into the test vessel and not due to problems with our sterilization technique. As discussed in Appendix 4, section 3.3.1, large items must be manipulated in order to place them in a bath of the solution used for sterility testing. They found the long sensor cord difficult to deal with when they first began testing. The trial will therefore be repeated with three additional reference clips and the results of these tests will be evaluated prior to using the reference clip in our clinical study. 5.2.2.2 Distal Locking Tool Since the DLT had not previously been sterilized, a sterilization method had to be developed and validated according to the guidelines presented in Appendix 4, section 3. Because of the intolerance of both the sensor and ABS material to high temperatures, steam sterilization was not appropriate. In discussion with the SPD at V G H , there was concern expressed about the use of EtO for sterilization of this device. Although it is made of the same material as the reference clip, the small dimensions of the DLT and possible effects of EtO on ABS plastic (Rogers 2006) could pose a problem for EtO sterilization. These factors, as well as economic concerns, led us to choose electron-beam radiation for sterilizing the DLT. 65 Maximum Dose Determination As discussed in Appendix 4, section 4.3, the dose required to sterilize a device produced under normal factory conditions is typically 25 kGy. We therefore sterilized devices at 25, 50, 75, 100, and 125 kGy to determine if any negative effects resulted from these doses. Post-sterilization, these devices were examined for any visual changes, tested by insertion and removal into the IMN, and tested for sensor accuracy. A slight yellowing of the tool was noticed with the higher doses, but all performance was satisfactory after sterilization had been applied. The torque tests described in section 2.5.1 were slightly altered to accommodate the oversized sensors used for this trial. The DLTs could not be completely inserted into the IMN but were locked into the distal holes by insertion from the distal end of the IMN. The range of moments required for removal (0.006 to 0.0085 Nm) were similar to those reported in section 3.3.1 (mean 0.011 Nm). As described in this section, the moment necessary to remove a DLT decreases with increased number of insertions and removals. We conclude that the decreased moment necessary to remove the irradiated DLTs is likely due to the increased number of trials they had undergone. Minimum Dose Determination In order to determine the efficacy of sterilization, 12 devices were sterilized with varying doses (see Table 5.1). A l l sterilizing was performed by an FDA recognized e-beam sterilization facility (Iotron Industries Inc, Port Coquitlam, BC) 66 Table 5.1: Radiation Doses Applied to the DLTs. Four tools were radiated at each radiation dose tested. The doses tested were 25, 35, and 45 kGy Tool# Radiation Dose 1 to 4 25 kGy 5 to 8 35 kGy 9 to 12 45 kGy After sterilization, the devices were sent to an accredited microbiology lab (1G Micromed, Richmond, BC) where the required sterility assurance tests will be completed. Because of the problems described in section 5.2.2.1, the sterility testing was delayed to allow the lab to do some preliminary testing on unsterilized tools. Once they have determined the optimal handling of our tools, sterility testing will be performed. 5.2.3 Final Approval Pending positive results from the sterility testing of both tools and the mechanical integrity testing of the sensor after removal from the distal locking tool, we expect to receive approval from the Medical Device Development Committee. We have collected all other elements necessary for VCHR1 approval and have been in close contact with the VCHRI Clinical Trials Administrator throughout this process. As a result, we have been assured that our application for VCHRI approval will be expedited through the system. We therefore expect to be able to start our clinical trial in early September. 5.3 Expected Contributions Success of the clinical trial will be initially be determined by determining the deviation between the hole axis calculated from the electromagnetic system and the using the fluoroscopic method. If deviations are within the clinically acceptable range (less than 2.5 mm lateral deviation and less than 8°angular deviation, see section 4.1) a simulation of the surgical task will be completed (when software development is complete) to train the surgeons in the methods that will be used 67 during actual OR use. Pending satisfactory results in this test, a randomized clinical trial will commence. If the results of the bystander study are not within the acceptable range, one of two possible situations may be occurring: either the electromagnetic tracking technique may not be accurately predicting the hole axis or the fluoroscopic technique may not be reporting the actual locking hole axis. In order to clarify which of these cases is occurring, an in depth surgical simulation will be completed. By calculating the drilling axis and comparing it to the actual hole axis, we can quantify the performance of the system without the uncertainty of determining the location of the hole axis using fluoroscopy. This testing will also be performed in the presence of all surgical equipment (C-arm, surgical table and surgical tools) to determine if the error seen in the bystander study was the result of distortions to the electromagnetic field by these items. Results of these tests will determine whether further modifications need to be made to the system prior to its use in the OR. 68 6 Conclusion 6.1 Design and Testing of the Distal Locking Tool Evaluation of the Aurora EMTS has shown it to be sufficiently accurate to target the distal locking holes of an intramedullary nail. Enclosing the miniature six degree of freedom Aurora sensor in an intramedullary nail causes distortions of only 0.1 mm and 0.05°. The standard deviations of three-dimensional translational and screw angle axis readings from the Aurora sensor in the mid-to-high range of sensor to field generator distances were 0.16 mm and 0.20° respectively. The insertion repeatability of the distal locking tool is high with maximal one-dimensional standard deviations of 0.20 mm and 1.59°. The three dimensional standard deviations of predicting the drilling axis using the DLT and a drill bit mounted tracker are 0.89 mm and 1.7°. Removal of the DLT from the IMN requires only 7% of the maximal moment that can be produced using the thumb and index finger to twist the tool's proximal end. The stresses induced during this process are predicted to be approximately 1/500th of the yield stress of the material. Insertion and removal of the DLT resulted in the production of approximately 8,580 ± 4,330 particles for tools that were not filed prior to use. A mean of 1,980 ± 760 particles were produced when filing was performed prior to testing. The smallest particle recorded had an edge length of 1.2 um and the mean particle size was 8.2 pm. The particles produced are both too small in size and too few in numbers to cause osteolysis in vivo. 69 The distal locking tool can be safely and easily inserted and removed from the IMN. Accuracy testing indicates that targeting of distal locking holes using this method is likely to be successful. 6.2 Evaluation of the Method and Apparatus The protocol for mechanical testing and sterilization validation necessary to ensure a safe and effective clinical trial according to all the applicable guidelines has been established. The evaluation of all the tools to be used in the testing of our approach has begun according to this protocol. Pending satisfactory results of these tests, a clinical trial will be completed to assess the relative accuracy of the electromagnetic system and the currently accepted fluoroscopic technique. If the results of this test are positive, the commencement of a full scale randomized controlled clinical trial will be planned. We hypothesize that our method is both accurate enough to target distal locking holes without the use of radiation and efficient enough to decrease the surgical time necessary for distal locking. If the results of the initial clinical trial are not satisfactory, further testing of our approach using surgical simulation will take place in order to refine the method. The introduction of a radiation-free technique for distal locking will decrease the exposure of the orthopaedic team to potentially harmful radiation. Development of a more efficient targeting technique will decrease the surgical time necessary for the intramedullary nailing procedure. 70 References Archibeck MJ, Jacobs JJ, Roebuck K A , Giant TT. The Basic Science of periprosthetic osteolysis. JBJS (A) 2000; 82:1478-89 . AAOS On-Line Service February 2001 Bulletin. http://www2.aaos.org/aaos/archives/bulletin/feb01/fline4.htm Aurora User Manual. Revision 1.0 Northern Digital Inc. August 2005 BC Ministry of Health, Patient Safety Branch. Best Practice Guidelines for the Cleaning, Disinfection and Sterilization of Medical Devices in Health Authorities. 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Navigation with Electromagnetic Tracking for Interventional Radiology Procedures: A Feasibility Study../ Vase Interv Radiol 2005; 16:493-505 76 Appendix 1: Design Evolution of the Distal Locking Tool In order to target the distal locking holes of the intramedullary nail from within the central canal of the nail, a distal locking tool was necessary. The requirements for this tool were: 1. It must be able to fit through the insertion handle which has a diameter of 3.5 mm. 2. It must stop when it encounters the distal locking holes. 3. It must lock into the distal locking holes repeatably. 4. It must fix the sensor's location relative the locking holes reliably. 5. It must be easy to remove from the intramedullary nail. In order to address all of these issues, we started by focusing on the distal end of the tool that would lock into the distal locking holes. In order to fit through the insertion handle (3.5 mm) and expand into the intramedullary nail (inner diameter 4.5 mm) so that it can lock into the locking holes, we decided to design an end bit with locking plugs that match the locking hole diameter (5 mm) and locking arms which can be compressed to allow the insertion of the tool. Both the torsional rigidity and the bending stiffness will affect the locking and removal process. These properties depend on the material chosen, the cross-sectional area of the locking arms and the length of the locking arms. The material used must be biocompatible and must not interfere with the electromagnetic sensor being used for targeting. We therefore chose to use a polymer. The combination of the small dimensions of our tool and the plastic material made it very difficult to machine. A rapid prototyping machine was therefore used to manufacture the tools. Of the materials available for this machine, A B S P400 was the most economical material that displayed all of the properties we were looking for. To ensure that the locking plug would fit securely into the locking holes, it was designed with a raised locking plug. This locking plug has a spherical proximal end to promote easy removal and a cylindrical distal end in order to stop the locking plug when it reaches the distal locking hole. Figure 1: Distal Locking Tool Plug. The distal ends (left) of the DLT are designed with plugs to engage the locking holes of the IMN. The distal surface of the plugs are cylindrically shaped so that they do not slide past the 77 locking holes. The proximal (right) surface of the plugs are spherically shaped in order to facilitate removal of the DLT. In order to test variations in cross section and length of the locking arms, we created many different variations of end bits. The first design had a constant cross section with straight locking arms. This design was manufactured with locking arm lengths of 15, 25, 35 and 45 mm. Figure 2: Straight Locking Arms. This design was tested with arm lengths of 15, 25,35 and 45 mm (left to right). The base of these tools had diameter 3.5 mm. The locking arms of these tools did not expand sufficiently when inserted in to the intramedullary nail. A new design that included a bend in the locking arms was made. This design was manufactured for locking arm lengths of 15, 25 and 35 mm. Figure 3: Bend Design. Locking arms with a gradual bend were manufactured with arm lengths of 1.5, 2.5 and 3.3 cm. This design was more successful but there was still too little rigidity of the locking arms. The smallest arm length was also found to be inappropriate due to the high forces necessary to compress the arms. The next design of the locking arms included a gradually decreasing cross-sectional area. This allowed for an increase in rigidity while maintaining a maximum diameter (when the locking arms are compressed) of 3.5 mm. This design was manufactured for arm lengths of 25 and 35 mm. Figure 4: Bend Design. Locking arms with a gradual bend were manufactured with arm lengths of 1.5, 2.5 and 3.3 cm 78 This design proved to lock very well into the distal locking holes. The 25 mm arm length was chosen as this length showed the best balance between ease of insertion and ease of removal. The tool was then extended so that it had a total length of 475 mm. The portion of the tool that extends towards the proximal end of the tool has a c-shaped channel built into it. The diameter of this channel is 2.5 mm and is designed to allow the Aurora sensor to be laid into it. Figure 5: The distal locking tool is Fitted with a C-shaped channel to house the Aurora sensor (2.5 mm). This gives a final design as shown below, with a 50 mm distance between locking plugs and sensor. By designing the locking arms with a relaxed separation of 10 mm, insertion and removal of the tool can be accomplished easily and repeatably. locking plugs sensor location ,....„.....;. • 10 mm locking arms = 25 mm Figure 6: Distal Locking Tool. The final design of the distal locking tool has a relaxed locking arm separation of 10 mm. The distance between the sensor location and the locking plugs is 50 mm. 79 Appendix 2: ABS Material Specifications F D M T E C H N O L O G Y >., M A T E R I A L S A true industrial thermoplastic. A B S is widely used throughout industry. When combined with the Fused Deposition Modeling (FDM) systems by Stratasys, this material is ideal for the rapid production of prototypes, tooling and the direct (tool-less) manufacturing of production parts. Tensile Strength, Type t. 0.125 ASTM D638 Tensile Modulus, Type 1, 0.125 ASTM D638 Tensile Elongation, Type 1, 0.125 ASTM D638 Ftexural Strength ASTM D790 Ftexural Modulus ASTM D790 IZOD Impact, un-notched ASTM D256 IZOD Impact, notched ASTM D256 3,2000 psi 236,000 psi 6,000 psi 266.000 psi 4 tl-lb/in 2 tt-lb/in 22 MPa 1,627 MPa 6% 41 MPa 1334 MPa Heat Deflection (HDT) Glass Transition (Tg) Coefficient of Thermal Expansion Melt Point ASTM D648 DMA (SSYS) 205° F 2ie°F 5.60E-05 in/in/F Not Applicable' 96° C 104°C Not Applicable' Specific Gravity Vertical Buring Test Rockwell Hardness Dielectric S (kV/mm) Dielectric C (#60Mhz) ASTM D792 UL 94 ASTM D785 IEC 60112 IEC 60250 1.05 HB R105 32 2.4 APPEARANCE • White available on all FDM systems • Colors available on the FDM Maxum: • Black. Blue. Green. Grey (light). Grey (steel). Red and Yellow • Custom color program available • Colors available on FDM Prodigy Plus: • Black. Blue. Green, Red and Yellow • Custom color program available SYSTEM AVAILABILITY • FDM Maxum • FDM Titan Tl • FDM Vantage SE • FDM Vantage S • FDM Vantage / (when configured with ABS) • FDM Prodigy Bus Th» fafaoMfen prmnUri »<• typtral v«/uw MwdW h, mfevnc* and t i » m « i « i P"'***"* "¥ Tl*y <***" '«* tptKaHom o: qaHr control w o w End-on mitral :•->••••.>•-•* em bo mptcfd <+/•) by. but not Imxfd to, put eloign. Mhm OOMMMW M conciMns. «te Actual ntoM W» my w<A bu,id m M W K I g U ( / a - /s iw) s/ofc 2 Do 10 amorphous nmiro, nuttonil doos nor display a nWfwp poM For more information about Stratasys systems and materials, contact your representative +1 888.480.3548 or visit www.stratasys.com 6 2005 SUfttasy*. ItK. All nglrtt, t*s*fv»d Piottuct sf*ctfk*«iG09 aw MtyKI 1° clw«g» w*h<*ft notice. MF*BS 3*05 S T R A T A S Y S ' Appendix 3: Theoretical Force to Remove DLT and Factor of Safety Calculations In order to determine the theoretical force necessary to remove the DLT from the IMN, we determined the force necessary to compress the locking arms of the distal end of the DLT sufficiently to release it from the locking holes. Figure 1: Distal Locking Arms. The deployed height of the distal locking arms is 5 mm. In order to remove the DLT from the IMN, the locking arms must be compressed this distance. In order to do this, we approximated that the force necessary to compress the locking arms would be similar to the force necessary to deform a straight beam to the final expanded state. We also modeled the shape of the locking arms to be constant cross-sections and compared the results for a) rectangular cross-section and b) circular cross-section. The standard equation for deflection of a beam under cantilever loading was then used to determine the force required to deflect the beam by 5 mm. L = mm F / 3 F = My, max max 3EI 1 .Model locking arm as a constant rectangular cross section: bh3 12 • The force necessary to move the locking arms is: F = 3.2N 81 2. Model locking arm as a constant circular cross section: / = 64 • The force necessary to move the locking arms is: F = 1.9 N Factor of Safety Take the force necessary to deform the locking arms as the average of the rectangular and circular cases: F = 2 .6N Assuming that this force was only being applied to the portion of the DLT that is engaged by the distal locking holes, the working stress for this situation was determined. This working stress was compared to the yield stress for the ABS material to determine the factor of safety. yieldstress Factor of Safety workingstress a = — = 1.5-105 N /m 2 A Flexural Strength of ABS = 41MPa FoS = 4 l M P a ^275 OASMPa 82 Appendix 4: Planning and Implementation of a Clinical Trial in a Research Setting In the past, new medical devices developed at the University of British Columbia (UBC) for use in clinical trials at one of the Vancouver Coastal Health Authority (VCHA) sites have been required to obtain U B C Clinical Research Ethics Board and Vancouver Coastal Health Research Institute (VCHRI) approval. The major components of the later simply involved obtaining approval from the Biomedical Engineering Department (BME) that devices were electrically and mechanically safe and developing a sterilization method in collaboration with the hospital's Sterile Processing Department (SPD). In March of 2007, the British Columbia Ministry of Health (MoH) released a Best Practice Guideline for Cleaning, Disinfection and Sterilization of Medical Devices in Health Authorities (MoH March 2007). In June of this year, the Ministry of Health released a further communique requiring all health authorities to conform with the aforementioned guidelines (Macatee 2007). Adoption of this policy invalidated the approval process that had previously been in place at the VCHRI. In order for development and testing of novel medical devices within our institution to continue, a new approval process was necessary. Ours was the first clinical trial to request approval after the introduction of this new policy and as a result, it was necessary for me to find a method of satisfying all the requirements set out in the MoH and to determine a new path through the VCHRI approval process. In order to facilitate VCHRI approval for all future researchers intending to bring new medical devices into a surgical environment, I have compiled all the necessary information to guide decision making and approval into this chapter. Figure 1 illustrates the main steps in obtaining approval for a clinical trial. Each of these requirements will be discussed in detail below. Ster i l i t y A s s u r a n c e Development and testing of sterilization method B i o m e d i c a l E n g i n e e r i n g • Electrical/ Mechanical Safety Testing Health Canada Exemption Medica l Dev ice D e v e l o p m e n t Safety C o m m i t t e e A p p r o v a l CREB Approval VCHRI Approval 1 Clinical Trial Figure 1: Approval Process. This chart displays all of the necessary steps to obtain approval of a clinical trial at VCHRI. The items in bold (left) are new requirements that have been created in response to new legislation governing the use of medical devices. Descriptions of each of these steps can be found in this chapter. 1. Clinical Research Ethics Board Approval The CREB application involves filling in an online application, preparing a detailed protocol and preparing any other necessary documents such as a consent form for subjects. The steps necessary for this procedure are well documented by UBC's Office of Research Services and can be found at rise.ubc.ca. Examples of these documents in the form of our approved protocol, consent form, and online application can be found in Appendix 5, 6 and 7 for further reference. One portion of the online application has particular significance to researchers who have developed a medical device for use in clinical trial. Section 7.8B reads as follows: 84 7.8B For clinical trials involving investigational drugs/devices or marketed drugs/devices outside their approved indications, indicate whether or not approval has been obtained from the appropriate federal regulatory agency for this purpose. For medical devices, the appropriate federal regulatory agency is Health Canada. The Medical Devices Regulations (MDR 1998) govern the use of medical devices and their licensing. Custom-made medical devices, medical devices for special access and medical devices for investigational testing involving human subjects do not require Health Canada device licenses. Medical devices for special access are defined as devices that can be used for emergency use or if conventional therapies have failed, are unavailable or are unsuitable. These devices require Health Canada approval and are regulated according to Part 2 of the Medical Devices Regulations (MDR 1998, Section 68). Part 2 of the M D R applies to custom made devices only if devices are to be imported or sold. Devices for investigational testing involving human subjects also require Health Canada approval and are regulated by part 3 of the MDR but this approval is also only necessary for medical devices that are to be imported or sold (MDR 1998, Section 79). Because medical devices that are developed by a given institution for testing in that institution do not fall under any of the aforementioned categories, Health Canada approval is not necessary. Researchers should contact the Regulatory and Scientific Section, Device Licensing Division of the Medical Devices Bureau of Health Canada via email and request an explicit Health Canada exemption. It is advisable that you clarify the details of the device with the Biomedical 85 Engineering (BME) department at the appropriate hospital site and request that they contact Health Canada. Health Canada classifies medical devices according to the potential risk they pose to patients and healthcare workers (I- lowest risk, IV-highest risk). The details provided to the B M E department should include the risk classification of the device. A l l surgically invasive devices, defined as invasive devices that are intended to enter the body through an artificially created opening that provides access to the body structures and fluids, are a minimum of class II. If the device is designed to diagnose, monitor, or control elements of the central nervous system, cardiovascular system, or a fetus in utero or if the device is intended to be absorbed by the body or remain in the body for more than 30 days, the device will fall under a higher classification. A complete definition of the risk classification of medical devices can be found in Schedule One of the Medical Devices Regulations (MDR 1998). 2. Vancouver Coastal Research Institute Approval In order to obtain permission to conduct a clinical trial at one of the VCHRI sites, there are several steps necessary. A detailed description of the application process can be found in Appendix 8: Approval to Conduct Research at Vancouver Coastal Health Authority and Appendix 9: Guideline for Obtaining Approval to Conduct Research at Vancouver Acute. A l l forms and guidelines can also be found at http://www.vchri.ca/s/FormsLogos.asp. It is important to note that the Principal Investigator must have a medical appointment at V C H , be a V C H employee, or have received a V C H Affiliated Investigator Appointment. 86 The new MoH policy as it pertains to clinical trials and our protocol to satisfy this policy are discussed below. 2.1 Best Practice Guidelines for the Cleaning, Disinfection and Sterilization of Medical Devices in Health Authorities Unlike the Health Canada device license requirements, all equipment and devices, regardless of their source, must meet the standards set out in the Best Practices Guidelines (MoH March 2007). One of the major consequences of the communique for device developers is that it explicitly states that manufacturers are responsible for supplying written information regarding the safe and appropriate reprocessing of the medical equipment or device (MoH, section 5.4). It further specifies that disinfection and sterilization procedures must include information regarding the type and concentration of chemical products, the duration and temperature of exposure, and physical and chemical properties that could potentially have an impact on the efficacy of sterilization (MoH, section 8.1). Finally, the document emphasizes that the sterilization process must be validated thoroughly before being used in a clinical setting and at regular intervals thereafter (MoH, section 13.4). The recommendations made by the manufacturer must then be reviewed by infection control and sterile processing personnel. There is also a requirement that biomedical engineering verifies the safety of the device prior to its use in a clinical setting (MoH, section 2.3). 3. Guidelines for Medical Device Development and Testing for Use in Clinical Trials at Vancouver Coastal Health Acute Sites In order to satisfy the new regulations of the aforementioned policy change and clarify the VCHRI requirements that are already in place, I have proposed a protocol for all researchers who 87 plan on completing a clinical trial at V C H A sites. In order to evaluate this protocol, a collaboration of experts from a variety of hospital units was necessary. These experts have formed what we refer to as the Medical Device Development Safety Committee (MDDSC). The committee members are listed in Table 1. Table 1: Members of the V G H Medical Device Development Safety Committee. Name Aff i l iat ion Dr. Elizabeth Bryce Regional Manager, Infection Control Darren Kopetsky Regional Manager, Risk Management Stephania Manusha Regional Manager, Clinical Trials Administration Mona Sharman Head, Sterile Processing Department Gord McConnell Head, Biomedical Engineering Department Debbie Hendricks Manager, Operating Rooms Murray Dore Biomedical Engineering Departement The objective of this protocol is to provide a detailed description of the requirements for using custom-made medical devices within the Vancouver Coastal Health Authority. For the reasons described in section 1 of this appendix, this protocol does not apply to medical devices imported or sold to researchers for use at V C H A sites, as these devices require Health Canada approval. This protocol does not replace the CREB or VCHRI approval processes described earlier in this chapter. Instead, it provides a means of satisfying several of the VCHRI requirements all at once. In order to obtain this stage of approval, researchers will be required to pass electrical and mechanical safety testing and develop and validate a sterilization protocol. Sterilization validation requires the participation of third-party processors and testing that lasts several weeks. Researchers are advised to plan their timelines accordingly. The first step to obtain approval from the MDDSC is completion of aforementioned safety tests and the development of a cleaning, packaging and sterilization protocol. Following completion 88 of these tests and development of the sterilization protocol, a Medical Device Development Proposal must be submitted to the MDDSC. This submission should include the CREB protocol, the results of safety testing, the sterilization method and any additional information relating to device design or function that the developer deems necessary (Figure 2). Details of all of these requirements will be discussed below. Mechanical Safety Tests Electrical Safety Tests CREB Protocol Proposed Sterilization Method Additional Design/ Function Info (if necessary) Medical Device Development Proposal Figure 2: The Medical Device Development Proposal. This proposal should include all the required mechanical and electrical safety tests as well as the proposed sterilization method and C R E B protocol. A n y additional information regarding design of function of the device may also'be included. 3.1 Electrical Safety Requirements Any equipment that will be used during the trial must meet the relevant Electrical Safety for Medical Devices standards (CSA 601 Series). Any components that are commercially available and designed for medical use will likely already be appropriately certified. Testing of custom-built powered devices should be discussed with the Biomedical Engineering Department at the appropriate hospital site. CSA compliance testing can be arranged for new devices but researchers should expect an additional cost and plan for the time necessary to complete these tests. Compliance with electrical safety standards will be checked by the Biomedical Engineering Department. 89 3.2 Mechanical Integrity The developer must show that the device remains intact and retains function after exposure to the environment and stresses it will be subjected to throughout sterilization and use cycles. For multiple use items, any handling of the device that will occur between uses must be tested. The developer must treat the device exactly as it will be treated after it has been used; for example, if the device must be recalibrated, or if some portion of the device must be replaced, the device should be disassembled, cleaned, reassembled and calibrated as it would be prior to another trial. Functional tests as well as mechanical integrity testing must be performed. Mechanical integrity testing must include observation of the device under microscope to look for any nicks or cuts that may affect re-sterilization. It is not necessary to complete sterilization between tests for this stage of testing. The number of reprocessing cycles tested must exceed the allowed number of uses defined for the device. 3.3 Cleaning, Packaging and Sterilization Method The choice of an appropriate sterilization method to meet the requirements of a particular device is an involved process. There are many different factors including material response to sterilization and the relative costs of both routine sterilization and the validation trial. A detailed guide to choosing a sterilization modality for a device will be presented in Section 4 of this Appendix. 90 Once the type of sterilization has been chosen, there are several tests that need to occur to show the efficacy of the proposed method. These are: maximum dose determination, minimum dose determination and, when radiation is used, dose mapping (Figure 3). Max. Dose Determination Min. Dose Determination 1 Dose 1 I M a p p i n g J Sterilization Validation Figure 3: Sterilization Validation Trial. The sterilization validation trial must consist of maximum and minimum dose determination. If radiation validation will be used, dose mapping is also necessary. 3.3.1 Minimum Dose Determination The minimum sterilization dose necessary to ensure sterility must be determined. In order to complete this process, a third party microbiology lab must be employed to complete sterility testing. Four devices for each different level of sterilization (eg. radiation dose or exposure time for ethylene oxide) must be cleaned, sealed, and sterilized according to the proposed method. Depending on the type of sterilization chosen and the volume of devices required for the clinical trial, sterilization may be possible through the hospital SPD. Otherwise, it is the responsibility of the researcher to find an appropriate third-party sterilization company. This company should be FDA or equivalently approved to perform sterilization of medical devices. The name and any accreditations of the sterilization company must be included in the medical device development proposal. 91 After sterilization, the device must be sent to a microbiology lab for sterility testing. The testing that must be completed by the lab involves washing the device (post-sterilization) in a special solvent for a given amount of time, filtering the solvent and then incubating the filters in both aerobic (oxygen rich) and anaerobic (oxygen-free) environments for 14 days. If any contamination exists after sterilization, bacterial growth will occur in one of these two environments. If there is no growth, the device is sterile. The microbiology lab must provide the researcher with a report outlining the results of sterility testing. It should be noted that the majority of sterility testing at small microbiology labs is performed on small devices or pharmaceuticals. The researcher is therefore encouraged to be detailed in the description of their device when choosing a lab to complete the testing in order to ensure that their facilities can accommodate the device. It may also be necessary to provide an unsterilized device for the lab to use in the determination of the optimal handling of the device for sterility testing. The third-party laboratory must be comfortable and experienced with the necessary testing. They must also be appropriately accredited or certified (eg. Standards Council of Canada, Health Canada, FDA) to perform these tests. The suitability of the third-party will be judged by the committee during evaluation of the proposal. Along with the details of the method of sterilization chosen, the researcher must include a description of their planned sterilization validation trial- including the name and certifications of all third parties- in the medical device development proposal. 92 3.3.2 Maximum Dose Determination Testing must be performed in order to determine the maximum sterilization dose that can be applied to the device without compromising its function or safety. Sterilization doses may fluctuate slightly from case to case or from one area of a device to another. It is imperative that the developer shows that their device can withstand the results of such fluctuations. Single use devices must be sterilized to a dose of twice the intended sterilization dose (eg. time for steam and EtO, radiation dose) to ensure function after sterilization. Re-usable devices should be subjected to a dose in excess of the total dose that can be applied to the device based on the number of reprocessing cycles allowed. The mechanical integrity and function of the device must be tested after the maximum dose is applied. The methods that will be used to test mechanical integrity and function as well as the details of doses that will be applied during maximum dose determination must be included in the medical device development proposal and should be discussed with B M E in advance. 3.3.3 Dose Mapping for Irradiation Sterilization Devices that will be sterilized using irradiation techniques must undergo a dose-mapping procedure. Dose mapping allows determination of the zones of minimum and maximum dose in the device package by placing dosimeters at strategic locations. This process allows for the dose being applied at various areas of the device to be correlated to the dose measured at a position outside the device packaging. This is necessary to ensure that the minimum dose is applied to the entire device. Dose mapping should be completed by the facility performing the irradiation of the 93 device. The researcher should ensure that the company contracted to complete sterilization is equipped to complete dose mapping as well. 3.3.4 Sterilization Challenge During proposal evaluation, the MDDSC may require a sterilization challenge test to be performed in addition to the requisite sterility test previously described. This may be the case if the device is likely to be difficult to sterilize due to the presence of small lumen or crevasses that may not be penetrated during sterilization. The sterilization challenge involves inoculating the device with a known concentration of organisms, processing it with the proscribed cleaning and sterilization technique, and then performing the aforementioned sterility tests. Should it be required, the details of this test should be discussed with the appropriate members of the MDDSC (Infection Control and Sterile Processing representatives) in order to determine whether inoculation should be performed by the hospital representatives or by the microbiology lab. 3.4 Obtaining Final MDDSC Approval Once the sterilization validation has been successfully completed, the researcher must submit a final report including the results of this test and the timeline for planned sterilization method audits. Provided there are no significant changes to the design, manufacture, packaging, or raw materials used for the device, only the minimum dose must be re-validated on a regular basis. The sterility testing previously described must be repeated after a given time period to ensure sterility is being maintained. Process auditing is required quarterly for Health Canada licensed devices (MDR 1998) but this timeline may not be appropriate for research devices due to their infrequency of use. The auditing process for research devices has not yet been finalized. 94 It is the responsibility of the device developer to ensure that the device is only used according to its approved protocol. The developer must train all of the appropriate staff in the methods necessary for device use, cleaning and sterilization. Any changes to the design, use, or processing of the approved device must be approved by the most appropriately qualified member of the committee, who may request approval by the whole committee if they feel the issue requires broader input. A form to be completed for these purposes is planned but not complete at this time. Vancouver Hospital will bear the legal responsibility for use of the device in a surgical setting and will indemnify the researchers once approval of the Medical Device Development Safety Committee has been granted. Once the device has been approved by the committee, the developer should submit the standard Request for Approval to Conduct Research at Vancouver Coastal Health Authority. The Medical Device Development Report should be included with this submission. 95 Mechanical Safety Tests Electrical Safety Tests Proposed Sterilization Method CREB Protocol Additional Design/ Function Info Medical Device Development Proposal Accepted Max. Dose Determination Min. Dose Determination Timeline for Process Auditing M. Sterilization Validation Dose Mapping I MDDSC Approval Application for * VCHRI Approval Figure 4: Final MDDSC Approval. Once sterilization validation results and a timeline for process auditing are submitted to and approved by the MDDSC, application for VCHRI approval should be submitted. 4. Choosing a Sterilization Method For engineers and other researchers developing novel devices, mechanical integrity and function testing are a normal part of the design process. Sterilization concerns, however, are not as routine 96 in our line of work. For this reason, I would like to share the information that I have collected in the design of our clinical trial and the creation of the protocol just described. Medical devices are most commonly sterilized using one of three methods: gas, irradiation, or steam. Gas sterilization is performed by sealing a device in a chamber, removing the air from the chamber and infusing it with Ethylene Oxide (EtO). EtO kills any microorganism with which it comes into contact. After the period of gas exposure is complete, the EtO is removed from the chamber and repeatedly aerated to remove unwanted gas residue. Irradiation sterilization by gamma rays or electron beams destroys microorganisms by compromising their D N A and causes them to fragment. Steam sterilization relies on high temperatures to degrade the D N A and proteins of microorganisms (Fact Sheet on Ethylene Oxide Sterilant Alternatives 1997). Each of these methods has its advantages and disadvantages. This document aims to help the researcher chose which method may be most appropriate for their device. The major factors that must be taken into account when choosing a sterilization method are whether or not the device can withstand the particular method and maintain function, whether you have access to the sterilization method, and the cost of sterilization and validation. A summary of the response of various plastics to the aforementioned sterilization techniques is presented in Table 2. A detailed look at each of the three sterilization modalities can be found below. Table 2: Response of Various Plastics to Steam, Radiation, and Ethylene Oxide Sterilization Methods. (source: Rogers 2006) ^ _ Plastic Steam Response Radiation Response EtO Response Acetal Good No Good Acrylic Poor Good Good Acrylonitrile butadiene styrene Varies Good Varies High-density polyethylene Good Good Good 97 Nylon Varies Good Good Polycarbonate Varies Good Good Polyester Poor Good Good Polyethylene Poor Good Good Polyglycolic acid No No Good Polymethyl pentene Good Poor Good Polypropylene Good Varies Good Polypropylene and polyethylene copolymer Good Good Good Polystyrene Poor Good Good Polysulfone Good Good Good Polyurethane Poor Good Good Polyvinyl chloride Varies Varies Good Polyvinylidene fluoride Good Good Good Silicone Good Good Good 1 Teflon Varies No Good 4.1 Ethylene Oxide Sterilization Considerations It is possible to design an effective EtO sterilization process for almost every medical device, but the challenge lies in the large number of variations possible. Temperature, pressure, humidity, EtO concentration and gas dwell time are all critical parameters in an EtO sterilization cycle (Sordellini 1998). Other factors that must be considered when contemplating EtO methods are physical configuration, material of the device, the response of the device to pressure changes, the natural bioburden (number of microorganisms typically present on a device prior to sterilization), the maximum heat tolerance, and any potential chemical reactions with water vapour or ethylene oxide (Sordellini 1998). Complex devices can be difficult to sterilize using EtO due to the difficulty associated with gas penetration to parts of the device with limited accessibility. In order to overcome this problem, a 98 more stringent sterilization cycle can be employed. This may involve increasing the depth of the vacuum, increasing gas concentration or increasing the temperature in the chamber. However, each of these processes may have a negative effect on the device. EtO can diffuse several millimeters into surfaces but may have limited effectiveness if a product is very dense (Leventon 2002). Another important factor in EtO sterilization is the propensity of the device material to absorb EtO. Plastics tend to absorb a much larger amount of EtO than metals (Leventon 2002). The more EtO absorbed, the more must be removed from the product during aeration, prior to use. Residual analysis is a key step in any sterilization validation trial involving EtO. A list of the response of various plastics to EtO sterilization is shown in Table 2. 4.2 EtO Sterilization Validation The two tests that need to be performed during EtO sterilization validation are sterility assurance and residual analysis. Table 3 shows the cost, number of samples, and the time necessary to complete an EtO validation at a major medical device testing facility (Nelson Laboratories Inc., Salt Lake City, UT). The price quoted assumes no failures of the devices during the validation process. An additional $250 is charged for each additional test that must be performed due to device failure. This price also does not include the cost of preparing an FDA report, which would cost an additional $275. Such a report would be necessary if the researcher plans on applying for Health Canada approval. This is not necessary for clinical trials being completed at VCHRI but would be necessary in the future i f the device is to be used at any other institution. 99 Table 3: EtO Sterilization Validation Trial Test Cost # Samples Time (wks) Sterility $3,300 •> 3 Residual Analysis $275 3 1.5 Total $3,575 6 4.5 4.3 R a d i a t i o n S te r i l i za t i on Cons ide ra t i ons Gamma and electron-beam sterilization are among the most popular choices for sterilization of devices containing polymers. However, the sterilization process can cause changes to the polymer including embrittlement, stiffening, softening, colour change, production of an odor, changes to melt temperature, or changes in chemical resistance (Hemmerich 2000). The changes to mechanical properties are a result of excitation or ionization of atoms (Hemmerich 2000). The two main mechanisms which can affect the mechanical properties of the device are chain scission and cross-linking. Chain scission is the random rupturing of bonds; this reduces the molecular weight, and consequently the strength, of the polymer. Cross-linking of adjacent long molecules results in large three-dimensional molecular networks. Initially this can cause an increase in tensile strength of the material. Cross-linking can also decrease impact strength and cause the polymer to become more brittle with increased dose (Hemmerich 2000). In most polymers, a combination of both of these processes will occur upon irradiation. It can therefore be difficult to predict the effects of radiation on your device. Table 2 gives a general guide to the response of various plastics to radiation. For a more detailed description of the response of polymers to irradiation, please see Appendix 10: Radiation Stability of Polymer Materials. 100 Gamma radiation generally has more deleterious affect on materials than electron-beam radiation. The advent of materials designed to minimize radiation-induced cross-linking and chain scission in the last decade has reduced the effects of both types of radiation on polymers. These materials are typically infused with anti-rads which either combine readily with free radicals generated in the polymer during radiation or act as primary energy absorbers which prevent the radiation from interacting directly with the polymer. However, care should still be taken when selecting a sterilization method (Leventon 2002). Electron-beam radiation is compatible with about 70% of medical devices in production (Leventon 2002) but items containing batteries or electronic components may be adversely affected. E-beam sterilization has a surface penetration of about 50% that of gamma irradiation, it is therefore possible that the beams will not reach every small crack. Shadowing of certain portions of the device may also occur if there is any stacking of the device within its container. In order to prevent any dangers associated with these problems, dosimeters are placed in hard to reach places to record the radiation dose. This dose mapping process ensures that the entire device is exposed to the minimum dose required for sterilization. As a reference, the minimum radiation dose for devices manufactured in a clean room is typically 15 kilo Gray (kGy). Devices manufactured in regular factory conditions usually require 25 kGy and devices that experience more handling during manufacture require 35 kGy (correspondence with Alex English, Quality Manager, Iotron Industries Canada, May 22 n d , 2007). 4.4 Radiation Sterilization Validation The tests necessary for sterilization validation of irradiation are threefold: sterility assurance, material response, and dose mapping. Table 4 outlines the time, number of samples, and costs for 101 completion of a radiation validation trial by a major US laboratory (Nelson Laboratories Inc., Salt Lake City, UT). These costs do not include the price of an FDA report nor the cost of producing the devices required. If desired, an FDA report would be an additional $275. Table 4: Radiation Validation Completed by a well known American Laboratory. Test Cost # Samples Timeline Sterility $1,400 30 7-8 wks Material Response $400 10 1 wk Dose Mapping $850 1 wk Total $2,650 40 9-10 wks However, when we looked into finding local companies to complete the same trials, we were able to accomplish the testing with a smaller number of samples, in a shorter timeline, and for a lower cost. Table 5 shows the time, number of samples, and costs associated with completing the validation trial using qualified local companies (Iotron Industries Inc., Port Coquitlam, BC and IG Micromed, Richmond, BC). Table 5: Radiation Validation Completed By Qualified Local Companies • 1 1 1 1 1 Test Cost # Samples Timeline Sterility $600 12 2 wks Material Response $400 5 1 wk Dose Mapping 1 wk Total $1,000 17 4 wks 4.5 Steam Sterilization Considerations 102 Steam sterilization is a popular sterilization method due to its simplicity and low cost. It produces virtually no waste and equipment costs are approximately one third that of EtO and one quarter that of radiation equipment. Steam sterilization is an effective method of killing microbial organisms as well as inactivating resistant nonpathogenic thermopile spores and extremely resistant prions that survive other sterilization methods (Rogers 2006). That being said, steam sterilization is rarely used in the medical device industry. The temperatures necessary for this procedure range from 100°C to 134°C, as can be seen in Table 6. Surgical instruments, which are typically made of metal, can easily withstand these extreme temperatures. Most medical devices, however, do not retain function after being exposed to these conditions because of damage to plastic or electronic components. Table 2 shows the responses of various plastics to steam sterilization. Table 0.6: Time required for steam sterilization at different temperatures. Temperature Time (min) 132°-134°C 3-4 121°C 8-30 115°C 35-45 l i r e 80-180 4.6 Steam Sterilization Validation The tests required for validation of a steam sterilization method are sterility assurance and dry-time verification. The cost of performing these tests at a large US laboratory (Nelson 103 Laboratories, Salt Lake City, UT) are shown in Table 7. Preparation of a formal F D A report would also cost an additional $275. Table 7: Steam Sterilization Validation Completed by a well known American Laboratory. Test Cost # Samples Timeline Sterility $1,850 3 3 Dry-Time Verification $750 1 wk Total $2,600 3 4 wks 4.7 Sterilization Packaging Packaging for sterilization by steam and EtO is available in the SPD of all V C H A sites. These are typically Wipak Medical Steriking products (Winpak Medical, Winnipeg, MB). These envelopes are usually made of a see-through plastic film and a layer of medical paper (Figure 5). Some see-through films are made from polypropylene and may therefore not be suitable for radiation sterilization. It is important to ensure that your sterilization packaging is suitable for your chosen sterilization method. Table 8 outlines the performance of various Wipak Table 8: Suitability of Packaging to various types of Sterilization. (source: http://www.wipak.com/medical/safety suitability.html) Description Special Properties Temperature Durability Steam E t O Radiation Hot Air Hydrogen Plasma Steriking See-through Pouches & Rolls; made of Polyester / Polypropylene film and Medical Paper Heat-sealable, porous, transparent, peelable 138°C/280°F YES YES NO NO OK* I P * -Figure 5: Packaging for sterilization. Envelopes usually consist of a sheet of medical paper and a plastic film (source: Wipak Medical Inc., www.wipak.com) products. 104 Steriking Tyvek See-through Pouches & Rolls; made of Polyester / Polyethylene fdm and White Tyvek Heat-sealable, porous, transparent, peelable 100°C/212°F NO YES YES NO YES Steriking Crepe Creping increases Papers; made of flexibility, special 134°C/273°F YES OK* YES NO NO medical pulp fibers clean pulp Creping & plastic Steriking Nonwoven fibers increase Sheets; made of pulp smoothness, 134°C/273°F YES OK* YES NO NO and plastic fibers special clean materials Steriking Hot A i r Rolls; tubing made of Polyamide Heat-resistant, transparent 200°C / 392°F NO NO YES YES NO Steriking Cover Bags; Heat-sealable, made of Polyester / transparent, 100°C/212°F NO NO YES NO NO Polypropylene film peelable Researchers should contact SPD in order to determine what products are available and contact Wipak directly to inquire about alternatives. 4.8 Routine Sterilization of the Device The final consideration one should make when deciding on a sterilization technique is the availability and cost of routine sterilization of the device. In a large urban centre such as Vancouver, we have accessible to us every possible modality. However, there remains a large 105 difference in price amongst the various techniques. Steam sterilization, which can be performed in the sterile processing department of any hospital, costs just pennies to operate. The only cost associated with this technique is the labour necessary to disassemble and reassemble the device pre and post sterilization. Ethylene oxide, which can also be accomplished by the SPD at major hospitals such as Vancouver General Hospital, costs approximately $150 per run, plus the cost of assembly/disassembly labour. Radiation sterilization is typically about $400 per run, but one run can accommodate multiple devices, depending on their size. Figure 6 shows a comparison of the cost of sterilization validation and routine sterilization of 5 devices. This figure illustrates a key trade off that must be considered in order to determine the optimum sterilization procedure for your device. $4,000 • Routine Cost/ 5 devices Steam EtO Radiation Radiation (NL) (local) Figure 5: Sterilization Costs. Sterilization validation costs (black) and the cost of routine sterilization of 5 devices (gray) differ significantly from one sterilization technique to another. 106 Appendix 5: Clinical Research Ethics Board Application: Protocol for DLIMN Trial Protocol for Evaluation of a Computer-Assisted Technique for Distal Locking of Femoral Intramedullary Nails Background Literature Review: Mid-bone fractures of long bones such as the femur and tibia are often repaired using intramedullary nails. The implant used is a hollow tube of 10-15 mm in diameter that is placed into the central canal of the bone. The implant is locked into place with screws that are drilled through the bone and implant at both the proximal and distal ends. Inserting the nail into the intramedullary canal often leads to unpredictable deformation of the implant. This makes it difficult for surgeons to identify the position of the distal locking holes. The conventional solution involves the use of a portable x-ray machine (fluoroscope) to visualize the holes. The surgeon must adjust the positioning of the fluoroscope until the holes appear as perfect circles. They must then place a radiolucent drill guide in the correct orientation and drill under x-ray guidance. This method has two major disadvantages: it is not time efficient and it exposes the surgical team to a significant amount of radiation. Distal locking of the implant accounts for over 23% (11 minutes) of the total surgical time and up to 53% of the total fluoroscopic screening time [Krettek 1999]. The accumulation of radiation exposure over the course of an orthopaedic surgeon's career is a rising concern and has received significant attention in the literature of late [Hafez 2005, Singer 2005, Madan 2002, Herscovici 2000]. A l l of these studies emphasize the need to minimize fluoroscopic time and to avoid being in the direct path of the x-ray beam. Hafez, in particular, has argued that previous studies have significantly underestimated the actual radiation exposure received at a surgeon's fingertips, especially for surgeons early in their training. Several alternative locking techniques have been developed in order to address these problems. These alternatives include nail mounted mechanical guides, self-locking nails, computer-assisted fluoroscope navigation and magnetic-based targeting systems. Unfortunately, none of these methods have come into widespread use. The first generation of nail-mounted mechanical guides was unsuccessful due to the difficulty of quantifying the deformation of the nail as it enters the intramedullary canal. A more recent mechanical guide requires the surgeon to drill a 6-10 mm working channel into the cortex of the bone near the pin hole locations so that the screw holes can be palpated and located directly using a guide-hook. [Krettek 1999] This method is unpopular due to the additional time required and the risks associated with drilling a working channel, which can cause stress concentrations which weaken the bone [Whatling 2005]. Self-locking nails have obvious advantages in decreasing both surgery time and radiation exposure. However, the two different types of self-locking nails proposed to date - self-engaging bolts and inflatable nails - have been heavily criticized for their lack of torsional stability. These implants are still in the prototype stage but researchers and surgeons have not expressed confidence that this solution will take off [Whatling 2005]. More recently, a technique known as virtual fluoroscopy has been developed in which two or more fluoroscopic images are acquired while the position of the patient is tracked, typically with an optical position measurement system. If the optical tracker also simultaneously measures the position of a surgical tool such as a drill, the current position of the drill can be displayed on the previously-acquired x-ray images without requiring additional exposures. This enables distal nail locking to be accomplished with as few as two single-shot x-ray exposures. On the positive 107 side, this method has succeeded in reducing both x-ray exposure time (7.3 vs 108 seconds) and the time necessary for distal locking (13.7 vs 19.9 minutes), but using the system generally requires more surgical time overall due to equipment setup (approximately 40 minutes) and tool registration processes [Suhm 2004]. Although there are over 500 hospitals worldwide currently using virtual fluoroscopy techniques for intramedullary nailing or other orthopaedic procedures, the relatively high equipment costs ($100,000-250,000) and the additional overall surgical time needed have limited their widespread use [Hazan 2003]. Very recently, a novel approach has been proposed which involves the use of a magnet and magnetic field sensor. This radiation-free technique relies on the fact that the implants used for tibial and femoral fracture contain a small open space within the centre of the nail. A permanent magnet on a probe is inserted into this space and is sensed by a magnetic sensor integrated into a drill-mounted guiding system. This system allows the drill to be aligned with the axis of the locking holes by sensing local changes in the magnetic field [Hollstien 2006]. A prototype system has recently been licensed to DePuy Products Inc. We believe that this concept is promising, but the use of a system based on this concept would be largely limited to this single procedure. It would therefore be difficult to promote to surgeons. In contrast, navigation equipment for a wide variety of computer-assisted orthopaedic procedures is becoming relatively common and its market share will likely continue to increase. We therefore propose to develop a radiation-free targeting process based on a more general-purpose measurement tool that can be used in a variety of surgical procedures. In order to determine the location and orientation of the holes for the Distal Locking of an Intramedullary Nail (DLIMN), we require a sensor which can be placed within the nail itself and be detected with sufficient accuracy by an instrument outside the bone. The recent development of 6 degree of freedom magnetic sensors for the Aurora Electromagnetic Tracking System (Northern Digital Inc, Waterloo, ON) makes this system a likely candidate for this intramedullary nail locking application. The 5 DOF version of the Aurora system is already commonly used in computer-assisted surgical procedures, which makes it a more flexible choice than a system developed solely for this procedure. Purpose of Study: We have developed a computer-assisted surgical technique for distal locking of an intramedullary nail (DLIMN) used for femur fracture fixation which is intended to decrease exposure to radiation by reducing the need for fluoroscopic imaging. It can also potentially reduce the overall time of the operation. In lab testing, we have demonstrated that the sensor has sufficient accuracy when inserted down the nail to make our proposed approach feasible. However, in order to move our technique towards clinical deployment, we need to determine whether it can reliably measure the hole locations under clinical conditions, so the primary purpose of the proposed study is to measure in live surgeries the relative positions of the hole axis as estimated by our system and the reference screw axis as found using the conventional fluoroscopic technique. This will also give us preliminary insight into clinical practice issues which may need to be addressed in our final design and into the length of time that might be required for our computer-assisted procedure relative to the conventional technique. Hypotheses: 1. The proposed CAS approach is sufficiently accurate to allow the surgeon to target the locking screws without using fluoroscopy. 2. The proposed CAS approach is efficient enough to decrease total surgical time. 108 Justification: The current fluoroscopic-based targeting method for D L I M N exposes the surgical team to radiation which, when accumulated over a working lifetime, may reach harmful levels. The method also requires a high level of skill to properly adjust the positioning of the fluoroscope and align the drill appropriately based on the two-dimensional images provided by the fluoroscope. Our CAS approach is intended to eliminate the use of radiation during the targeting phase of locking the distal end of the nail and to provide an intuitive 3D targeting display which may significantly shorten the learning curve and decrease the time needed to perform this procedure, thereby decreasing the time during which the patient is under anaesthetic and increasing the efficiency of the operating room. Objectives: The primary outcome of this study will be an estimate of how closely the drill axis found using the proposed CAS technique approximates the axis actually drilled by surgeon using the standard fluoroscopic technique. The times required to find the axis using the standard fluoroscopic technique and to insert the navigation instrument will also be recorded in order to determine the potential impact on surgical time. Research Design: Patients presenting at Vancouver General Hospital with diagnosed femoral shaft fractures will be invited to participate in this study. Consenting patients who meet the inclusion criteria will undergo standard Intramedullary (IM) Nailing of the femur. Our intent is to enroll approximately 10-15 patients at this stage as the purpose of this study is to obtain some pilot data which will allow us to better estimate the variances needed for computing the number of patients required in a future randomized control trial. This surgical procedure consists three stages: 1. Opening of the Intramedullary Canal 2. IM Nail Insertion 3. Stabilization of IM Nail Using Locking Screws The first two stages of this procedure will be unaffected by our study. The third stage of the procedure is comprised of two steps: distal and proximal nail locking. It is at this point in the procedure that small deviations from the standard protocol will take place. After the IM Nail has been inserted, we will introduce two sensors into the OR. The sensors used will be Aurora Electromagnetic sensors (Northern Digital Inc, Waterloo, ON). The electromagnetic field produced by this system is not harmful to patients or the surgical team. It has been used previously in several experimental surgical procedures designed to improve navigation in biopsy, angiography and radiotherapy. [Krucker 2006, Wood 2005, Kirchstein 2005] One sensor will be inserted into the hollow canal down the centre of the IM Nail. In order to protect the sensor and fix it into place within the nail, an Insertion Tool (IT) has been designed. The IT is a cylindrical tube made of A B S i (P500), a special grade of ABS plastic that is resistant to chemicals that medical devices often come into contact with. The distal end of the IT is designed to fit snuggly into the distal locking holes of the IM Nail. The IT will be pre-calibrated so that the location of the locking holes relative to the location of the sensor is known pre-surgery. The second sensor will be fixed to the drill used for distal drilling. Since there are a variety of drills available to complete this stage of the surgical procedure, intra-operative calibration is necessary. Once the sensor is in place, 30 seconds of data will be collected while the drill is moved in a prescribed way. This will allow us to accommodate the surgeon's choice of drills. Both the IT and sensors can be sterilized using a standard ethylene oxide gas sterilization protocol. 109 Current Protocol Experimental Protocol 1. OpenIM Canal 1. Open IM Canal - no changes 2. Reduce fracture / insert IM nail 2. Reduce fracture / insert IM nail - no changes 3. a. Distal Locking - align drill using fluoroscope - insert locking screw 3. a. Distal Locking -attach drill sensor and calibrate (2 min) -insert IT (1.5 min) - align drill using fluoroscope -collect data from both sensors (1 min) -remove IT (1 min) - insert locking screw -remove drill attachment (1 min) Total Extra Time = 7-8 minutes b. Proximal Locking b. Proximal Locking- no changes Once both of the sensors are in place, the surgeon will proceed with aligning the drill using the standard fluoroscopic protocol. Once the drill is in the correct position, data will be collected from both the IT and drill sensors. The IT will then be removed from the IM Nail and drilling will proceed in the standard manner. The sensor on the drill will then be removed and the remainder of the procedure will be unaffected. Lab-based testing has shown that inserting and removing the sensors and calibrating the drill will add less than 8 minutes to the overall surgical time. Risks: The only risk associated with this study is potential failure of the Insertion Tool (eg, separation of the sensor from the insertion tube or breaking off of the locking tips). The forces involved in IT insertion and removal are very small and make this a very unlikely event. If failure of the IT does take place, it will be contained within the small inner canal of the IM Nail where it poses no immediate risk. The IT will be removed prior to inserting any locking screws. When it is removed, it will be carefully inspected for any damage. If any portion of the IT is missing, the I M Nail can and will be removed from the patient and the missing piece located. The IM Nail will then be re-inserted into the patient. This entire process will take less than 10 minutes and will not adversely affect the patient. If any unforeseen complications occur during surgery, the sensors can be quickly removed and the trial can be abandoned. Since the actual nail locking is performed using the standard procedure, there is no risk associated with instrumentation errors. Statistical Analysis: Our primary goal is to measure the difference between the drill axes as measured by the new magnetic sensor and as actually drilled using the standard fluoroscopic technique. We will measure the absolute angular deviation between these two axes across at least 10 patients and will report the mean absolute angular deviation and the 95% CI for this estimate. 110 Our secondary goal is to estimate the amount of time needed to perform targeting using the CAS approach compared with the time needed for the conventional fluoroscopic approach. We propose to use a (non-parametric) ranked pairs Wilcoxon test to test for differences in the mean time needed. Anticipated Impact: This study will enable us to quantify differences between the drill axes as targeted by the conventional and proposed techniques. If the CAS technique reliably locates the target axis within a small range around the actual drill axis, we will be justified in moving forward with a randomized control trial in which surgeons actually use the CAS technique to target the distal locking screws. Measured differences in time needed to perform the targeting process (presuming that the CAS technique does take less time to perform) may also support further development of this technique. If the CAS technique ultimately proves successful, this intervention will be able to be performed with decreased radiation exposure to orthopaedic surgeons, healthcare workers, and patients and with improved utilization of scarce operating room resources through decreased operating time. References: Hafez M A et al. Radiation Exposure to the Hands of Orthopedic Surgeons: are we underestimating the risk? Arch Orthop Trauma Surg 2005; 125:330-335 Whatling G M , Nokes L D M . Literature Review of current Techniques for the insertion of distal screws into intramellary locking nails. Injury, Int. J. Care Inj. 2005; 1-11 Krettek C, Konemann B, Miclau T, Kobli R, Machreich T, Tscherne H. A Mechanical Distal Aiming Device for Distal Locking in Femoral Nails. Clin. Re. Rel. Res. 1999; 364:267-275 Suhm N , Messmer P, Zuna I, Jacob L, Regazzoni P. Fluoroscopic guidance versus surgical navigation for locking of intramedullary implants A prospective,controlled clinical study. Int. J. Care Injured 2004;35:567-574 Herscovici D et al. The effects, Risks, and Guidelines for Radiation Use in Orthopedic Surgery. Clin, Orthop. Rel. Res. 2000; 375: 126-132 Hollstien, DS. Method and Apparatus for Distal Targeting of Locking Nails in Intramedullary Nails 2006; U.S. Patent 7 029 478 B2 Hazan E, Joskowicz L. Computer-Assisted Image-Guided Intramedullary Nailing of Femoral Shaft Fractures. Tech. Orthop. 2003; 18(2) Slomczykowski M A , Hofstetter R, Sati M , Krettek C, Nolte LP. Novel Computer-Assisted Fluoroscopic System for Intraoperative Guidance: Feasibility Study for Distal Locking of Femoral Nails. J. Orthop. Trauma 2001; 15(2): 122-131 Krucker J., X u S., Viswanathan A. , Shen E., Glossop N . , Wood B. Clinical evaluation of electromagnetic tracking for biopsy and radiofrequency ablation guidance. Int J CARS 2006; 1:169-171. Wood B.J., Zhang H. , Durrani A. , Glossop N . , Ranjan S., Lindisch D., Levy E., Banovac F., Borgert J., Krueger S., Kruecker J., Viswanathan A. , Cleary K. Navigation with Electromagnetic Tracking for Interventional Radiology Procedures: A Feasibility Study. J Vase Interv Radiol 2005; 16:493-505 Kirchstein U . , Kronberg K. , Hein A. , Concept and Preliminary Experiments of Navigated Imaging with an Electromagnetic Position Measurement System, CURAC 2005; Berlin, September 22-24,2005 Singer G. Radiation Exposure to the Hands From Mini C-Arm Fluroscopy. J Hand Surg 2005; 30A: 795-797 111 Madan S., Blakeway C. Radiation Exposure to surgeon and patient in intramedullary nailing of the lower limb. Int J Care Injured 2002; 33:723-727 Blattert T.R., Fi l l U.A. , Kunz E., Panzer W., Weckbach A. , Regulla D. Skill Dependence of radiation exposure for the orthopaedic surgeon during interlocking nailing of lon-bone fractures: a clinical study. Arch Orthop Trauma Surg 2004; B124:659-664 112 Inclusion Criteria You are eligible to participate in this study if you satisfy each of the following conditions: • You are at Vancouver General Hospital with a femoral shaft fracture which surgeons feel will be best treated with a femoral nail • You are over 19 years of age • You are competent to give informed consent in English Exclusion Criteria You should not participate in this study if any of the following applies: • You are currently under 19 years of age • You are unable to give informed consent in English Study Procedures: A l l preparations and procedures for the operative treatment of your fracture will be the same whether you choose to participate or not. The only difference i f you choose to participate is that prior to inserting the locking screws, your surgeon will attach two position measurement devices to the surgical equipment. One will be attached to the drill and a second will be inserted into the hollow shaft of the nail. The surgeon will then prepare to insert the locking screws using the standard x-ray based method. Just before they insert the screws, we will measure where the nail and the drill are. We will then remove the measurement device inside the nail and will insert the screws in the usual manner. We will also remove the measurement device from the drill and the rest of the procedure will continue unaffected. The attachment, data collection and removal of the devices will add less than 8 minutes to the overall surgical time. The sensor is electromagnetic and is not harmful in any way. You will not be asked to complete any post-operative questionnaires or procedures outside of the standard care for your type of fracture. Reimbursement: You will not be paid for your participation. U B C , as a public institution, and the investigators may seek patent rights to the device being used in this study and may seek to commercialize it in future. Your participation in this study will not entitle you to any rights related to the device's commercialization, should it occur. Benefits: You will not benefit directly from the study. Regardless of whether or not you choose to participate, your fracture will be cared for by a surgeon using modern treatments and you will be followed by a team with a special interest in your type of fracture. Your participation may assist in the development of an improved surgical method that may be of value to future orthopaedic patients. Risks: The risks involved in this study are minimal. There is a very low chance that the tube or wire connected to the sensor will break while the sensor is still inside the nail. However, since the sensor is enclosed by the femoral nail, a break cannot cause any harm. The sensor will be removed before the nail is locked into place and will be inspected carefully for damage. If any portion is missing, the nail will be removed and the broken piece will be retrieved. The nail will then be re-inserted. 114 By signing below I consent to participate in this study. Subject Signature Date Printed Name of the Subject signing above. Witness Signature Date Printed Name of the Witness signing above. Principal Investigator / Delegated Representative Date Printed Name of the Principal Investigator or Delegated Representative signing above. Appendix 7: Clinical Research Ethics Board Application: Online Application Form H06-03500 Computer-Assisted DLIMN (Version 1.0) Principal Investigator: Antony J. Hodgson 1. Principal Investigator & Study Team - Human Ethics Application fView Forml 1.1. Principal Investigator Please select the Principal Investigator (PI) for the study. Once you hit Select, you can enter the Pi's name, or enter the first few letters of his or her name and hit Go. You can sort the returned list alphabetically by First name, Last name, or Organization by clicking the appropriate heading. Last First „ , c -i Department Email Name Name . . UBC/Applied Antonv Hodgson T • Science/Mechanical ahodgson@mech.ubc.ca Engineering 1.2. Primary Contact Provide the name of ONE primary contact person in addition to the PI who will receive ALL correspondence, certificates of approval and notifications from the REB for this study. This primary contact will have online access to read, amend, and track the application. Last First Institution/Department Rank Name Name T , , „ Research Johal Raman Coord/Nurse 1.3. Co-Investigators List all the Co-Investigators of the study. These members WILL have online access which will allow them to read, amend and track the application. These members will be listed on the certificate of approval (except BC Cancer Agency Research Ethics Board certificates). If this research application is for a graduate degree, enter the graduate student's name in this section. Last First Institution/Department Rank Name Name UBC/Applied Graduate Beadon Katherine Science/Mechanical Student Engineering G Pi rre UBC/Medicine, Faculty Assistant uy lerre 0f/Orthopaedics Professor O'Brien Peter J UBC/Medicine, Faculty Associate nen e er . 0f/Orthopaedics Professor 1.4. Additional Study Team Members - Online Access List the additional study team members who WILL have online access to read, amend, and track the application but WILL NOT be listed on the certificate of approval. Last Name First Name Institution/Department Rank 1.5. Additional Study Team Last First Institution/ Rank/Job Email 117 Members - No Online Access Click Add to list study team members who WILL NOT have online access to the application and will NOT be listed on the certificate of approval. Name Name Department Title Address 1.6.1. All Graduate Students: Yes 1.6.2. All Medical Residents: N / A (no medical residents participating in this study) Comments: 1.7. Project Title Enter the title of this research study as it will appear on the certificate. If applicable, include the protocol number in brackets at the end of the title. Evaluation of a Computer-Assisted Technique for Distal Locking of Femoral Intramedullary Nails (Protocol 2.0) 1.8. Project Nickname Enter a nickname for this study. What would you like this study to be known as to the Principal Investigator and study team? Computer-Assisted D L I M N NOTE, if this application was converted to RISe from our previous database, ORSIL, here is the previous ORSIL application number for your information. 2. Study Dates & Funding Information - Human Ethics Application [View Forml 2.1. A. Start date: March 1,2007 2.1. B. End date: March 1, 2008 2.2. Types of Funds Please select the applicable box(es) below to indicate the type(s) of funding you are receiving to conduct this research. You must then complete section 2.3 and/or 2.4 to enter the name of the source offunds to be listed on the certificate of approval. Other (Enter details below) Grant If you selected Other, specify the type of funding below. NSERC Industrial Postgraduate Scholarship 2.3. Research Funding Application/Award Associated with the Study Submitted to the UBC Office of Research Services Please click Add to identify the research funding U B C Number Title Sponsor 118 application/award associated with this study. Selecting Add will list the sources of all research funding applications that have been submitted by the PI (and the person completing this application if different from the PI). If the research funding application/award associated with this study is not listed below, please enter those details in question 2.4. 2.4. Research Funding Application/Award Associated with the Study not listed in question 2.3. Please click Add to enter the details for the research funding application/award associated with this study that is not listed in question 2.3. Title Sponsor . , , „ . r. Natural Sciences and Advanced Tools for . . , ^ . . . Engineering Research r „ . -. Computer-Assisted _ & ., r % , IDetailsl » , 0 Council of Canada Orthopaedic Surgery (NSERC) Natural Sciences and Industrial Postgraduate Engineering Research metailsl Scholarship Council of Canada (NSERC) 2.5. Conflict of Interest Do any of the following statements apply to the Principal Investigator, Co-Investigators and/or their partners/immediate family members? Receive personal benefits in connection with this study. For example, the researcher or study team being paid by the funder for each subject enrolled, or for consultancy. Have a non-financial relationship with the sponsor (such as unpaid consultant, advisor, board member or other non-financial interest). Have direct financial involvement with the sponsor (source of funds) via ownership of stock, stock options, or membership on a Board. Hold patent rights or intellectual property rights linked in any way yes 119 to this study or its sponsor (source of funds). 3. Conflict of Interest - Human Ethics Application [View Forml 3.1. In the box below, please answer the following questions, if applicable. Include the corresponding letter (A, B, C, D, E) before each answer. A. Describe any personal benefits that the investigators and/or their partners/immediate family members will receive, connected to this research study. B. State how much money (in Canadian dollars) the investigator or research group is paid by the funder for each subject enrolled. C. Explain what this amount covers with respect to the direct costs associated with doing this research. D. Explain if this amount covers any indirect costs associated with doing the [research, for example, providing \the funder with advice on study [design, conference expenses for {presenting results or any other [costs. E. Explain if investigators \and/or their partners/immediate family members have a non-financial relationship with the sponsor (such as unpaid consultant, advisor, board member or any other type of non-financial relationship or interest). A. Katherine Beadon has received an NSERC Industrial Postgraduate Scholarship in Partnership with Northern Digital Inc. (Waterloo, ON). This scholarship is made up of a $6000 contribution from Northern Digital and $15,000 from NSERC over the course of one year. B. No money paid for subjects enrolled. C. N / A D. N / A E. No relationship with funding agency (NSERC) or Northern Digital Inc. 3.2. In the last three years, how much money (in Canadian dollars) has each investigator (or any company owned or managed by each investigator) received from the funder and for what \purpose did they receive these funds? (e.g. consultancy) The PI has received an annual NSERC Discovery Grant, currently in the amount of $30,370 per year. In addition, he was the recipient of a Collaborative Health Research Projects grant (CHRP) in the amount of $137,000 over three years (2003-2006) and an Equipment Grant in the amount of $14,514 (2004). Katherine Beadon began receiving an NSERC Industrial Postgraduate Scholarship in the amount of $21,000 per year in September 2006. \3.3. Give details if any of the | investigators and/or their [partners/immediate family \members have direct financial no involvement 120 involvement with the sponsor (source of funds) via ownership of stock, stock options, or membership on a Board. 3.4. Give details if any of the investigators and/or their partners/immediate family members hold patent rights or intellectual property rights linked in anyway to this study or its sponsor (source of funds). Pending positive results of this study, the PI intends to submit a patent application for the computer-assisted technique whose feasibility is being examined. Any patent prosecution will be undertaken by the University Industrial Liaison Office. Northern Digital is not interested in pursuing patent rights; they are only interested in the potential marketing of their product that would arise from licensing the technology to Computer Assisted Surgery companies. 3.5. Are the UBC COI declarations for the Principal Investigator and Co-Investigators who are also UBC Faculty up to date? Yes, all COI declarations are current. Comments: 4. Study Review Type - Human Ethics Application [View Forml 4.1. UBC Research Ethics Board Indicate which UBC Research Ethics Board you are applying to and the type of study you are applying for: Clinical Research Ethics Board - Clinical 4.2. Institutions and Sites for Study A. Enter the locations for the institutions and sites where the research will be carried out under this Research Ethics Board approval (including specimens processed by pathology, special radiological procedures, specimens obtained in the operating room, or tissue requested from pathology). Click Add and enter the appropriate letter to see the locations for the institutions and sites where the research will be carried out under this Research Ethics Board approval: B for BC Cancer Agency Cfor Children's and Women's Health Centre of BC P for Providence Health Care Ufor UBC Campus Vfor Vancouver Coastal Health (VCHRI/VCHA). If you are NOT using any of these Institution Site Vancouver Coastal Health Vancouver General (VCHRI/VCHA) Hospital ! i 121 sites select N/A from the list. B. Please enter any other locations where the research will be conducted under this Research Ethics Approval (e.g. private physician's office, community centre, school, classroom, subject's home, in the field-provide details). 4.3. A. If this proposal is closely linked to any other proposal previously/simultaneously submitted, enter the Research Ethics Board number of that proposal. B. If applicable, please describe the relationship between this proposal and the previously/simultaneously submitted proposal listed above. 4.4. A. External peer review details: The overall proposal for developing advanced computer-assisted surgical tools and processes has been reviewed by NSERC, although the specific project proposed here was not envisioned at the time of application for the Pi's NSERC Discovery Grant. B. Internal (UBC or hospital) peer review details: Approval by supervisory committee (graduate student research). Most recent assessment occurred in January 25, 2006 committee meeting. Research protocol approved by Drs Antony Hodgson (Mechanical Engineering), Peter Cripton (Mechanical Engineering), Peter O'Brien (Orthopaedics) and Pierre Guy (Orthopaedics). 4.5. If this research proposal has NOT received any independent scientific/methodological peer review, explain why no review has taken place. 4.6. After reviewing the minimal risk criteria on the right, does your application fall under minimal risk (and therefore is eligible to be considered for Expedited Review)? no 5 Summary nf Study and Recruitment - Human Ethics Application [View Form] 5.1. Please summarize the research proposal. 1) Purpose We have developed a computer-assisted surgical technique for distal locking of an intramedullary nail (DLIMN) used for 122 femur fracture fixation which is intended to decrease exposure to radiation by reducing the need for fluoroscopic imaging. It can also potentially reduce the overall time of the operation. In lab testing, we have demonstrated that the sensor has sufficient accuracy when inserted down the nail to make our proposed approach feasible. However, in order to move our technique towards clinical deployment, we need to determine whether it can reliably measure the hole locations under clinical conditions, so the primary purpose of the proposed study is to measure in live surgeries the relative positions of the hole axis as estimated by our system and the reference screw axis as found using the conventional fluoroscopic technique. This will also give us preliminary insight into clinical practice issues which may need to be addressed in our final design and into the length of time that might be required for our computer-assisted procedure relative to the conventional technique. 2) Hypotheses a) The proposed CAS approach is sufficiently accurate to allow the surgeon to target the locking screws without using fluoroscopy. b) The proposed CAS approach is efficient enough to decrease total surgical time. 3) Justification jThe current fluoroscopic-based targeting method for DLIMN | exposes the surgical team to radiation which, when | accumulated over a working lifetime, may reach harmful levels. The method also requires a high level of skill to properly adjust the positioning of the fluoroscope and align the drill appropriately based on the two-dimensional images provided by the fluoroscope. Our CAS approach is intended to eliminate the use of radiation during the targeting phase of locking the distal end of the nail and to provide an intuitive 3D targeting display which may significantly shorten the learning curve and decrease the time needed to perform this procedure, thereby decreasing the time during which the patient is under anaesthetic and increasing the efficiency of the operating room. .4) Objectives The primary outcome of this study will be an estimate of how closely the drill axis found using the proposed CAS technique approximates the axis actually drilled by surgeon using the standard fluoroscopic technique. The times required to find the axis using the standard fluoroscopic technique and to 123 insert the navigation instrument will also be recorded in order | to determine the potential impact on surgical time. 5) Research Design Patients presenting at Vancouver General Hospital with diagnosed femoral shaft fractures will be invited to participate | in this study. Consenting patients who meet the inclusion criteria will undergo standard Intramedullary (IM) Nailing of | the femur. Our intent is to enroll approximately 10-15 patients at this stage as the purpose of this study is to obtain some pilot data which will allow us to better estimate the [variances needed for computing the number of patients required in a future randomized control trial. (This surgical procedure consists three stages: 11. Opening of the Intramedullary Canal j2. IM Nail Insertion 13. Stabilization of IM Nail Using Locking Screws The first two stages of this procedure will be unaffected by our study. The third stage of the procedure is comprised of |two steps: distal and proximal nail locking. It is at this point I in the procedure that small deviations from the standard [protocol will take place. After the IM Nail has been inserted, [we will introduce two sensors into the OR. The sensors used will be Aurora Electromagnetic sensors (Northern Digital Inc, Waterloo, ON). The electromagnetic field produced by this system is not harmful to patients or the surgical team. It has been used previously in several experimental surgical procedures designed to improve navigation in biopsy, ; angiography and radiotherapy. One sensor will be inserted into the hollow canal down the centre of the IM Nail. In order to protect the sensor and fix it into place within the nail, an Insertion Tool (IT) has been designed. The IT is a cylindrical tube made a special grade of I ABS plastic that is resistant to chemicals that medical devices often come into contact with. The distal end of the IT is designed to fit snuggly into the distal locking holes of the IM Nail. The second sensor will be fixed to the drill used for distal drilling. Once both of the sensors are in place, the surgeon will proceed with aligning the drill using the standard fluoroscopic protocol. Once the drill is in the correct position, data will be collected from both the IT and drill sensors. The IT will then be removed from the IM Nail and drilling will proceed in the standard manner. The sensor on the drill will then be removed [and the remainder of the procedure will continue unaffected. 124 Lab-based testing has shown that inserting and removing the sensors and calibrating the drill will add less than 8 minutes to the overall surgical time. Both the IT and sensors can be sterilized using a standard ethylene oxide gas sterilization protocol. 6) Statistical Analysis Our primary goal is to measure the difference between the drill axes as measured by the new magnetic sensor and as actually drilled using the standard fluoroscopic technique. We will measure the absolute angular deviation between these two axes across at least 10 patients and will report the mean absolute angular deviation and the 95% CI for this estimate. Our secondary goal is to estimate the amount of time needed to perform targeting using the CAS approach compared with the time needed for the conventional fluoroscopic approach. We propose to use a (non-parametric) ranked pairs Wilcoxon test to test for differences in the mean time needed. 5.2. Inclusion Criteria. Describe the subjects being selected for this study, and list the criteria for their inclusion. For research involving human pluripotent stem cells, provide a detailed description of the stem cells being used in the research. over 19 years old femoral fracture Competent to give Informed Consent in English \5.3. Exclusion Criteria. Describe •which subjects will be excluded from participation, and list the \criteriafor their exclusion. \5.4. Provide a detailed description of the method of Irecruitment. For example, \describe who will contact Iprospective subjects and by what means this will be done. Ensure [that any letters of initial contact [or other recruitment materials are attached to this submission on Page 9. Patients under 18 incompetent to consent 15.5. Describe how prospective \normal/control subjects will be [identified, contacted, and \recruited, if the method differs from the above. These fractures usually present to the emergency department where the Orthopaedic Trauma Service is called to examine the patient and determine appropriate treatment plans for the patient. Once preliminary tests, history and physical exams are completed the patient (if deemed to be eligible for participation) will be informed of the study and invited to participate by a designate of the surgeon or a member of the health care team within Orthopaedic Trauma. N A - No normals to be recruited 125 A l l femoral shaft fractures for planned IM nailing will receive standard clinical care regardless of their choice to participate in the study or not. The only difference if they choose to participate is that prior to inserting the locking screws, the surgeon will insert a sensor into the hollow shaft of the nail and a second sensor will be attached to the drill. The surgeon will then prepare to insert the locking screws using the standard fluoroscopic method. Just before the screws are inserted, data on the location of the sensor within the nail as well as the location of the drill will be collected. The sensor will then be removed and the screws will be inserted in the usual manner. 5.6. Summary of Procedures The difference between the drill axes as measured by the sensor within the nail and the actual drill axis using the fluoroscopic method will be determined. The time required to align the drill, time to insert the two sensors, and time to remove the sensors will be recorded to compare the operative efficiency of the two methods. The sensors are electromagnetic and are not harmful in any way. This system has been used in numerous experimental navigation techniques in operating rooms around the world. The sensors and sensor fixation devices can be sterilized using the standard gas sterilization protocol. 6. Subject Information and Consent Process - Human Ethics Application [View Forml 6.1. How much time will a subject be asked to dedicate to the project beyond that needed for normal care? 6.2. If applicable, how much time will a normal/control volunteer be asked to dedicate to the project? 6.3. Describe what is known about the risks (harms) of the {proposed research. The additional surgical time for insertion and removal of the navigation instrument will be less than 10 minutes. n/a The only risk associated with this study is potential failure of the Insertion Tool (eg, separation of the sensor from the insertion tube or breaking off of the locking tips). The forces involved in IT insertion and removal are very small and make this a very unlikely event. If failure of the IT does take place, it will be contained within the small inner canal of the IM Nail where it poses no immediate risk. The IT will be removed prior to inserting any locking screws. 126 When it is removed, it will be carefully inspected for any damage. If any portion of the IT is missing, the IM Nail can and will be removed from the patient and the missing piece located. The IM Nail will then be re-inserted into the patient. This entire process will take less than 10 minutes and will not adversely affect the patient. If any unforeseen complications occur during surgery, the sensors can be quickly removed and the trial can be abandoned. Since the actual nail locking is performed using the standard procedure without reference to the system being evaluated, there is no risk associated with instrumentation errors. 6.4. Describe any potential benefits to the subject that could arise from his or her participation in the proposed research. Patients participating in this study will have the satisfaction of contributing to an improved surgical technique. 6.5. Describe any reimbursement for expenses (e.g. meals, parking, medications) or payments/gifts-in-kind (e.g. honoraria, gifts, prizes, credits) to be offered to the subjects. Provide full details of the amounts, payment schedules, and value of gifts-in-kind. No reimbursements will be provided. 16.6. Specify who will explain the • consent form and invite the subject to participate. Include details of where the consent will be obtained, and under what circumstances. i i Consent will be obtained by either (a) the surgeon or (b) surgeon's designate or (c) the Orthopaedic Trauma research assistant. These kinds of injuries present to the Emergency Room where the Orthopaedic Trauma Service is responsible for assessing injuries and providing for appropriate treatment. This type of fracture requires 'Emergent' surgery and therefore necessitates the patient being informed of the study after assessment and prior to surgery. c I | 16.7. How long after receiving the j consent form will the subject have \to decide whether or not to \participate? If this will be less \than twenty-four hours, provide an explanation. As stated in 6.6 the time between assessment and surgery is often less than 24 hours but, the time is also difficult to estimate due to wait times and available operative resources. It can therefore be approximated that anywhere from 2 to 8 hours could be the time available for the potential subject to consider participating or not in the study. 127 6.8. Will every subject be competent to give fully informed consent on his/her own behalf? Please click Select to complete the question and view further details. Will T , . If not, every , sub"ect be J . Details of the will competent to give fully informed consent? Yes If not, will he/she be nature of the consent able to give incompetence on assent to his/her participate? behalf? If Yes, explain how assent will be sought. rDetailsl 6.9. Describe any situation in which the renewal of consent for this research might be appropriate, and how this would take place. N /A 6.10. What provisions are planned for subjects, or those consenting on a subject's behalf, to have special assistance, if needed, during the consent process (e.g. consent forms in Braille, or in languages other than English). No provisions have been planned - all subjects must be capable of consenting on their own behalf. 6.11. Describe any restrictions regarding the disclosure of information to research subjects (during or at the end of the study) that the sponsor has placed on investigators, including those related to the publication of results. none 7. Number of Subjects and Drugs - Human Ethics Application For Clinical Study [View Forml \7.1. Is this a multi-centre study [(involves centres outside of those [appliedfor under this Approval?) no 7.2. A. How many subjects (including controls) will be enrolled in the entire study? 15 \B. How many subjects (including controls) will be enrolled at institutions covered by this Research Ethics Approval? Of these, how many are controls? 7.3. Enter the name of any 15 0 N A - no investigational drugs are involved in this study 128 Igeneric drug(s), investigational lor marketed, used outside of its I approved indication. 7.4. Enter the name of any marketed drug(s) used within its approved indication. 7.5. Enter the name of any Natural Health Products used: |NA - drugs outside of standard of care are not included in the | study. None 7.6. Enter the name of any new investigational devices, or marketed devices used in experimental mode, that will be used outside of their approved indication. N / A No devices are being used outside their approved indication. 7.7. Enter the name of any positron-emitting radiopharmaceuticals (PERs). N A - None 7.8. A. Name the sponsor/institution/investigator responsible for filing a Clinical Trial Application (CTA) or Investigational Testing Authorization (ITA) with Health Canada or Other. N / A B. For clinical trials involving investigational drugs/devices or marketed drugs/devices outside of their approved indications (including natural health products and PERs), indicate whether or not approval has been obtained from the appropriate federal regulatory agency for this purpose. Not Applicable \C. If approval has been obtained lor a request for approval is in [progress, click Add to enter the name of the regulatory agency and the date of approval (if received). Name of Agency Date of Approval 7.9. Click Add to enter the Health Canada No Objection Letter (NOL) control number and date of approval if available for the initial application and subsequent NOLs for amendments. A copy of Health Canada N O L Control Number Date of Approval 129 the NOL from Health Canada must also be attached in question 9.1 when it becomes available. 7.10. Does this research fall within the categories of pluripotent stem cell research that need to be submitted to the CIHR Stem Cell Oversight Committee (SCOC)? no 7.11. Registration for Publication of Clinical Trials A. Does this clinical study fall within the definition stated on the right (in the guidelines)? no B. If Yes, click Add to enter the following information. Has it been l ™ ^ ^ r. • * E n t e r Yom Clinical .„ Authorized Registry . , . . , .... registered? , Trial unique identifier: " used: 7.12. Is there a requirement for this research to comply with United States regulations for research ethics? no 8. Data Monitoring- Human Ethics Application For Clinical Study [View Forml 8.1. Describe the provisions made to break the code of a double-blind study in an emergency situation, and indicate who has the code. None as the subject and surgeon will not be blinded. 8.2. Describe data monitoring procedures while research is ongoing. Include details of planned interim analyses, Data and Safety Monitoring Board, or other monitoring systems. N / A 8.3. Describe the circumstances under which the study could be stopped early. Should this occur, describe what provisions would be put in place to ensure that the subjects are fully informed of the reasons for stopping the study. N / A 8.4. Describe how the identity of the subjects will be protected both during and after the research study. Subjects will be assigned a unique study number which is not related to any identifying numbers. These study ids will be kept in a flat file not linked to any system containing identifiers. A l l identifying data is maintained on a password protected PC accessible only to the PI and Research Staff. 130 Correlated data will not contain identifiers. 8.5. Explain who will have access to the data at each stage of processing and analysis, and what steps will be taken to safeguard the confidentiality of the data at each stage. The PI, Research Staff will have access to identifying data but the identifying data will not be available to anyone else. A l l analysis will be done on grouped non-identified data. A l l hardcopies of data are kept in a locked cabinet in a locked office. Electronic data is kept on a password protected PC in a locked office. 8.6. Describe what will happen to the data at the end of the study, and what plans there are for future use of the data. The data may be submitted for publication to scholarly journals and may be presented at established educational rounds and used for educational purposes. The data will be maintained for 5 years. 9. Documentation - Human Ethics Application TView Forml 9.1. Protocol Please view the examples on the right, then click Add to enter the required information and attach the documents. Name Version Date Protocol: Computer-Assisted . „ January 25, r \ ^ „ , i D L I M N 1 0 2007 Protocol: Computer-Assisted - „ February 27, r , r , D L I M N 2 - ° 2007 9.2. Consent Forms Please view the examples on the right, then click Add to enter the required information and attach the forms. Name Version Date Consent Form: Computer- ~ ft March 28, rviewl Assisted D L I M N 2007 L ^ ~ i CF: Computer-Assisted 1 n January 23, r y . . D L I M N U 2007 9.3. Assent Forms Please view the examples on the right, then click Add to enter the required information and attach the forms. Name Version Date 9.4. Investigator Brochures/Product Monographs (Clinical applications only) Please click Add to enter the required information and attach the documents. Name Version Date 9.5. Advertisement to recruit subjects Please view the examples on the right, then click Add to enter the required information and attach the documents. Name Version Date 9.6. Questionnaire, questionnaire cover letter, tests, interview Name Version Date 131 scripts, etc. Please click Add to enter the required information and attach the documents. 9.7. Letter of initial contact Please click Add to enter the required information and attach the forms. Name Version Date 9.8. A. Other documents: Please view the examples on the right, then click Add to enter the required information and attach the documents. Name Version Date B. If a Web site is part of this study, enter the URL below. Since URL's may change over time or become non-existent, you must also attach a copy of the documentation contained on the web site to one of the sections above or provide an explanation. 10. Fee for Service - Human Ethics Application for Clinical Study [View Form] Please indicate which of the following methods of payment will be used for this application. Enter information stating when the fee will be sent: 11. Hospital Information - Human Ethics Application for Vancouver Coastal Health [View Forml 11.1 Have you already received approval from VCHA to conduct this study? no If Yes, please provide the VCHA/VCHRI approval number (e.g. V06-0000) 11.2. A. Does the Principal Investigator in question 1.1 have a medical appointment with VCHRI/VCHA and a UBC faculty appointment? no 11.2.B. Does the Principal \lnvestigator in question 1.1 have a medical appointment with VCHRI/VCHA (but not a faculty appointment at UBC), or is the Principal Investigator an no 132 employee of VCHA? Select the Browse button to attach the declaration form. 11.2. C. Does the Principal Investigator in question 1.1 have a UBC appointment? yes Select the Site Investigator at VCHA if different from the Principal Investigator in question 1.1. lastName firstName Guy Pierre 11.3. Select the VCHA Health Service Delivery Area(s) that will be involved in this study. Vancouver Acute (Vancouver Acute encompasses the following sites: Vancouver General Hospital, U B C Hospital, GF Strong Rehabilitation Centre, Arthritis Research Centre of Canada, Mary Pack Arthritis Centre) \ 12. Save Application - Human Ethics Application [View Forml 133 Appendix 8: Approval to Conduct Research at Vancouver Coastal Health .Vancouver C6astalHea.ltH' Research Institute A P P R O V A L T O C O N D U C T R E S E A R C H A T V A N C O U V E R C O A S T A L H E A L T H A U T H O R I T Y (VCHA) All research studies and clinical trials involving human subjects {"Research Projects") that involve the use of VCHA services, facilities, records, staff or patients must receive approval from the Vancouver Coastal Health Research Institute ("VCHRI") office in the relevant Health Sen-ice Delivery Area ("HSDA") aad must be approved by a University of British Columbia ("UBC") research ethics board ("REB"). There are four VCHA HSDAs: Vancouver Acute. Vancouver Community, Richmond Health Services, and Coastal. If a Research Project will be conducted within more than one VCHA HSDA, the researcher must obtain approval from the VCHRI office in each of the relevant HSDAs (contact information for each VCHRI research office is listed at the end of this document). Once approval to conduct research has been granted by the applicable VCHRI office, the Research Project may begin at that site. The approval process ensures that all research involving humans conducted at VCHA is reviewed from an ethical, safety and resource use framework. DEFINITION OF RESEARCH A Research Project, regardless of how it is funded, will be considered under the terms of VCHA and UBC policy as being research invoking human subjects if: • A human is subjected to procedures, the purpose of which go beyond the subject's need for prophylaxis, diagnosis or therapy; or • A human is subjected to procedures which are experimental but which do not necessarily go beyond the subject's need for prophylaxis, diagnosis, or therapy: or • Procedures are used in which an invasion of privacy may be involved, for example, by examination of records, by interviews, by observations, by administration of a questionnaire or test, or by audio or video recording:or • Human tissue, biological fluids, embryos or fetuses are being studied; or Projects condt«:ted for quality assurance, continuous quality improvement, or program evaluation ma)! be excluded from the above definition of research: however, individuals are encouraged to consult with a UBC REB if they are unsure as to whether their proj ect constitutes quality improvement, program evaluation or research. Irrespective of the purpose of the Research Project, no work can be published without having received UBC REB approval before commencing the Research Project. Publication includes any V«r.:o-aDs!*. i8 May 2007 dissemination of results, by any mechanism (conference poster or presentation, web site, journal paper) outside of VCHA. SUBMISSION CRITERIA TO CONDUCT RESEARCH A T VCHA Research Projects (meeting the above definition), which meet any one of the following criteria, must be submitted to VCHRI for review and approval: 1. Research Projects that are conducted at any VCHA HSDA: 2. Research Projects where VCHA patieuts/clients/residents/staff are participants in the Research Project; 3. Research Projects where VCHA medical staff or VCHA employees participate in the conduct of the Research Project (Note: hi this case, criteria kl and/or criteria U2 must also apply). OBTAINING APPROVAL TO CONDUCT RESEARCH AT VCHA Three processes must occur before research is approved and may begin at VCHA: 1. Submission to a UBC REB for review and approval; 2. Submission to the VCHRI office of the relevant HSDA(s) for review and approval (forms and guidelines for the research approval process at each HSDA are located at httn://www.vclul.ca/s/ClltticalTilals-Foims.aso; and 3. Execution of the study contract/agreement (if applicable). Submission for VCHRI research review, the UBC REB review and for study contract/agreement review may be initiated in parallel. The study contract/agreement, if applicable, must be signed by the principal investigator. VCHA and UBC. Final authorization for research to begin will be given by the appropriate /VCHRI HSDA when the above three processes are satisfactorily completed. Version Date: 18 May 2007 Applications for approval to couduct research at VCHA should be directed to die VCHRI office of the relevant HSDA: HSDA Address! For Information or Assistance; Contact Information: Coastal (Coastal eucompasses hospitals, community health centres and residential care facilities in the following sites: North Vancouver, West Vancouver, Garibaldi. Sunshine Coast, Bella Bella, and Bella Coola) Lions Gate Hospital c/o Employee Engagement 231 East 15* Street* North Vancouver. BC V7L 2L7 Dr. Cynthia Hamilton Assistant Director, VCHRI (Coastal) Tel: (604)988-3131 Ext 4703 Email: . cvutliin.hnmlltonffivch.ca Richmond Health Services (Richmond Health Services encompasses the following networks: Richmond acute care, community care, primary health care, mental health and addiction sites.) Quality Initiatives Room 3004 7000 Westminster Highway Rielwiond, BC V 6 X 1A2 Ms. Marion Wardley Administrative Assistant Quality Initiatives Tel: (604) 244-5209 Email: marion.wnrdleviiBvch.cn Dr. Ingrid Sochting Assistant Director. VCHRI (Riclunond Health Services) Tel: (604) 278-97 H L o c : 4610 Email: inaiid.sochtinafftivch.cn Vancouver Acute (Vancouver Acute encompasses the following sites: Vancouver General Hospital (including Mary Pack Arthritis Centre), G.F. Strong Rehabilitation Centre, and U B C Hospital) Vancouver Coastal Health Research Institute Room 163 - 2647 Willow Street Vancouver. B C VSZ 3P1 Ms.WyloKayle Administrative Assistant, Cluneal Trials Administration Tel: (604) 875-4111 Loc: 68368 Email: wvlo.kavleti8vcu.ca Ms. Stephania Manusha Regional Manager. Clinical Trials Aduumstvation Tel: (604) 875-5649 Email: stenhanin.inanushaffivch.ca Vancouver Community (Vancouver Community encompasses community health centres, mental health centres, additional sites and residential care facilities in Vancouver) #200-520 West 6 t h Avenue Vancouver. B C VSZ 4H5 Ms. Nena Pineda Admuiistrative Assistant Vancouver Community Tel: (604)714-3787 Email: nena.piuednffivch.cn Ms. Val Munroe Assistant Director, VCHRI (Vancouver Community) Tel: (604) 730-7610 Email: vnl.munroe^Hxb.ca Version Dae: IS May 2007 GUIDANCE NOTE #6: INTERNAL MAILING INSTRUCTIONS/ADDRESS Include the mailing address where all correspondence regarding the Vancouver Acute research study submission should be sent. GUIDANCE NOTE #7: TYPE OF FUNDING SOURCE Include the type of funding the Principal Investigator has received to conduct the research study. GUIDANCE NOTE #8: NAME OF FUNDING SOURCE Include the name of the funding source(s). GUIDANCE NOTE #9: TYPE OF STUDY Indicate the type of research study. GUIDANCE NOTE #10: VANCOUVER ACUTE SERVICES OR RESOURCES REQUIRED FOR THE RESEARCH STUDY If a research study impacts on Vancouver Acute services or resources, the appropriate department or clinical unit approval must be obtained. The departments and clinical units require information about the resources that are required (i.e., clinic staff nursing time, clinic space, access to clinic patients for recruitment, lab technician time). It is the responsibility of the departments and clinical units to determine if those services will have sufficient impact as to require recovery from the research study budget to offset Vancouver Acute operating costs. It is the responsibility of the departments and clinical units to provide investigators with the cost of those services. The department's or clinical unit's signature indicates a willingness to participate and support the research study. In this section, the Principal Investigator must indicate which departments or clinical units the research study will impact. Enter the name of the clinic or ward that will be impacted on the form. PHARMACY The Pharmacy Department must review all research protocols that involve drugs (this includes both investigational drugs and drugs that have been approved for market). Study protocols are reviewed for: • The level of Pharmacy involvement needed and the implications for pharmacy operations. Pharmacy involvement is necessary for all studies that involve administration of study drugs to patients within the hospital. 139 • The appropriateness of the comparator treatment. Is the study drug being compared to the "standard of care" at our institution? Are any "extra" drugs needed to comply with the protocol that Pharmacy normally would not use, and if so, are they appropriate and will the sponsor supply them? • Determine if pre-printed Dr's orders, computerized order entry, medication administration need records and drug information sheets (for patients and/or staff) are needed. • Assess randomization and blinding procedures for potential problems and degree of pharmacy involvement. • Ensures facilities are available to store study drug as directed by the Protocol (i.e. monitored fridge or locked cupboard). • Ensure the study sponsor will cover any costs incurred for the study. • Ensure study medications intended for outpatient use are labeled appropriately and meet regulatory requirements. The pharmacy department requires the following documentation for review: • Cover letter; • A copy o f the research study protocol; and • A copy of the "Request for Approval to Conduct Research at Vancouver Acute" form. Once the above-listed documents have been received, reviewed and the "Request for Approval to Conduct Research at Vancouver Acute" form has been signed, the Pharmacy Department will contact the person listed on the cover letter to pick-up the signed form. RADIOLOGY If a research study involves the services or resources of the Radiology Department, the following documentation must be submitted to the Radiology Department for review: • Cover Letter (Include the number of research subjects that will be enrolled, the length of the research study, the services/resources that are being requested); • Copy o f the study protocol; • "Request for Approval to Conduct Research at Vancouver Acute" form. V G H : The above documentation should be sent to the attention of Christina Romero at G940 Ground th Floor, 899 West 12 Avenue. Please note that effective March 1, 2007, the Radiology Department at V G H will be charging a $100 fee for the review of all industry sponsored clinical trials. This review fee will not be charged on grant-funded studies. UBCH: The above documentation should be sent to the attention of the MRI supervisors, Karen Smith or Leslie Costley, MRI Supervisor. Please note that if a research study involves the use of PACS, the Radiology Department must sign the "Request for Approval to Conduct Research at Vancouver Acute" form. If the Principal Investigator already has access to PACS for clinical purposes, a signature from the Radiology Department must be obtained to access PACS for research purposes. 140 C L I N I C A L L A B O R A T O R Y If a research study involves the services or resources of the Clinical Laboratory, the following documentation must be submitted to the Clinical Laboratory Department for review: • Cover Letter (include the number of subjects and tests that are applicable to research); • Copy of the study protocol; • "Request for Approval to Conduct Research at Vancouver Acute" form. The above documentation should be sent to the attention of Romy Chan, Technical Support Coordinator, Laboratory Administration. O P E R A T I N G R O O M (OR) All research studies that take place in the Operating Room and/or impact the resources of the Operating Room must be reviewed and approved by the Operating Room prior to the start of the research study. The Principal Investigator must submit the following documentation to Ms. Debbie Hendricks, Manager, Equipment and Supplies, OR, or to Ms. Lorraine Ensminger, the Operating Room Patient Service Manager (PSM) at the Operating Room Administration Office, JPP North, Room 2304-2, for review: • Copy of the study protocol; • "Request for Approval to Conduct Research at Vancouver Acute" form; • "OR Research Form"; and • "Specimen Collection for Research - Special Handling Instructions" form (applicable only to studies involving the collection of tissue). The Operating Room will review the above documentation for all research studies that involve the OR, regardless if the procedure is considered standard of care. If it is determined that the Operating Room will be impacted by the research study, the Manager, Equipment and Supplies, Operating Room, or the Operating Room PSM will advise the Principal Investigator if any additional documentation is required. The Operating Room will sign the "Request for Approval to Conduct Research at Vancouver Acute" form once all Operating Room requirements have been met. If it is determined that the Operating Room will not be impacted by the research study, the Manager, Equipment and Supplies, Operating Room, or the -Operating Room PSM will state on the "Request for Approval to Conduct Research at Vancouver Acute" form that there is "no involvement of the Operating Room". For further details, please refer to "Guidelines For the Review and Approval of a Research Study Impacting V C H Operating Rooms" posted on the VCHRI website. If tissue specimens will be collected for research purposes during a surgical procedure in a Vancouver Acute Operating Room, Anatomical Pathology and the Operating Room must review and approve the study. Please see the "Guidelines For the Review and Approval of a Research Study Impacting V C H Operating Rooms" posted on the VCHRI website for more specific details on required forms and procedures. If blood specimens will be collected for research purposes during a surgical procedure in a Vancouver Acute Operating Room, Anesthesia must review and approve the study. Please submit the "Request for Approval to Conduct Research at Vancouver Acute" form along with a cover sheet outlining the requirements of the Anesthesiologist and submit this documentation to 2449 JPP2N, 910 West 10th Ave, c/o Dr. Raymer Grant for review and approval. A N A T O M I C A L P A T H O L O G Y If a research study involves the services or resources of Anatomical Pathology, the following documentation must be submitted to the Anatomical Pathology Department for review: • "Request for Approval to Conduct Research at Vancouver Acute" form; • "Anatomic Pathology Laboratory Resource Utilization" form; • The Study Protocol; and • "Specimen Collection for Research - Special Handling Instructions" form (studies involving the collection of tissue). Documentation should be submitted to Anatomical Pathology, c/o John Garratt, Technical Supervisor, Anatomical Pathology. Please note that if V C H Anatomical Pathology will process tissue specimens collected at V C H , the V C H Pathologist who will be responsible for processing the tissue specimens must be named as a co-investigator on the research study (on the "Request for Approval to Conduct Research at Vancouver Acute" form and on the UBC ethics certificate). G U I D A N C E N O T E #11: A P P R O V A L SIGNATURES R E Q U I R E D If the research study involves the resources or services of departments or clinical units located at Vancouver General Hospital or Mary Pack Arthritis Centre, print the name of the individual signing on behalf of the department or clinical unit under the "VGH Site - Name of Signatory" Column. If the research study involves the resources or services of departments or clinical units located at UBC Hospital, print the name of the individual signing on behalf of the department or clinical unit under the "UBC Hospital Site - Name of Signatory" Column. If the research study involves the resources or services of departments or clinical units located at GF Strong Rehabilitation Centre, please use the "Request for Approval to Conduct Research at GF Strong" form located on the VCHRI website. Obtain the signatures of the appropriate department head, patient service managers or other managers whose department or clinical unit may be impacted by the research study or whose services the Principal Investigator wishes to utilize. G U I D A N C E N O T E #12: D E P A R T M E N T C O S T ANALYSIS Indicate if a department cost analysis is required for any departments or clinical units the research study may impact. G U I D A N C E N O T E #13: D E P A R T M E N T H E A D A T V A N C O V U E R A C U T E , IF D I F F E R E N T F R O M U B C E T H I C S 142 Obtain the signature of the Principal Investigator/Site Investigator's V C H Department Head if that person is different from the person who has approved the UBC ethics application. Please print the name of the individual who is signing the form. The signature of the Principal Investigator's/Site Investigator's V C H Academic Department, School or Program Head indicates that the Principal Investigator/Site Investigator at V C H has the qualifications experience, and facilities to carry out the research study. If the Principal Investigator is a Department Head, the person who the Principal Investigator reports to, must sign the form. G U I D A N C E N O T E #14: DIVISION H E A D S I G N A T U R E Obtain the signature of the Division Head of the Principal Investigator /Site Investigator at V C H . Please print the name of the individual who is signing the form. If the Principal Investigator does not have a Division Head (i.e. research nurse, patient service manager, respiratory therapist, director etc.), a signature is not required. G U I D A N C E N O T E #15: S U P E R V I S O R / M A N A G E R S I G N A T U R E If the Principal Investigator is a V C H employee (research nurse, patient service manager, respiratory therapist, director etc.,) the Principal Investigator must obtain his or her supervisor's or manager's signature. Please print the name of the individual who is signing the form. G U I D A N C E N O T E #16: PRINCIPAL I N V E S T I G A T O R S I G N A T U R E Obtain the signature of the Principal Investigator/Site Investigator at V C H . G U I D A N C E N O T E #17: STUDY P E R S O N N E L a) Indicate the Principal Investigator's affiliation with V C H . Please select only one category. b) Indicate if there are research personnel involved with the conduct of the research study that are not affiliated with V C H . G U I D A N C E N O T E #18: P E R S O N A L H E A L T H I N F O R M A T I O N "Personal information" is defined in The Freedom of Information and Protection of Privacy Act (British Columbia) as any recorded information about an identifiable individual (excluding business contact information). Personal information can be recorded in any format including books, documents, maps, drawings, photographs, letters, vouchers, papers, and any other thing on which information is recorded or stored by graphic, electronic, mechanical or other means. Personal information includes information that can be linked back to or can identify a specific individual through association or inference. For example, generic information about an individual (e.g., ethnic origin) could be linked to one or more individuals if they lived in a small town with a limited number of people with that ethnic background. Examples of personal information include but are not limited to: 143 Appendix 10: Radiation Stability of Polymer Materials (source Hemmerich 2000) Material Radiation Stabil i ty Comments Polystyrene Excellent Polyethylene-various densities Good/Excellent High density grades not as stable as low or medium density grades Polyamides (nylon) Good nylons 10,11,12,6.6 are more stable than 6. Film and fiber are less resistant Polyimides Excellent Polysulfone Excellent Natural material is yellow Polyphenylene sulfide Excellent Polyvinyl chloride (PVC) Good Yellows, antioxidants and stabilizers prevent yellowing. High molecular weight organetin stabilizers improve stability; color-corrected radiation formulations are available Polyvinyl chloride/Polyvinyl acetate Good Less resistant than PVC Polyvinylidene dichloride (Saran) Good Less resistant than PVC Styrene/acylonitrile (SAN) Good/Excellent Polycarbonate Good/Excellent Yellows. Mechanical properties not greatly affected: color corrected formulations are avialable Polypropene natural Polypropelyne Stabilized Poor/Fair Physical properties greatly reduced when irradiated. Radiation-stabilized grades utilizing high molecular weights and copolymerized and alloyed with polyethylene should be used in most radiation applications. High-dose rate E-beam processing may reduce oxidative degredation. Fluoropolymers: Polytetrafluoroethylene (PTFE) Poor Perfluoro alkoxy (PFA) Poor Polychlorotrifluoroethylene (PCTFE) Good/Excellent Polyvinyl floride (PVF) Good/Excellent Polyvinylidene fluoride(PVDF) Good/Excellent Ethylene-tetrafluoroethylene (ETFE) Good Fluorinated ethylene propylene (FEP) Fair Celluloses: Esters Fair Cellulose acetate proprionate Fair Cellulose acetate butyrate Fair/Good Cellulose paper, cardboard Fair/Good Polyacetals Poor Irridation causes embrittlement. Color changes have been noted (yellow to green) ABS Good High-impact grades are not as radiation resistant as standard impact grades Acrylics (PMMA) Fair/Good Polyurethane Good/Excellent Aromatic discolors. Polyesters more stable than esters. Retains physical properties. Liquid Crystal Polymer (LCP) Excellent Commercial LCP excellent. Natural LCP not stable. 148 Polyesters Good/Excellent PBT not as radiation stable as PET Thermosets: Phenolics Excellent Includes the addition of mineral fibers Epoxies Excellent All curing systems. Polyesters Excellent Includes the addition of mineral or glass fibers Allyl diglycol carbonate (polyester) Excellent Maintains excellent optical properties after irradiation Polyurethanes: Aliphatic Excellent Darkening can occur. Possible breakdown products could be derived. Aromatic Good/Excellent Elastomers: Urethane Excellent EPDM Excellent Natural Rubber Good/Excellent Nitrile Good/Excellent Discolors Polychloroprene (neoprene) Good Discolors. The addition of aromatic plasticizers renders the material more stable to irradiation Silicone Good Phenyl-methyl silicones are more stable than are methyl silicones. Platinum cure is superior to peroside cure. Full cure during manufacture can eliminate most post-irradiation effects. Styrene-butadiene Good Polyacrylic Poor Chlorosulfonated polythylene Poor Butyl Poor Friable, sheds particulate. 149 Appendix 11: Aurora Approvals and Classifications Approvals and Classifications 10 Approvals and Classifications 10.1 Electrical Safety Approvals Table 10-1 Electrical Safety Approvals Standard Title UL 60601-1, First Edition (2003) Medical Electrical Equipment, Part 1: General requirements for safety CAN/CSA C22.2 No. 601.1 - M 9 0 Medical Electrical Equipment. Part 1: General Requirements For (R2001) Safety CAN/CSA C22.2 No. 601.1.S1-94 Supplement No. 1-94 to CAN/CSA C22.2 No. 601.1 - M90 (R1999) CAN/CSA C22.2 No. 601.1B-90 Amendment 2 to CAN/CSA C22.2 No. 601.1 - M90 (R2002) IEC 606'0l-l:1988+Al:1991+A2:1995 Medical Electrical Equipment. Part 1: General Requirements for safety w/ amendments 10.2 EMC/EMI Approvals Table 10-2 EMC/EMI Approvals Standard Title FCC CFR47, Part 15, Subpart B Class B Unintentional Radiators CISPR.il/EN55011 Class B, Industrial, Scientific and Medical Equipment EN6060l-l-2:2001 (2nd. Edition) Medical Electrical Equipment. Part 1: General requirements for safety - Collateral standard: Electromagnetic Compatibility -Requirements and tests Appendix 12: Cleaning and Sterilization Protocol for MIS Study UBC HOSPITAL REFERENCE NO. P A G E : P I C T U R E SAYRA - MIS STUDY' XAHSLE 8393-OOC: SHEATH - 8393-913 INSERT - 8393-281 UBC HOSPITAL REFERENCE SO. t>A08i 1 Of 2 SAYXA - MIS STUDY DEPARTMENT: STERILE PROCESSING LAST REVISION. JAN 2007 DISTRI B'JTI Hi: ASSEMBLY/DSCONTAM REVIEWED BY 1 MASTER A P P R O V E D BYJ DISASSEMBLE! h o l d fo roep A 3 flhown t u r n k n u r l e d l o c k i n g c o l l a r In d i r e c t i o n o f a r r o w a n d pi: I 1 o f f s h e a t h h o l d i n g s h e a t h f i r m l y , t u r n t h e jaw i n s e r t and r«5T.ov« i n s e r t f rom s h e a t h CLEAN? b r u s h lumen o f s h e a t h pXOC—« a l l p a r t s t h r o u g h washer d i * i n £ « c t o r T E S T t A S S E M B L E . s h e a t h m«8t be t e s t e d w i t h i i u m l « t i e c i t e s t e r i n s e r t 3»« i n s e r t i n t o s h e a t h and t u r n t o l o c k h o l d h a n d l e a* uliown • l i s * alKiith Into h a n d l e t u r n s h e a t h u n t i l i t c l i c k s i n t o p l a c e s c rew on knurled c o l l a r t e s t the { u n c t i o n of t h e t o r c e p , t hen loosen the knurled c o l l a r one l u l l turn i;o:»t:„. 152 OEC HOSPITAL REFERENCE NO. PASS: 2 of 2 SKtm - MIS STUDV 1 - c u r v e d g r a s p e r 5%'olfe - see p i c t u r e 7, - g r e y c o r d with t r a n s d u c e r 4A0314-02 1 MIS .hook. Storz 25775 yp I cord Kolf6 8106-035 PACKAGE: i n designated ZV x 9' b l u e p e r f o r a t e d container w i t h ambetf l i d l a b e l e d " S & y r a " STERILIZE: SIX) t O C A T l Q H : - L o a c - i r t ruck. Ethylene Oxide (EtO) Gas Sterilization Note: Before sterilization, all instruments must be thoroughly cleaned and all organic material, blood, and cleaning solution completely removed 1. Place the instruments in the sterilization tray 2. All sterilization cycles must include a pre-conditioning cycle: Temperature: 130 ± 5° F (55 ± 5° C) Time: 30 minutes 3. Sterilization has been validated for the following parameters: Gas Mixture EtO: HCFC* Temperature 130 ± 5°F(55±5°C) Relative Humidity 60 ± 20% Pressure 8 to 10 psi Exposure Time 120 minutes EtO concentration 600 ± 30 mg/L * gas mixture composed of 10% ethylene oxide and 90% chlorotetrafluoroethane (HCFC-124; percent by weight) 4. Aeration of the instruments can be accomplished in any aeration chamber at a temperature of 120 to 130° F (49-55° C) for 12 hours. 153 Maximum acceptable levels (per ANSI/AMMI7IS0 10993-7) of residues following EtO sterilization are as follows: ethylene oxide: < 20 mg ethylene chlorohydrin < 12 mg Appendix 13: Results for Sterility Testing of the Reference Clip Attn: Katie Beadon University of British Columbia 05 July, 2007 6250 Applied Science Lane Vancouver, BC V6T 1Z4 Ph: (604) 822-8785 Reference No: 139345. These are the results of the samples received June 14. Product Sampled: Two various samples were received in the laboratory for analysis. Product: Sterility Sample #: 1 No growth after 14 days incubation Clip Sample #: 2 Growth Wire Sterility test using USP 30 Sterility Testing <71> - 1 4 days incubation. 154 

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