Medicine, Faculty of
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Southern Medical Program (Okanagan)
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Biomimetics 9 (3): 145 (2024)
Wu, Kevin Y.
Tabari, Adrian
Mazerolle, Éric
Tran, Simon D.
In the forefront of ophthalmic innovation, biomimetic 3D printing and bioprinting technologies are redefining patient-specific therapeutic strategies. This critical review systematically evaluates their application spectrum, spanning oculoplastic reconstruction, retinal tissue engineering, corneal transplantation, and targeted glaucoma treatments. It highlights the intricacies of these technologies, including the fundamental principles, advanced materials, and bioinks that facilitate the replication of ocular tissue architecture. The synthesis of primary studies from 2014 to 2023 provides a rigorous analysis of their evolution and current clinical implications. This review is unique in its holistic approach, juxtaposing the scientific underpinnings with clinical realities, thereby delineating the advantages over conventional modalities, and identifying translational barriers. It elucidates persistent knowledge deficits and outlines future research directions. It ultimately accentuates the imperative for multidisciplinary collaboration to enhance the clinical integration of these biotechnologies, culminating in a paradigm shift towards individualized ophthalmic care.
Citation: Wu, K.Y.; Tabari, A.;Mazerolle, É.; Tran, S.D. TowardsPrecision Ophthalmology: The Role of3D Printing and Bioprinting inOculoplastic Surgery, Retinal, Corneal,and Glaucoma Treatment. Biomimetics2024, 9, 145. https://doi.org/10.3390/biomimetics9030145Academic Editor: Baiheng WuReceived: 31 December 2023Revised: 4 February 2024Accepted: 16 February 2024Published: 27 February 2024Copyright: © 2024 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).biomimeticsReviewTowards Precision Ophthalmology: The Role of 3D Printing andBioprinting in Oculoplastic Surgery, Retinal, Corneal, andGlaucoma TreatmentKevin Y. Wu 1 , Adrian Tabari 2, Éric Mazerolle 1 and Simon D. Tran 3,*1 Division of Ophthalmology, Department of Surgery, University of Sherbrooke,Sherbrooke, QC J1G 2E8, Canada; yang.wu@usherbrooke.ca (K.Y.W.)2 Southern Medical Program, Faculty of Medicine, University of British Columbia,Kelowna, BC V1V 1V7, Canada3 Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada* Correspondence: simon.tran@mcgill.caAbstract: In the forefront of ophthalmic innovation, biomimetic 3D printing and bioprinting tech-nologies are redefining patient-specific therapeutic strategies. This critical review systematicallyevaluates their application spectrum, spanning oculoplastic reconstruction, retinal tissue engineering,corneal transplantation, and targeted glaucoma treatments. It highlights the intricacies of thesetechnologies, including the fundamental principles, advanced materials, and bioinks that facilitatethe replication of ocular tissue architecture. The synthesis of primary studies from 2014 to 2023provides a rigorous analysis of their evolution and current clinical implications. This review isunique in its holistic approach, juxtaposing the scientific underpinnings with clinical realities, therebydelineating the advantages over conventional modalities, and identifying translational barriers. Itelucidates persistent knowledge deficits and outlines future research directions. It ultimately accentu-ates the imperative for multidisciplinary collaboration to enhance the clinical integration of thesebiotechnologies, culminating in a paradigm shift towards individualized ophthalmic care.Keywords: biomimetics; tissue engineering; 3D printing; bioprinting; ophthalmology; oculoplastic surgery;retinal tissue engineering; corneal transplantation; glaucoma; surgical simulation; clinical translation1. IntroductionAt the vanguard of ophthalmological innovation, biomimetics via 3D printing andbioprinting is paving the way for transformative advances in the field. These biomimeticstrategies not only replicate the structural intricacies of ocular tissues but are also unlockinggroundbreaking possibilities in oculoplastic and orbital surgery, retinal tissue engineering,corneal transplantation, and glaucoma intervention. This review provides a comprehensiveexamination of the current and potential applications of these technologies in ophthalmo-logical practices and research.In the realm of prototyping and simulation, we discuss the development of trainingmodels for surgical practice, highlighting the state-of-the-art models currently in use. Theimportance of preoperative surgical planning and simulation tools is underscored. Thereview also delves into specific applications within ophthalmology, including oculoplasticand orbital surgery. Here, innovations such as ocular prostheses, orbital implants, naso-lacrimal stents, adjustable eyelid crutches, drug-loaded punctal plugs, and their clinicalsignificance are explored.The review also covers the advancements in retinal applications through the useof 3D printing and bioprinting, particularly in the development of macular buckles andretinal tissue engineering. Similarly, in corneal applications, the focus is on the fabricationof specialized contact lenses and corneal tissue engineering. These advancements offerBiomimetics 2024, 9, 145. https://doi.org/10.3390/biomimetics9030145 https://www.mdpi.com/journal/biomimeticsBiomimetics 2024, 9, 145 2 of 28potential improvements over traditional treatment methods in terms of customization.The article further discusses the integration of these technologies in glaucoma treatment,highlighting the development of minimally invasive glaucoma surgery (MIGS) devices anddrug-eluting implants.Our literature review encompasses primary studies from 2014 to 2023, providing athorough analysis of the evolution and current state of these technologies in ophthalmology.Unlike previous reviews which focused predominantly on benchwork data, this studydistinguishes itself by its comprehensive approach. It evaluates not only the fundamentalscience behind biotechnologies but also their clinical implications, scrutinizing conventionaltreatments and methods alongside their challenges and drawbacks. This review articulatesthe advantages of 3D printing and bioprinting in addressing these challenges, comparesthese technologies to conventional methods, and identifies limitations and barriers toclinical translation. Furthermore, it elucidates knowledge gaps and proposes directions forfuture research, grounded in both basic science and clinical insights.The review gives a nuanced emphasis on the transformative potential of 3D printingand bioprinting in ophthalmology, acknowledging the challenges ahead, and highlightingthe need for continued interdisciplinary collaboration to advance these technologies fromthe laboratory to clinical practice. This dual approach fosters a deeper understanding ofthe trajectory from preclinical studies to clinical applications, facilitating a more effectivetranslation of these innovative biotechnologies into everyday clinical use.2. Applications of 3D Printing in Oculoplastic and Orbital Surgery2.1. Applications for Orbital Implants and ProsthesisOrbital implants and prosthetic devices are essential in re-establishing facial balanceand aesthetic appeal following surgical interventions such as evisceration and enucleation.The evisceration technique entails removing the internal contents of the eye but preservingthe sclera, extraocular muscles, and optic nerve, thereby keeping the structural relationshipsof the muscles, globe, eyelids, and fornices [1]. This preservation facilitates improved motil-ity of the prosthesis and simplifies its fitting process [2–4]. Evisceration is contraindicated incases where intraocular malignancy is suspected due to its conservative nature. Conversely,enucleation involves the excision of the entire eye, sparing the surrounding orbital tissues.It is predominantly employed for treating intraocular cancers such as retinoblastoma andchoroidal melanoma, particularly when they do not respond to alternative treatments [1].This method allows for a thorough histological examination, minimizing the risk of tumorcell spread as well as sympathetic ophthalmia (although this is debatable).Orbital implants serve a dual purpose: they compensate for the loss of orbital volumeand preserve the orbit’s architecture [5]. Additionally, these implants facilitate movement inthe ocular prosthesis placed above them, contributing to the restoration of eye movementsand promoting a more natural look [5]. Customization of the prosthesis occurs approx-imately four weeks after surgery, tailored precisely to fit the dimensions of the patient’sconjunctival fornices and overall anatomy [6]. This customization is critical for optimizingcosmetic outcomes, as it ensures the prosthesis closely resembles the contralateral eye interms of color, size, and positioning, thereby enhancing the overall aesthetic effect.Currently, providing patients with personalized prostheses is a tedious procedurecomposed of many precise steps [7]. Three-dimensional printing shows great potentialin minimizing imperfections and enhancing fabrication rates. Using computer-aideddesign (CAD/CAM) and rapid manufacturing (RM) technology, 3D-printed prostheses aremade possible.Ruiters et al. (2016) used patient-specific imaging provided by cone-beam computedtomography systems (CBCT) to reconstruct and design a personalized digital prosthesis thatwas then 3D-printed [8]. Compared to the conventional method of obtaining patient orbitstructure through direct mold impression, imperfections relating to soft tissue impressionthat could have otherwise occurred in the modeling process are mitigated [9]. Additionally,this technique allows for a reduction in production time by eliminating the molding step.Biomimetics 2024, 9, 145 3 of 28However, radiation exposure inhibits certain populations, such as children, from accessingthis service [8].Alam et al. (2017) provide a possible solution to radiation exposure by maintaining theuse of a direct impression of the orbit, digitizing the mold, and fixing imperfections virtuallybefore printing the prosthesis. Taking it a step further, the anterior of the virtual model isthen designed to be hollow, minimizing the weight of the final product. Patients reportedbetter comfort levels when using this prosthesis as compared to their conventionally madeprosthesis. Fabrication time and weight are also greatly optimized [10].Studies have also explored the potential of complete automated ocular prosthesismanufacturing, using technology to print the prosthesis itself and the aesthetic design of iriscolor and blood vessels [11–14]. Using a photograph of the contralateral unaffected eye, thephysical features of the eye are then placed on the 3D model by sublimation. This methodallows for a significant decrease in production time as pattern design would otherwise behand-drawn by an ocularist. Moreover, the blueprint of patient-specific prosthesis can besafely stored, allowing for quick replacement if needed [11–13]. This process is simple andadvantageous for beginner ocularists, as conventional ocular prosthesis design turnoutdepends on an ocularist’s experience [15].Further studies have explored the use of 3D printing for both the printing of theprosthesis and its pattern design [13,14]. The same benefits apply, though the color schemeis heavily limited by the color selection that the 3D printer offers [13]. Moreover, as ocularistexperience in automated pattern painting is less significant, experience in 3D graphics andmodeling becomes essential in producing these prostheses [14]. An important factor in the3D fabrication of such products is the use of biocompatible material, suitable for long-termwear by the patients.Kim et al. (2021) studied the biocompatibility of their 3D resin-printed, polymethylmethacrylate-coated prosthesis, which showed biological and physicochemical safety [11].However, there remains the need to establish a gold-standard material when producing3D-printed prostheses. Beyond ocular prosthesis, 3D-printed ocular resin implants havealso been explored and showed great results 12 months post-op without any systemiceffects observed [16]. Three-dimensional printing models can also act as guides for surgicalprocedures. Indeed, Weisson et al. (2020) used the facial topography of patients to digitallyconstruct an orbital prosthesis that is then 3D-printed. This product acts as a mold fromwhich silicone is cast to produce the final prosthesis. The results showed great potentialand required little to no consultation from prosthetists or ocularists. However, printing andsilicone casting remain rate-limiting steps of this procedure [15].Similarly, in the context of osseointegrated implants, virtually designed guides withholes indicating the location of drilling of implants are 3D-printed and overlaid on thesurgical site, allowing for reduced surgery time and increased surgical precision, resultingin a good outcome [17]. Furthermore, 3D printing can be advantageous to mitigate surgicalcomplications. For example, orbital migration can reduce aesthetic outcomes and causesurrounding tissue fibrosis. In this context, Dave et al. (2018) reported a case study where a3D-printed implant was incorporated into the migrated implant eye to recenter the orbit.Though the procedure left a bulge which the authors deemed normal for this type ofintervention, the application was successful [18].Lastly, 3D printing in the context of conformers for fornix deepening post-enucleationis possible [19,20]. Currently, the standard of care offers non-personalized conformers ofvarious sizes. However, well-fitted conformers are essential to preserve the shallowing ofthe fornices; hence the advantage of 3D-printed conformers, which allow for personalizedconformers and custom fixation holes [19].As various means of ocular prosthesis were explored, the advantages of this method seemto include the reduced production time [8,10,12,13,15,17], personalization [12,13,17,19,20],and access [11,15,16]. By adapting to patients’ personal anatomical traits, this can lead tooverall positive outcomes in terms of aesthetics and function. However, there remaingaps to be addressed. In fact, most studies discussed were based on case reports of a fewBiomimetics 2024, 9, 145 4 of 28patients [8,12,15,17–19] or pilot studies [10,11,21]; hence the importance of large-scale andlong-follow-up studies. Moreover, the method of topography, producing a detailed virtualreplica of the patient’s anatomy, remains complicated. The use of CT or CBCT exposespatients to radiation, which can be contraindicated in some, whereas MRI scans can causefurther artifacts [8]. Alternatives such as hand-held blue-light-based 3D scanners [15] andlight-intensity 3D scanners [12] have been explored and showed positive final results.Finally, the production material of the 3D-printed models is an area needing furtherresearch. As specific materials are starting to be deemed biocompatible [11], it is importantto explore all possible alternatives while considering the effect of such material on patientcomfort and overall experience [21].Table 1 provides an overview of the application of 3D printing in the creation of ocularprostheses, detailing the direct use of this technology in making various prosthetic devices.Table 1. 3D Printing in Ocular Prothesis.Usage Description Usage Studied Key Features Challenges ReferencesDirect Directly 3D-printed- Ocular prothesis- Orbital rehabpost evisceration- Full-color ocularprothesis- Conformers- Scleral covershell- Fast production time- Personalization- Optimized weight andcomfort- Cost varies based onmaterial type- Stored data for fast editsand identicalreplacement- Semi-automatic,beneficial for lessexperienced ocularists- Potential to minimizepatient visits for fittings- CT radiation exposure;pregnancy and children- Long-term follow-up todetermine the stability ofthese types of implants- Requires experience in 3Dgraphics and modelingsoftware- Still a need for manualwork in some usages, i.e.,full-color prothesis- 3D models are rough,irritating the eyelid- Identify idealbiocompatible material[8,10–12,16,20–22]Guide3D-printed model usedto guide the productionof a non-3D-printedprothesis- Osseointegratedimplant- Orbital prothesis- Migrated orbitalimplant- Optimize surgery time- Optimal patientoutcome- Precise, comfort, colormatching, potential toimprove global access- Need for a detailed timeand cost comparison todetermine effectiveness ofguides- 3D printing and castingare rate-limiting steps- Need for a larger studygroup and long-termfollow-up[15,17,18]2.2. Use of Orbital Implants in the Repair of Orbital Floor InjuriesOrbital trauma, frequently encountered in emergency consultations due to trauma, iscommonly associated with injuries to the facial bones and soft tissues, culminating in orbitalfloor fractures, also known as blowout fractures [22]. These fractures primarily occur whenthe orbit is struck by objects exceeding its opening in size. The underlying mechanisms,as described by the hydraulic theory and the buckling theory, involve a sudden rise inintraorbital pressure or deformation of the orbital rim, respectively. Such dynamics lead tofractures that may result in the displacement and entrapment of orbital contents into themaxillary sinus [23–26].The management of orbital floor fractures often involves a period of observation to al-low an edema and orbital hemorrhage to resolve naturally. However, surgical interventionbecomes necessary in certain cases. Surgical indications typically encompass persistentdiplopia, particularly with restricted upgaze and/or downgaze movements within 30 de-grees of the primary gaze, along with positive results on forced duction testing [22,27,28].These findings indicate a likely functional entrapment affecting the inferior rectus muscle.Additional surgical indications include enophthalmos greater than 2 mm, which is deemedcosmetically unsatisfactory, and fractures that compromise at least half of the orbital floor’sintegrity [22,27,28].The favored surgical technique for addressing orbital floor fractures typically utilizesan inferior transconjunctival incision. This approach includes lifting the periorbita awayfrom the orbital floor, freeing any herniated extraocular muscles and fat tissue entrappedBiomimetics 2024, 9, 145 5 of 28by the fracture, and securing an implant to cover the fracture site, thereby averting furtherherniation [29–31]. The primary goal of reconstructing the orbital wall is to re-establish thenormal anatomical configuration of the internal orbit.Orbital implants play an important role in post-traumatic orbital reconstruction, ensur-ing anatomical and orbital function and aesthetics. Current materials used in such implantsinclude autologous, allogenic, and alloplastic materials such as bone, lyophilized dura,and titanium respectively. These require surgical experience to bend and size the implantintraoperatively with great precision, as larger-than-needed dimensions could cause globedisplacement or extraocular muscle dysfunction.Current investigations into 3D printing technology explore its viability for craftingpersonalized orbital implants, with a significant body of research focusing on utilizing3D models for implant customization [32–44] and for the creation of directly printedimplants [45–50]. Chai et al. (2021) demonstrated the efficacy of using patient-specific3D-printed models as templates for intraoperative adjustments to implants, noting amarked decrease in both surgery duration and related complications [32]. This processinvolves digitally reconstructing the damaged orbit and overlaying this model onto theimplant, serving as a precise guide for surgical modifications [33,34]. Moreover, handlingautologous bone grafts, known for their delicacy and challenging manipulation, has beenimproved through the use of 3D-printed templates. Vehmeijer et al. (2016) highlightedthe benefits of this approach, including increased precision, operational efficiency, andcost-effectiveness [34].Research has also delved into the use of 3D-printed models as molds for orbitalimplants, offering a distinct approach from templates. In this method, the implant isshaped directly against the 3D model, ensuring a precise fit. This technique of pre-operativeshaping has been extensively studied with materials such as titanium mesh [35–39] andpolyethylene plates [40]. The consensus from these investigations suggests that utilizing3D-printed molds improves surgical outcomes and is advantageous over conventionalpreparation techniques.For example, Loneac et al. (2021) explored this idea in comminuted zygomatico-maxillary complex fractures, which resulted in significantly better orbital volume restora-tion and symmetrization when compared to traditional free-hand bending. Moreover,Sigron et al. (2020) highlighted the reduction in surgery time as well as its cost-efficiency,though this can vary amongst institutions. Personalized pre-bent implants also greatlydiminish the need for intraoperative fitting, further reducing surgery time [39,40]. Beyondfractures, the mold method can be applied to orbital pathologies. Mourits et al. (2016) useda 3D-printed model of a patient’s orbital cystic growth. This allowed for direct 3D visualiza-tion of the patient’s anatomy. Further, it allows for intraoperative implant manufacturingand modifications compared to direct 3D printing where material can only be removed andnot added [43].Finally, a 3D-printed pressing apparatus designed to press a real implant betweentwo 3D models of the implant is explored. Rather than the surgeon cutting or moldingthe implant, they hold and press the apparatus to obtain a ready-to-use personalizedimplant [41,42]. Though not directly compared to 3D-printed templates or molds, thistechnique shows excellent outcomes through quantitative [42] and qualitative [41] measures.However, these pressing apparatuses were only evaluated in small sample sizes.When looking at direct 3D printing of orbital implants, Kim S.Y. et al. (2019) demon-strated adequate postoperative results, mitigating infection or inflammatory response whilemaintaining functional outcomes [46]. Choi et al. (2022) applied direct printing as an optionfor aesthetic reconstruction in patients with previous facial fractures presenting with lateenophthalmos and hypoglobus, demonstrating the possible benefits of 3D implants inpostoperative care [47].Direct printing of implants in complex fractures is also deemed successful [44,48–50].To maintain the structure and function of complex fractures, a jigsaw puzzle techniqueis employed where small implants are 3D-printed and attached in vivo to construct anBiomimetics 2024, 9, 145 6 of 28overall larger implant. This allows for personalized and uneventful postoperative results.However, results are based on case reports; thus, the need for larger studies to examine thereliability of this application.Kim J.H. et al. (2020) [45] moved away from personalized implants to investigate thepotential of a standard inferomedial orbital strut implant to mitigate the manual bending oftraditional implants and the production time and cost of personalized 3D-printed implants.Through collecting data from 100 adult cadavers, a standard fit implant showing satisfactoryresults in simulated and real patients was created [51]. Most experiments relating to 3Dprinting highlight its ability to customize implants, though this study reveals a situation inwhich printing standard, non-personalized implants may yield similar benefits.In summary, 3D printing provides several benefits in terms of accuracy and surgical out-comes (Table 2), with most orbital implant guides made of titanium [35–39] and direct modelsmade of polycaprolactone [45–47]. Nonetheless, several gaps remain. For instance, when itcomes to the best way of digitally constructing the affected eye, some opted for mirroring theunaffected orbit [35–37,48–50]. This method was criticized by Tel et al. (2019), since humanfacial anatomy is not completely symmetric; thus, relying on the contralateral anatomy maycause design defects [33]. Instead, they applied spline interpolation techniques. Others ap-proached this by using reconstruction softwares to build adequate personalized implants [42],while some utilized a mixture of virtual and manual planning [39,43]. Regardless of thetechnique used to obtain a final implant, all showed adequate function when implemented.From templates to direct printing, there exists a wide range of 3D printing applications inthis domain that have shown great potential compared to conventional techniques. As thesemethods are analyzed further, studies comparing these new procedures with one another canbetter highlight each technique’s unique benefits and weaknesses.Table 2. Application of 3D Printing in Orbital Implants.Usage Description Usage Studied Key Features Challenges ReferencesTemplateImplant cutsuperimposed on the 3Dmodel- Pediatric orbitaltrapdoorfractures- Orbital floor- Reduced surgery time- Increased accuracy andefficiency, with great fit- Low-cost option- Potential in endoscopic,minimally invasivesurgery- Need for technicaland computationalknowledge infabricating thespline-basedreconstruction mold[32–34]MoldImplant molded ontothe 3D model prior tosurgery-Zygomaticomaxillaryfracture- Orbital blowout- Orbital wall andfloor- Orbital cyst- Individual and puzzleimplants possible- Fast, easy, precise- No significantpost-operativecomplications- Reduced operation time- Sample size- Post-op eyeprotrusionsignificantly higherthan pre-op- Uncertainties invirtual reconstructionof fractures[35–40,43,44]PressingapparatusPress real implantbetween the two sides of3D models of theimplant- Orbital floor- Orbital wall- Simple pressing action toobtain a custom implant- Cheaper alternative whencompared to a fully3D-printed implant- Cost of the printer is abarrier to access- Possible difficulties incomplex fractures- Small sample size[41,42]Direct printing The implant itself is3D-printed- Inferomedialorbital strut- Orbital wall- Aesthetic- Orbital floor- Simple and puzzleimplants possible- Positive clinical outcomesand patient satisfaction- Stiffness of 3D-printedimplant maintainsstructural stability- Long planning,production, andsterilization time- Relies on access to a3D printer- Lack of long-termfollow-up dataanalysis[45–50]2.3. Applications for Assorted Ophthalmic Procedures (Nasolacrimal Stents, Drug Delivery, andEyelid Crutches)3D printing has been explored in various domains relating to oculoplasty outside ofsurgery. Sun et al. (2019) investigated the application of 3D printing in addressing ptosisthrough universal eyelid crutches as a low-cost, non-operative treatment choice. ComparedBiomimetics 2024, 9, 145 7 of 28to current personalized eyelid crutches, they introduced an adjustable and easily removablecrutch that can be attached to various eyeglass designs. Though only a case report and thereremains a need to directly compare these to traditional crutches, Sun et al. (2019) highlightthe potential use of this 3D model in developing countries, where expensive personalizedcrutches may not be an option [52]. Furthermore, this study differentiates itself from othersby underlying the fact that a standard, universal apparatus design may sometimes be morebeneficial than custom-fitted ones. In dry eye disease, 3D-printed punctal plugs have beenstudied to treat dry eyes while simultaneously delivering drugs and increasing patient com-pliance compared to traditional topical drugs [53,54]. Xu et al. (2021) studied a 3D-printeddrug-loaded punctal plug in vivo, which showed extended release characteristics and theabsence of drug-photopolymer interaction when using dexamethasone and polyethylene gly-col [54]. Similarly, in the context of nasolacrimal stent, 2-Hydroxyethyl methacrylate hydrogelresin was found to be biocompatible in in vivo animal studies [55]. As research on this topiccontinues to evolve, clinical studies on various drug and printing material interactions remainto be studied. Radiotherapy eye shields, which are necessary when treating orofacial tumors,are traditionally personalized through open-eye impressions with the need for anesthesia.Using a commercial surface scanner to digitize patient anatomy eliminates direct contact withthe eye and allows for the fabrication of 3D-printed shields using readily available biocom-patible material, though post-scan digital modifications were needed due to scanner flashcausing scanning defects of the iris [51]. Despite the possibility of scanning difficulties needingpost-scanning adjustment, this method is a possible alternative to radiation exposure by CTscans. Finally, 3D printing bridges the fields of ocular pathology and engineering, creatingnovel solutions to important pathologies. For example, Yang et al. (2022) studied the use ofa drilling 3D microrobot as an alternative to nasolacrimal duct probing to remove primaryacquired nasolacrimal duct obstructions. This technology has shown great potential in theearly stages of phantom model testing, or objects designed to imitate the human body [56,57].In essence, there exist great opportunities for 3D printing in various non-surgical aspects ofocular disease. However, as of now, the majority remain developmental [52,53] in vivo [54,55],or simply case studies [51,53]. As novel research on the topic of 3D printing in ocular diseasecontinues to emerge, large-scale clinical studies to properly depict the outcomes of such newtechnology remain important.Table 3 summarizes the advances in 3D printing for nasolacrimal stents. Table 4 detailsthe use of 3D printing in non-surgical ophthalmic applications, such as drug delivery throughpunctal plugs, ptosis treatment with eyelid crutches, and radiation protection with eye shields.Table 5 presents a summary of case report data and clinical study data concerning 3D printedocular and orbital prostheses, conformers, and repair of orbital floor fractures.Table 3. 3D Printing for Nasolacrimal Stents.Application Usage Key Features Challenges ReferencesLacrimal duct stent Lacrimal duct bypass- Material compatible withhuman tissue, nocomplications, mildinflammation thatdisappeared after 8 weeks- Data from abstract, testedin vivo on rabbit modelsonly[55]Magnetic micro-drillersystem Duct recanalization- 3D-printed parts for amicrorobot using a magneticactuation system- automated removal ofblockage and built-in forcesensor- Automated path isunidirectional- Further research on ex vivoexploration before in vivotesting[56]Biomimetics 2024, 9, 145 8 of 28Table 4. 3D Printing in Non-Surgical Ophthalmic Applications.Application Usage Key Features Challenges ReferencesPunctal plugs Drug delivery- Personalized for patient punctum size- Short production time, cost-effective- Potentially lesscytocompatible than controls- Need for clinical studies[53,54]Eye-lid crutches Ptosis- Low-cost- Easily removable and adjustable by thepatient- Attaches to various frames- Flexible printing material allows foreasier eye closure- Non-universal design- Complications still present- Need for a large sample sizeand long-term research[52]Eye shield Radiation- 3D print model is a mold for siliconeimpression- Non-contact scanning, no use ofanesthesia- Simplified laboratory work- Quick, easy, precise- 3D scanner has difficultycapturing the precise site ofthe iris- Need for scanned dataadjustment prior to print- Future printing of the shieldsthemselves[51]Table 5. Summary of Case Report Data and Clinical Study Data.Procedure: CAD OcularProsthesis3D-PrintedOrbitalProsthesis3D-PrintedConformers 3D Printing in Orbital Floor Fracture RepairParticipants(n) 1 n.d. 3 3 10 1 9 5 14 1 12 22 1 4 28 1AdverseEvents Severe 0 0 0 0 0 0 0 0 0 1Non-severe 0 0 0 0 1Pain 1Infection 0 0 0 0Pruritis 0Dryness 2Parasthesias 2Enophthalmos 0 0 1 2 0Diplopia 1 0 1 0 1Biochemical markerelevation 0Inflammation 0Functional/CosmeticProblems 5 1 0 0 0 0Device Extrusion 0 0ObservationTime(weeks)24 4 4 n.d. 12 n.d. 156 16 (onaverage) n.d. n.d.22(median) n.d. 4Up to24 26 n.d.References [8] [10] [11] [15] [16] [17] [19] [20] [33] [34] [36] [37] [40] [41] [44] [49]Procedure: 3D Printing in Orbital Wall Repair Orbital FloorReconstruction3D Printing forZygomaticomax-illary Fracture3D-PrintedOrbitalRim Recon-struction3D Printing inOrbitalMalformationParticipants(n) 82 (44 study grp.) 104 11 22 3 1 19 3 1AdverseEvents Severe 0 0 0 0 0 0Non-severe 0 0 0Pain 1Infection 0 0 0 0Degradation 1Hypoesthesia 2 0 2Enophthalmos 0 0 1Diplopia 2 0 0 2 0 0 0Biomimetics 2024, 9, 145 9 of 28Table 5. Cont.Procedure: CAD OcularProsthesis3D-PrintedOrbitalProsthesis3D-PrintedConformers 3D Printing in Orbital Floor Fracture RepairInflammation 0Functional/CosmeticProblems 0 0Device Extrusion 0ObservationTime(weeks)26 (minimum) 23.5 26 n.d. 26 26 26 n.d.References [38] [39] [42] [46] [48] [43] [35] [47] [50]Procedure: 3D-Printed Conformers Orbital RimReconstruction3D-PrintedEye-Shield forRadiotherapy3D-PrintedEyelidCrutchesOrbitalMalformationReconstructionParticipants(n) 9 3 2 1 4AdverseEvents Severe 0 0 0Functional/CosmeticProblems 5 1Discharge Common (but number not specified)Scarring 1Luxate/Extrusion 1ObservationTime(weeks)87 (mean) Up to 1 year9 months 22.5 days 22 43.5References [19] [47] [51] [52] [58]‘n.d.’ indicates a value not determined.3. Retinal ApplicationsThe clinical uses for bioprinted and 3D-printed materials in retinal medicine are vast.These uses include retina-targeted drug delivery platforms, retinal tissue models for in vivoresearch, ophthalmologist training, and retinal prosthetics for treating retinal degenerativedisease. The 3D printing and bioprinting of ocular devices, scaffolds, and tissue modelsoffer benefits including product standardization and fine tailoring of the shape, porosity, andcurvature of products. However, there are many obstacles left to overcome when attemptingto create a model that emulates the anatomical complexity of the retina (Figure 1).Biomimetics 2024, 9, x FOR PEER REVIEW 10 of 31 when attempting to create a model that emulates the anatomical complexity of the retina (Figure 1). Figure 1. Structure and Composition of Retinal Layers (BioRender, https://app.biorender.com/, ac-cessed on 26 January 2024). 3.1. Study of Retinal Disease through Retinal Modeling The retinal pigment epithelium (RPE) is a layer of single, polygonal cells sandwiched between photoreceptor cells and Bruch’s membrane at the outermost retinal layer. The RPE forms the outer blood–retinal barrier through tight junctions [59] and regulates the passage of substances in and out of the retina. RPE damage is implicated in degenerative diseases including retinitis pigmentosa, wet and dry age-related macular degeneration (AMD), and Stargardt’s disease. A well-developed in vitro retinal model can be used to study such retinal degenerative diseases, elucidate pathophysiological mechanisms for disease development, or test new pharmacotherapy. Due to the complex interplay of junc-tion proteins and hormonal signaling between retinal layers, this is a challenging task. An ideal model needs to have cells with appropriate polarity, tight junction protein expres-sion, proper attachment to Bruch’s membrane, and the release of hormones such as human vascular endothelial growth factor (hVEGF) at physiologically similar levels, among other things. Several bioprinting technologies exist and can be used to help develop these retinal models [60]. Figure 2 illustrates various bioprinting technologies that are employed in the devel-opment of retinal and corneal applications, detailing different methods under the catego-ries of vat polymerization, extrusion-based, and jetting-based bioprinting. Figure 1. Structure and Composition of Retinal Layers (BioRender, https://app.biorender.com/,accessed on 26 January 2024).Biomimetics 2024, 9, 145 10 of 283.1. Study of Retinal Disease through Retinal ModelingThe retinal pigment epithelium (RPE) is a layer of single, polygonal cells sandwichedbetween photoreceptor cells and Bruch’s membrane at the outermost retinal layer. The RPEforms the outer blood–retinal barrier through tight junctions [59] and regulates the passageof substances in and out of the retina. RPE damage is implicated in degenerative diseasesincluding retinitis pigmentosa, wet and dry age-related macular degeneration (AMD),and Stargardt’s disease. A well-developed in vitro retinal model can be used to studysuch retinal degenerative diseases, elucidate pathophysiological mechanisms for diseasedevelopment, or test new pharmacotherapy. Due to the complex interplay of junctionproteins and hormonal signaling between retinal layers, this is a challenging task. Anideal model needs to have cells with appropriate polarity, tight junction protein expression,proper attachment to Bruch’s membrane, and the release of hormones such as humanvascular endothelial growth factor (hVEGF) at physiologically similar levels, among otherthings. Several bioprinting technologies exist and can be used to help develop these retinalmodels [60].Figure 2 illustrates various bioprinting technologies that are employed in the develop-ment of retinal and corneal applications, detailing different methods under the categoriesof vat polymerization, extrusion-based, and jetting-based bioprinting.Biomimetics 2024, 9, x FOR PEER REVIEW 11 of 31 Figure 2. Bioprinting Technologies Used in Retinal and Corneal Applications. Shi et al. developed a bilayer, photoreceptor–retinal tissue model using microvalve bioprinting. ARPE-19 and Y79 cells were either bioprinted or manually seeded onto scaf-folding. Manual cell seeding forms aggregates with uneven cell layers while microvalve bioprinting develops an organized cell monolayer with high zonula occuldens-1 (ZO-1) and claudin-1 (C-1) expression. The orderly distribution of cells using bioprinting is thought to enhance the expression of these cell–cell adhesion proteins [61]. Tight junction development is needed for an effective RPE model given its role in the blood–retinal bar-rier. With these characteristics, this model demonstrates potential use as an in vitro model for retinal disease research. This study also clearly demonstrates a common benefit of most bioprinting technologies compared to manual seeding—the speed at which cell lay-ers can be seeded onto scaffolding. Like ARPE-19 and Y79 cells, the growth and differen-tiation of Müller (retinal glial) cells depends on the structural characteristics of the growth medium. Jung et al. found that physiological differences exist between 2D cultured & 3D bioprinted Müller cells, specifically in potassium and water channel expression, and cell cytokine and growth factors [62]. Given cell scaffolds and bioprinting techniques can di-rectly affect cell protein expression, the expression of important proteins should be com-pared between in vitro and in vivo retinal cells for potential differences. Proper RPE tight junction development is also likely to be more dependent on bi-oprinting than the presence of scaffolding. Masaeli et al. developed a scaffold-free, dual-layered retinal cell model using inkjet-based bioprinting composed of an RPE and photo-receptor layer. Similar to the research by Shi et al., high ZO-1 and C-1 expression was noted, but hVEGF, an endothelial angiogenic and vasopermeability factor, was also de-tected [63]. Kim et al. furthered this idea by hypothesizing that RPE printing onto polymer scaffolding is insufficient to lead to full RPE maturation. A Bruch’s membrane-mimetic substrate (BMS) was found to have more influence on RPE layer development versus an uncoated Transwell scaffold. The layered BMS-RPE on a Transwell scaffold had higher ZO-1 and phototransduction enzyme expression and higher transepithelial electrical re-sistance (TEER), a measure of barrier function. Furthermore, there is potential for the use Figure 2. Bioprinting Technologies Used in Retinal and Corneal Applications.Shi et al. developed a bilayer, photoreceptor–retinal tissue model using microvalvebioprinting. ARPE-19 and Y79 cells were either bioprinted or manually seeded ontoscaffolding. Manual cell seeding forms aggregates with uneven cell layers while microvalvebioprinting develops an organized cell monolayer with high zonula occuldens-1 (ZO-1)and claudin-1 (C-1) expression. The orderly distribution of cells using bioprinting isthought to enhance the expression of these cell–cell adhesion proteins [61]. Tight junctiondevelopment is needed for an effective RPE model given its role in the blood–retinal barrier.With these characteristics, this model demonstrates potential use as an in vitro model forretinal disease research. This study also clearly demonstrates a common benefit of mostbioprinting technologies compared to manual seeding—the speed at which cell layers canbe seeded onto scaffolding. Like ARPE-19 and Y79 cells, the growth and differentiation ofBiomimetics 2024, 9, 145 11 of 28Müller (retinal glial) cells depends on the structural characteristics of the growth medium.Jung et al. found that physiological differences exist between 2D cultured & 3D bioprintedMüller cells, specifically in potassium and water channel expression, and cell cytokineand growth factors [62]. Given cell scaffolds and bioprinting techniques can directly affectcell protein expression, the expression of important proteins should be compared betweenin vitro and in vivo retinal cells for potential differences.Proper RPE tight junction development is also likely to be more dependent on bioprint-ing than the presence of scaffolding. Masaeli et al. developed a scaffold-free, dual-layeredretinal cell model using inkjet-based bioprinting composed of an RPE and photoreceptorlayer. Similar to the research by Shi et al., high ZO-1 and C-1 expression was noted, buthVEGF, an endothelial angiogenic and vasopermeability factor, was also detected [63].Kim et al. furthered this idea by hypothesizing that RPE printing onto polymer scaffoldingis insufficient to lead to full RPE maturation. A Bruch’s membrane-mimetic substrate(BMS) was found to have more influence on RPE layer development versus an uncoatedTranswell scaffold. The layered BMS-RPE on a Transwell scaffold had higher ZO-1 and pho-totransduction enzyme expression and higher transepithelial electrical resistance (TEER),a measure of barrier function. Furthermore, there is potential for the use of BMS-RPE forin vivo transplantation as the cell layers can easily be removed from the underlying scaffoldand transplanted subretinally and subcutaneously [64].In a recent study, Song et al. designed a more comprehensive, multilayered retinalmodel with the development of an outer blood–retinal barrier (oBRB) tissue composed ofendothelial cells, pericytes, and fibroblasts bioprinted on the basal side of a scaffold with anRPE monolayer on top. The oBRB tissue acts as an excellent model for retinal degenerationin vitro. Both wet and dry AMD phenotypes were induced in the oBRB tissue—complementactivation manifests as dry AMD (drusen development and choriocapillaris breakdown)while HIF-α stabilization or STAT3 overactivation leads to the development of type-I wetAMD (choriocapillaris neovascularization) [65]. Three-dimensional bioprinted retinal tissuemodels can also be used to study external environmental factors on ocular health. Kim et al.found that oxidative stress induced by cigarette smoke can disrupt RPE tight junctionstrength and blood–retinal barrier function [66]. This information can be used to furtherexplore causative links between smoking and retinal degeneration.Orientation and polarity are also important in the survival and development of manytypes of ocular cells, including retinal ganglion cells (RGCs). RGCs help project retinalsignals to the brain’s visual centers. Kador et al. [22] combined a technique known aselectrospinning [23] with thermal inkjet 3D bioprinting to create a nanoporous scaffoldwith RGC growth. The scaffolding helped correctly orient a proportion of growing neurites(71.9% of axons, 49.3% of dendrites) [22], correctly demonstrating that the nanoporescreated by electrospinning create an acceptable scaffold for future retinal tissue growth.Without in vivo testing, we cannot determine if this model may provide clinical benefit fordiseases requiring RGC implantation.3.2. Retinal Cell Delivery ScaffoldsAge-related macular degeneration (AMD) is a degenerative retinal disease that affectsthe retinal macular region at the RPE level. Drusen formation occurs between Bruch’s mem-brane and the RPE, and depending on the extent of drusen development—based on size,and number—AMD may be diagnosed and categorized as wet (exudative/neovascular)or dry (non-exudative/non-vascular) AMD [67]. The mainstay of wet AMD treatment isintravitreal anti-vascular endothelial growth factor (anti-VEGF) injection. Poor adherenceto therapy is common due to the need for inconvenient and irritating repeated intravitrealinjections [68]. Repeated intravitreal injections also increase the risk of endophthalmi-tis [69] and physical tears in the RPE layer [70]. Even with optimal adherence, visualfunction still deteriorates gradually over time [71] with anti-VEGF therapy, so significantroom for improvement in AMD therapies still exists. A school of research is currentlyexploring cell transplantation as a potential treatment for degenerative retinal diseases likeBiomimetics 2024, 9, 145 12 of 28AMD in patients unresponsive or resistant to conventional pharmacotherapy. Furthermore,3D-bioprinted scaffolds have the potential to replace or augment the diseased RPE.Retinal cells cannot regenerate [24], meaning diseases of the retina are degenerative,worsening over time without improvement. Pharmacologic therapy has made significantprogress with the commercialization of anti-VEGF therapies for conditions like AMD [25];these therapies are not curative, however. New research on these diseases focuses oncell replacement therapy to replace damaged retinal cells [26], but barriers preventingtheir clinical use still exist, including effective ways to deliver the cells to the retinal layer.Retinal cell delivery through intravitreal injection has risks of unpredictable cell viability,uncontrolled cell proliferation in the vitreous cavity, macrophage infiltration, and ocularinflammation [27]. The use of 3D-printed biocompatible scaffolds to grow and deliver cellscould be a viable option. The ideal scaffold should encourage cell growth with the correctorientation and polarity.Due to poor printing resolution, 3D printers can act as the constraining factor whendesigning materials. Poor resolution prints can result in flat, ‘two-dimensional’ scaffoldstructures which encourage unorganized cell growth. Two-photon polymerization (2PP)3D printing allows better resolution than most other 3D printing techniques. Using 2PP,Worthington et al. developed organized, porous scaffolds seeded with induced pluripotentstem cell (iPSC)-derived retinal progenitor cells. Maximum cell loading occurred in the25 µm diameter pores with correct cell polarity and cell viability throughout. Seeding cellson a physical support substrate is hypothesized to be the reason for improved cell viabilityand proliferation compared to bolus injections of cell suspensions [28]. The challenge with2PP is material degradation due to the high-energy lasers used in the process [29] whichmay not be suitable for all types of scaffolding materials. In vivo subretinal implantation ofa scaffold device similar to the one developed by Worthington et al. [28] was developed byThompson et al. [30]. The implantation in a porcine model of retinitis pigmentosa showedno sign of inflammation, toxicity, or infection after one month. The potential for 2PP todevelop clinically useful 3D cell-delivery scaffolds for the treatment of retinal diseasesexists, but the extent of the research is limited as the majority of research on RPE celltransplantation involves non-3D-printed scaffolding [31,72].3.3. 3D-Printing Assisted Macular BucklingMacular buckle (MB) is a surgical technique used to reshape the posterior segmentwall when treating high myopia. The axial elongation of the eye in untreated MB can causethe stretching of ocular structures and eventually retinal degeneration [73]. Zou et al. usedoptical coherence tomography, 3D modeling, and 3D printing to assist in the treatment ofmyopic foveoschisis (MF) via MB surgery. MRI imaging data was used to reconstruct a3D model of the patient’s eye and a 3D print of the model allowed clinicians to design atitanium stent for MB surgery. The clinical endpoints for MF post-MB surgery were positive,including significant visual acuity improvement and axial length reduction at 1 year. Three-dimensional modeling also helped with MB stent positioning. It is notable, however, thatMB surgery typically uses commercial stents and Zou et al. make no comparison betweenthe ease of use or effectiveness of printed stents versus commercial stents. Furthermore, thestent modeling and printing required additional time, leading to prolonged hospitalizationand additional costs to the patient [74]. The need for a custom-designed MB stent is stilluncertain given the lack of comparison to existing commercial stents.3.4. Retinal Drug Delivery PlatformsThree-dimensional printing technology shows promise in its ability to create biodegrad-able scaffolds for sustained drug release in the retina. This could be used as an alternativemethod for drug delivery in diseases like wet AMD which require repeat intravitreal in-jection of anti-VEGF agents [75], risking the development of endophthalmitis and othercomplications. Won et al. developed a 3D-printed rod with a drug depot containing beva-cizumab and dexamethasone. Structurally composed of a polymeric shell and a hydrogelBiomimetics 2024, 9, 145 13 of 28core structure each with a separate drug depot, this device can release two drugs withdiffering release kinetics in the vitreous humor. Significant in vivo reduction of angiogenicand inflammatory markers (isolectin B4 and CD45, respectively) were noted two weekspost-intravitreal injection of the depot device in a rat model. In vivo studies showed morelong-term sustained drug release using the rod versus direct intravitreal injection. Al-though this technology may reduce the need for repeated intravitreal injection, there wasno mention of the rod disintegrating in the vitreous humor, whether the device needs to beremoved, or the ability of the drug depot to release past 60 days [76].3.5. Ophthalmologist & Patient TrainingThree-dimensional printing technology can be used to develop and improve ocularmodels for both ophthalmologist surgical training and patient education. Currently, fewrealistic ocular models for ophthalmologist retinal laser surgery training exist. The ma-jority of current models have rigid casings and a limited view of the fundus due to poorstructural designs differing from actual ocular anatomy. Pugalendhi et al. developed a 3Docular model to correct these two differences. The resulting model improved the fundusviewing area by almost 17%, creating a more realistic model to help with surgical train-ing [77]. In patient education, the complex mechanisms of ocular disease can be difficultfor patients to visualize and challenging for physicians to explain. Yap et al. developed3D-printed models of the retina to demonstrate the pathophysiology of AMD and howthe different layers of the retina are affected by the disease [78]. Although outcomes ofpatient understanding were not quantified, in general, good communication improvespatient satisfaction and adherence to therapy [79]. Such 3D models could therefore improvephysician–patient communication.Ultimately, the potential use of 3D-printed and bioprinted materials for retinal use isvast, from patient education to the seeding of RPE cells in a scaffold for the treatment ofAMD. Specifically, with RPE cell implantations for wet AMD, long-term concerns such asthe risk of infectious complications and the effectiveness of intervention versus anti-VEGFtherapy still exist. For more clinical applicability, more in vivo animal and human trials areneeded for most of the research discussed in this section.4. Application of 3D Printing and 3D Bioprinting in Corneal DevicesLike the application of 3D printing and bioprinting in retinal applications, cornealapplications must also be biocompatible, otherwise the risk of autoimmune responses,rejection, and infection exists. Given the versatility of 3D printing, possibilities in cornealapplications are vast, including corneal tissue models for in vitro research, tissue grafts forkeratoplasty procedures, contact lenses for improved drug delivery through the cornea,and corneal models for ophthalmologist training.4.1. Corneal ModelingThe cornea is composed of five cell layers, as seen in Figure 3. The stroma, a collagen-rich layer, comprises the majority of the corneal thickness. Bowman’s layer and epitheliumare found exterior to the stroma, and Descemet’s membrane and endothelium are on theinterior stromal surface. Functionally, the cornea provides protection to the inner eyecomponents and about two-thirds of the eye’s refractive power [80]. Some challenges withdeveloping a cornea graft for research and transplant purposes include optical aberrations,sufficient tensile strength, and appropriate curvature.The development of a synthetic corneal graft usable in humans is still in the earlyphases of research, but significant progress has been made in better understanding cornealcell behavior. For example, an increased slope gradient on a 3D-printed convex scaffoldresults in stronger adhesion and better alignment of rabbit corneal epithelial cell (RCEC)organization [81]. During the development of corneal scaffolds, curvature should beconsidered for epithelial strength, but balanced with the potential for optical alterationswith excess curvature. A bioprinted cornea should have a similar tensile and compressiveBiomimetics 2024, 9, 145 14 of 28modulus to a human cornea. The long-term viability and optical properties of bioprintedcorneas unable to replicate such qualities are highly uncertain [82]. Furthermore, the bioinkused to 3D bioprint cells must also be biocompatible and non-toxic to allow future testing inhumans. A novel, crosslinked, hyaluronic acid-based bioink was developed by Mörö et al.,and through extrusion-based 3D printing a corneal graft was bioprinted. It showed effectiveex vivo integration within a porcine cornea with no cytotoxicity detected [83]. Given itssafety and effectiveness in bioprinting, this crosslinked hyaluronic acid bioink may have arole in bioprinting in vivo human corneal grafts.Biomimetics 2024, 9, x FOR PEER REVIEW 15 of 31 Figure 3. Structure of Corneal Layers. The development of a synthetic corneal graft usable in humans is still in the early phases of research, but significant progress has been made in better understanding corneal cell behavior. For example, an increased slope gradient on a 3D-printed convex scaffold results in stronger adhesion and better alignment of rabbit corneal epithelial cell (RCEC) organization [81]. During the development of corneal scaffolds, curvature should be con-sidered for epithelial strength, but balanced with the potential for optical alterations with excess curvature. A bioprinted cornea should have a similar tensile and compressive mod-ulus to a human cornea. The long-term viability and optical properties of bioprinted cor-neas unable to replicate such qualities are highly uncertain [82]. Furthermore, the bioink used to 3D bioprint cells must also be biocompatible and non-toxic to allow future testing in humans. A novel, crosslinked, hyaluronic acid-based bioink was developed by Mörö et al., and through extrusion-based 3D printing a corneal graft was bioprinted. It showed effective ex vivo integration within a porcine cornea with no cytotoxicity detected [83]. Given its safety and effectiveness in bioprinting, this crosslinked hyaluronic acid bioink may have a role in bioprinting in vivo human corneal grafts. 4.2. Corneal Graft Development and Corneal Transplants 4.2.1. Keratoplasty Keratoplasty, also known as a corneal transplant, is a surgical procedure to replace defective corneal tissue with a tissue graft. Multiple types of keratoplasty exist, each with different procedures and removal of diseased or damaged corneal layers [84]. Penetrating Keratoplasty is a full-thickness transplant, used when the full cornea is affected. Lamellar Keratoplasty (LK) is an overarching category for all partial thickness keratoplasty proce-dures. These include Deep Anterior Lamellar Keratoplasty (DALK), Descemet’s Stripping Endothelial Keratoplasty (DSEK), and Descemet’s Membrane Endothelial Keratoplasty Figure 3. Structure of Corneal Layers.4.2. Corneal Graft Development and Corneal Tr nspl nts4.2.1. KeratoplastyKeratoplasty, also known as a corneal transplant, is a surgical procedure to replacedefective corneal tissue with a tissue graft. Multiple types of keratoplasty exist, each withdifferent procedures and removal of diseased or damaged corneal layers [84]. PenetratingKeratoplasty is a full-thickness transplant, used when the full cornea is affected. LamellarKeratoplasty (LK) is an overarching category for all partial thickness keratoplasty proce-dures. These include Deep Anterior Lamellar Keratoplasty (DALK), Descemet’s StrippingEndothelial Keratoplasty (DSEK), and Descemet’s Membrane Endothelial Keratoplasty(DMEK). DSEK and DMEK are subcateg rized under LK as End thelial Keratoplasty,which involves th replacement of posterior corneal layers. Lastly, keratoprosthesis is a fullcorneal removal followed by the implantation of an artificial cornea (Figure 4).Biomimetics 2024, 9, 145 15 of 28Biomimetics 2024, 9, x FOR PEER REVIEW 16 of 31 (DMEK). DSEK and DMEK are subcategorized under LK as Endothelial Keratoplasty, which involves the replacement of posterior corneal layers. Lastly, keratoprosthesis is a full corneal removal followed by the implantation of an artificial cornea (Figure 4). Figure 4. Categorization of various keratoplasty procedures. Corneal transplants require grafts from human donors [85], and this can pose signif-icant challenges with the corneal donor material shortage [86], the limited graft survival time post-harvest, and the risk of graft rejection. The development of 3D-bioprinted cor-neas from collagen or other biocompatible materials may be able to address these concerns. Earlier research had shown potential for the 3D printing of a synthetic corneal graft. Isaac-son et al. used a pneumatic 3D dual extrusion bioprinter to develop a structure resembling the corneal stroma. Using a collagen-based bioink, corneal keratocytes showed viability after 7 days. There was no consideration for long-term cell survival, cell–cell adhesion, and cell differentiation, and therefore it cannot be used as a model for disease research by itself. There was, however, significant promise and a precedent set for further testing and refining [87]. Since then, improvements have been made to bioink composition for better transparency, safety, and biocompatibility. Kim et al. developed a bovine cornea-derived extracellular matrix (Co-dECM)-based bioink with turbinate-derived mesenchymal stem cells (hTMSCs). The Co-dECM group caused the differentiation of hTMSCs into kerato-cytes which are needed for stromal generation. Transparency in the bioprinted cornea was calculated at 75% of the visible light spectrum passing through [88], whereas the human cornea has 80% to 94% light transmittance at 450 nm to 600 nm respectively [67]. The clin-ical significance of this difference in light transmittance remains unknown until in vivo human trials are conducted. A current challenge with bioprinted corneal grafts is host integration and the colla-gen structure within the stroma. Using a graft developed with rabbit corneal epithelial cells (CEC) and adipose-derived mesenchymal stem cells (MSC), He et al. noted good in-tegration within the cornea post-anterior lamellar keratoplasty [68]. The bioink formu-lated with GelMA (Gelatin methacrylate) and biocompatible PEGDA (long-chain poly(ethylene glycol) diacrylate) allowed for the appropriate growth and geometry of col-lagen fibrils. Without the orthogonal alignment of fibrils, the optical and mechanical prop-erties of the cornea will be compromised. Alginate hydrogels are another common bioink material, though their rigidity can prevent cell proliferation and differentiation [69]. By altering the sodium citrate/sodium alginate ratios within the alginate gel, Wu et al. found Figure 4. Categorization of various keratoplasty procedures.Corneal transplants require grafts from human donors [85], and this can pose significantchallenges with the corneal donor material shortage [86], the limited graft survival timepost-harvest, and the risk of graft rejection. The development of 3D-bioprinted corneas fromcollagen or other biocompatible materials may be able to address these concerns. Earlierresearch had shown potential for the 3D printing of a synthetic corneal graft. Isaacson et al.used a pneumatic 3D dual extrusion bioprinter to develop a structure resembling thecorneal stroma. Using a collagen-based bioink, corneal keratocytes showed viability after7 days. There was no consideration for long-term cell survival, cell–cell adhesion, andcell differentiation, and therefore it cannot be used as a model for disease research byitself. There was, however, significant promise and a precedent set for further testingand refining [87]. Since then, improvements have been made to bioink composition forbetter transparency, safety, and biocompatibility. Kim et al. developed a bovine cornea-derived extracellular matrix (Co-dECM)-based bioink with turbinate-derived mesenchymalstem cells (hTMSCs). The Co-dECM group caused the differentiation of hTMSCs intokeratocytes which are needed for stromal generation. Transparency in the bioprintedcornea was calculated at 75% of the visible light spectrum passing through [88], whereasthe human cornea has 80% to 94% light transmittance at 450 nm to 600 nm respectively [67].The clinical significance of this difference in light transmittance remains unknown untilin vivo human trials are conducted.A current challenge with bioprinted corneal grafts is host integration and the collagenstructure within the stroma. Using a graft developed with rabbit corneal epithelial cells(CEC) and adipose-derived mesenchymal stem cells (MSC), He et al. noted good integrationwithin the corne post-ant rior lamellar keratoplasty [68]. The bioink formulated withG lMA (Gelatin metha rylate) and biocompatibl PEGDA (long-chain poly( thylene glycol)diacrylate) allowed for the appropriate growth geometry of collagen fibrils. Withoutthe orthogo al alignment of fibrils, the optical and mech nical properties f the c rneawill be compromised. Alginate hydrogels are another common bioi k aterial, thoughtheir rigidity an prevent cell proliferation and differentiation [69]. By altering the sodiumcitrate/sodium alginate ratios within the alginate gel, Wu et al. found that the matrix wasmore easily degraded by the extrusion-b sed 3D-pr nted uman corneal epithelial cells.With easier degradation, cell proliferation capacity also improved [70]. These findings helpimprove alginate-based bioinks for corneal tissue development, but as no in vivo testingwas done, the biocompatibility of alginate gels within the cornea is still uncertain.Biomimetics 2024, 9, 145 16 of 284.2.2. KeratoprosthesisKeratoprosthesis is a surgical procedure involving full-thickness removal of the corneaand replacement with an artificial cornea. The most common type of keratoprosthesis isthe Boston type I keratoprosthesis (BI-KPro), used when poor outcomes are predicted withpenetrating keratoplasty, or with repeated corneal graft failures [71]. There are challengeswith the existing materials used in BI-KPro—the rigidity of the polymethyl methacrylate(PMMA) and titanium can lead to elevated intraocular pressure, retroprosthetic membraneformation, corneal melt, and/or vitritis. BI-KPro also requires a corneal donor, which isdifficult to obtain with the donor corneal tissue shortage [89]. Magalhães et al. developed anovel keratoprosthetic implant to bypass the need for a donor corneal graft and using theexisting cornea. The implant materials were the same as for BI-KPro, but the titanium backplate was 3D-printed. In vivo implantation in a rabbit model led to significant post-surgicalcomplications including retroprosthetic membrane development, elevated IOP, cornealmelting, and infectious keratitis [89]. With these complications, its future application tohumans seems unlikely, but a comparison to BI-KPro post-surgical issue incidence maygive a better comparison of relative risk differences.4.3. Corneal RegenerationBoix-Lemonche et al. developed a mesenchymal stromal cell-loaded hydrogel usingextrusion-based 3D bioprinting. The implant was placed into porcine eyes that had under-gone Femtosecond-Laser-Assisted Intrastromal Keratoplasty. By day 14, although de novoextracellular matrix materials, including collagen, had been synthesized, the MSCs hadmigrated out of the implanted scaffold. As no healing occurred around the corneal flap atthe site of the excisions [90], the quick MSC migration likely did not allow the stroma tofully regenerate. With stromal regeneration and collagen formation, the concern of collagenfibril directionality also exists. If a collagen-based bioink is used, shear stress, adjusted bythe bioprinting nozzle diameter, can be used to help align the collagen fibril deposition [91].4.4. Drug-Eluting Contact LensesHigh-resolution 3D printers can fabricate contact lenses (CL) or CL-like devices withbuilt-in channels or reservoirs for drug delivery. Such devices are useful for conditionsrequiring prolonged drug release like dry eye disease, bacterial or allergic conjunctivitis,glaucoma, post-surgical antibiotic prophylaxis, and post-surgical anti-inflammatory treat-ment. A drug-eluting CL can provide benefits for patients with dexterity challenges whilereducing medication loss through tears and nasolacrimal drainage permitted by sustaineddrug release. A timolol-loaded ethylene-vinyl acetate copolymer-polylactic acid (PLA/EVAblend) contact lens was 3D-printed via fusion deposition modeling by Mohamdeen et al.Unfortunately, the CL had poor drug release kinetics with 50% of the total drug releasedin the first 5 h. The reloadability of the CL drug reservoir was not mentioned, nor wereany in vivo trials done to determine clinical significance [92]. Urbánek et al. developed a3D-printed contact-lens-like drug delivery device (CLLD) embedded with levofloxacin andtetracaine and compared the drug release and penetration profile through the cornea versustopical eye drops ex vivo. The amount of released API (tetracaine/levofloxacin) from theCLLD was significantly greater compared to the predicted typical ocular absorption of thedrugs from eye drops [93]. Although no in vivo testing of the device for infection controland prophylaxis was conducted, given the amount of API absorption measured, its clinicalbenefit would likely be very similar to commercially available eye drops.4.5. Ophthalmologist TrainingThe 3D printing of ophthalmologist training materials can be a cost-effective andpractical educational resource. A corneal trauma simulation model was developed using amulti-material polyjet 3D printer by Fu, Hollick, and Jones. In the event, 84.3% of partici-pants agreed that the corneal trauma model was appropriately realistic for suture practice,and ophthalmologists self-reported an increase in confidence in corneal suturing afterBiomimetics 2024, 9, 145 17 of 28using the model [94]. This could be used as an alternative to animal or cadaver eyes whereaccess and supply may be limited. For drug-eluting contact lenses and similar devices,3D printing can allow fine-tuning of lens thickness, curvature, and microporosity for drugstorage. These products may be close to in vivo testing and future commercialization giventheir safety and practicality.Significant challenges and concerns still remain with the in vivo use of bioprintedcorneal tissue grafts, including graft cell viability, optical aberrations, graft rejection, poorre-epithelialization, and healing. Some of the studies discussed also had de-differentiationof corneal keratocytes back into mesenchymal stem cells which pose problems if stromalhealing and regeneration have not been completed. Additional research and improvementsare needed before a viable, bioprinted corneal tissue graft can be developed; however,significant progress has been made towards this goal in recent years (Table 6).Table 6. Summary of 3D-Printed Corneal Devices.Procedure Material Used Printing Type Results Setting Advantage/Disadvantage Reference3D-printed implantscaffold for cornealregenerationGelMA, type IcollagenPneumatic, dualextruder printerIncreased slope gradienton the scaffold results instronger adhesion andaligned cell organization.In vitroUnderstanding of howimplant shape affectsfactors concerningcorneal regeneration.[81]Corneal bioprintingutilizingcollagen-basedbioinksType Icollagen-basedbioinkDrop-on-demand(DoD) bioprintingCell viability confirmedat 7 days. Significantlyless compressivemodulus in printed vs.human cornea.In vitro Optical properties ofprinted cornea unknown. [82]Use of hyaluronicacid-based bioinkfor 3D printing ofhuman cornealstromaHuman adiposestem cells (hASCs)and hASC-derivedcorneal stromalkeratocytes,hyaluronicacid-based bioinkwith hydrazonecrosslinkingExtrusion-based 3DprintingDevelopment of abiocompatible bioinkwith future clinicalpotential and humantesting.In vitro & exvivoBioprinted cornealstructure showedeffective ex vivointegration to porcinecornea. Potential forfuture in vivo humantesting. No cytotoxicitydetected.[83]3D bioprinting of acorneal stromaCorneal keratocytes,methacrylated type Icollagen, sodiumalginatePneumatic 3D dualextrusionbioprintingThis is an earlier studytrying to establishpotential in the use of 3Dprinting for developmentof a corneal stroma.In vitroKeratocytes showedsurvivability and notoxicity noted.No consideration oflong-term cell survival,cell adhesion, layering,and differentiation.[87]Development of anovelcornea-specificbioinkBovinecornea-derivedextracellular matrix)bioinkNot givenBioink found to bebiocompatible andallows for thedifferentiation ofturbinate-derivedmesenchymal stem cells(hTMSCs) andkeratocytes.In vitroBiocompatibleestablished in vitro, nocytotoxicity observed.Seemingly appropriatetransparency of theprinted cornea.[88]3D printing of anepithelium/stromallayer for an anteriorlamellarkeratoplastyGelMA, long-chainpoly(ethyleneglycol) diacrylate,rabbit cornealepithelial cells,rabbitadipose-derivedmesenchymal stemcellsDigital LightProcessing (DLP)Bioprinted scaffold(epithelial and stromallayer) integrates into theexisting rabbit corneawell leading tore-epithelialization andstromal regeneration.In vivoBiocompatible, goodin vivo integration andpotential for futurehuman testing.[68]Finding anappropriate sodiumcitrate/sodiumalginate ratio forbioprinting cornealcellsAlginate-basedbioink and humancorneal epithelialcellsExtrusion-based 3Dcell-printingBy altering the sodiumcitrate/sodium alginateratio in the gel, its abilityto degrade improves,allowing better cornealcell proliferation.In vitro High cell viability wasmaintained. [70]Novel method forKeratoprosthesisusing 3D printingand the recipient’sown cornea3D-printed titaniumback plate, PMMAfront stemNot givenSuccessful technique,improving on thestandardkeratoprosthesisprocedure which requiresdonor corneal tissue.In vivo Many post-surgicalcomplications. [89]Biomimetics 2024, 9, 145 18 of 28Table 6. Cont.Procedure Material Used Printing Type Results Setting Advantage/Disadvantage ReferenceUse of3D-bioprintedscaffolds withmesenchymalstromal cells for akeratoplastyprocedure3 differentmultipotentmesenchymalstromal cells(adipose-derived,bonemarrow-derived,and cornealstroma-derived)Extrusion-based 3DbioprintingFemtosecond-Laser-Assisted IntrastromalKeratoplasty was highlyeffective for cornealexcision. Thekeratoplasty procedureand bioink did notundergo appropriatehealing and celldifferentiation.In vivoMesenchymal stromalcells did not undergodifferentiation towardscorneal keratocytes. Poorhealing aroundimplanted corneal flap.[90]Development of a3D-printeddrug-eluting contactlensEthylene-vinylacetate andcopolymer-polylactic acid blendFusion depositionmodelingSuccessful developmentof a drug eluting contactlens, but poorpharmacologiccharacteristics.In vitroPoor drug releasekinetics (majority of drugreleased in the first 24h—poorly sustained,long-term releasekinetics).[92]Development of a3D-printeddrug-eluting contactlensCollagen basedmaterial,levofloxacin,tetracaineNot givenSuccessful production ofa drug-eluting contactlens embedded withlevofloxacin andtetracaine.In vitroReleased API from thedrug delivery device wassignificantly greater vs.the predicted typicalocular absorption of thedrug from eye drops.However, clinicalsignificance was notmeasured.[93]5. Applications in Glaucoma TherapeuticsGlaucoma, infamously referred to as the “silent thief of sight”, insidiously advanceswithout noticeable early symptoms, often resulting in a delay in diagnosis and treatment.This disease, a leading cause of irreversible blindness worldwide, manifests as glaucoma-tous optic neuropathy. This pathology is identified by characteristic optic disc cuppingor excavation, axonal degeneration, and apoptosis of retinal ganglion cells, leading topermanent vision loss [95]. The complex origins of glaucoma involve a combination ofgenetic and environmental factors. Elevated intraocular pressure (IOP) remains the onlymodifiable risk factor for the onset of glaucoma [95].5.1. Diagnostic and Monitoring ToolsThree-dimensional printing technology has enabled the development of cutting-edgetools for researching, diagnosing, and monitoring glaucoma. A pioneering team developeda rapid, portable, and cost-effective glaucoma-detecting device consisting of a 3D-printedreadout box and a smartphone camera, suitable for point-of-care settings, promoting theearly identification of glaucoma [96]. Furthermore, 3D printing’s high resolution andcustomization capabilities with various ink materials can be applied to smart contactlens fabrication. One notable application involved the generation of 3D-printed smartsoft contact lenses capable of constant IOP monitoring in a less invasive and convenientmanner, substantially enhancing disease management, and raising the possibility of tailoredpersonal treatment plans [97].5.2. Minimal Invasive Glaucoma SurgeryCurrent glaucoma treatment involves medication, generally in the form of eye dropsand surgical procedures such as trabeculectomy, drainage implants, and minimal inva-sive glaucoma surgery (MIGS). The main objectives of these interventions are to reduceIOP and prevent further damage to the optic nerve. MIGS has been developed in recentyears, involving the use of microsurgical devices, and making smaller incisions in the eyecompared to traditional trabeculectomy. Three-dimensional printing technology has signifi-cantly advanced MIGS procedures requiring high accuracy and micro instrumentation [95].For instance, Sverstad’s study tested a 3D-printed MIGS stent in vitro, featuring multiplechambers for modifiable aqueous humor drainage to better control IOP [98]. Anothergroup employed 3D printing to develop a MIGS stent injector device, which is superiorBiomimetics 2024, 9, 145 19 of 28in offering precise placement and adaptability to various stent designs [99]. Furthermore,additive manufacturing of 3D printing layer by layer allows complex, structured, andmulti-functional instruments to be printed into one piece without assembling. The cus-tomizable nature of 3D printing allows for the generation of instruments fitted to the patientand surgeon’s ergonomics. These tailored instruments may greatly improve outcomesand efficiency in minimized invasive surgeries by providing better control and precision,indirectly minimizing surgical errors [100–102].5.3. Drug-Eluting ImplantsThe integration of 3D printing technology enables research teams to develop cus-tomizable and sustainable drug-eluting implants for glaucoma patients. Compared totraditional eye drop treatments, these implants offer convenience in long-term medicationmanagement, improve patient adherence, and potentially reduce side effects [92,103,104].Also, 3D printing revolutionizes the production of drug-eluting contact lenses, offeringhigh-resolution manufacturing for lenses with drug-storing apertures, ensuring sustainabledrug release for an extended period. Current state-of-the-art 3D-printed drug-elutingcontact lenses utilize printing methods such as hot melt extrusion and fusion depositionmodelling to fabricate timolol maleate-loaded contact lenses [92,105]. An alternative drugdelivery method for glaucoma patients, ensuring sustained drug release, involves punctalplugs with drug-eluting capabilities [106]. Researchers have been exploring high-resolution3D printing techniques, such as digital light processing, to create drug-loaded punctalplugs with smooth surfaces [55]. The technology allows for localized delivery and pre-cise customization of dosage administration for individual eyes, enhancing both comfortand personalized treatment [107]. In addition, a team demonstrated the possibility ofusing 3D-printed antimetabolite drug-release implants to prevent conjunctival fibrosis afterglaucoma surgery [108]. However, most 3D-printed devices are still in the early stagesof development and await further clinical trials. They face challenges such as a lack ofstandardization and regulatory guidelines and the limited availability of biocompatible ma-terials. Nevertheless, more medical research teams are developing implants for glaucomapatients according to needs as 3D printing technology continues to advance and becomemore accessible [103,104,108].In summary, the integration of 3D printing technology in glaucoma therapeutics offersvarious applications, including diagnostic tools, minimal invasive glaucoma surgery, anddrug-eluting implants. Table 7 provides a summarized overview of the methods, parame-ters, results, and potential disadvantages/complications associated with each application.Biomimetics 2024, 9, 145 20 of 28Table 7. Application of 3D Printing in Glaucoma Therapeutics.Usage 3D Printing Methods Used Results Types of Study Challenges ReferenceDiagnosis & Monitoring3D-printed (printer not specified) readoutbox and lateral flow assay (LFA) caseRapid, portable, and cost-effectiveglaucoma-detecting device by LFAquantification of BDNF concentration inartificial tear fluids; suitable forpoint-of-care settingsPrototype development andcharacterizationLimited experimental detectionlimit; limited stabilityinformation[95]Automated nozzle injection system(Nordson EFD) equipped on a three-axiscomputer-controlled translation stage3D-printed smart soft contact lenses forconstant IOP monitoring; intrinsicproperties unchanged compared tocommercial soft contact lens:biocompatibility, softness, transparency,wettability and oxygen transmissibilityin vivo - [96]MIGSMicro-precision three-dimensional printerwith projection micro stereolithographytechnology and photosensitive materialsProof of concept for a glaucoma stent withmultiple lumina that can be separatelyopened with an argon laser trabeculoplasty(ALT)-like procedure for a predictablepressure-lowering effectin vitro Further in vivo study issuggested [97]A microstent injector device wasmanufactured using a fused depositionmodelling (FDM) 3D printer (Form2 printer, Formlabs Inc) and variousphotoactive polymersDevelopment of a 3D-printed antifibroticdrug-eluting MIGS stent with modifiableaqueous humor drainage.in vitroLimited in vivo, invitro andclinical data of the device; furtheroptimization of the drug-elutingcoating is required[98]3D-printed multi-steerable cable-driveninstrument printed using Digital LightProcessing (DLP) (Perfactory1 Mini XL,EnvisionTEC GmbH)Fully 3D-printed, customizable instrumentsfor better control and precision based onergonomic principles. Potential applicationsin MIGSComparison studies:questionnaires and taskperformances; instrumentmechanical evaluationLimited availability ofbiocompatible materials;familiarization of instrumentrequired to avoid excessive forceand instrument breakage[99–101]Biomimetics 2024, 9, 145 21 of 28Table 7. Cont.Usage 3D Printing Methods Used Results Types of Study Challenges ReferenceDrug-Eluting ImplantsTriamcinolone acetonide-loadedpolycaprolactone-based ocular implantsfabrication using GeSiM 2.1 Bioscaffolder3D BioprinterCustomizable (in shapes and drugloadings); sustainable drug-elutingimplants (6 months); biocompatible, safeocular application (>90% cell viability)in vitroEarly stage of development;further in vivo studies andclinical trials are required toensure the safety of implants[102]The device is not 3D-printed; the paperbrought up the possibility of PCL-baseddrug delivery implantDeveloped an intracameralpolycaprolactone glaucoma device(spin-casting made PCL thin filmsencapsulating proprietary hypotensiveagent); long-term (23 weeks), effective IOPreduction with drug-eluting implants;3D-printed injector device for preciseplacement.in vivo (rabbit eye model) - [103]3D-printed PCL and chitosan-baseddrug-eluting implant using heat extrusiontechnologySustained, long-term (8 weeks)5-fluorouracil drug-releasing implant;effective in suppressing fibroblastcontractility and preventing conjunctivalfibrosis after glaucoma surgery;biocompatible (no significant changes incell viability) and biodegradablein vitroIn vivo experiments required;risks of allograft rejection forbiomaterials[107]Hot melt extrusion coupled with fusiondeposition modelling (FDM) to printethylene-vinyl acetate copolymer–polylacticacid blendsSustained drug release of timolol maleatefor extended periods (3 days); introductionof drug-eluting contact lenses withhigh-resolution 3D printing manufacturingPrototype development andcharacterizationDrug release optimization,in vitro and in vivo studiesneeded[91]Modified commercial inkjet printer(O2Nails V11 inkjet printer) and Form 1+3D printer with v4 clear resin (FormlabsInc., MA, USA)Contact lenses drug-release over at least 3 h,longer than eye drops; accurate drugdose-loading quantification withnear-infrared (NIR) spectroscopyin vitro - [104]Digital light processing (DLP) 3D printingwas employed to assemble polyethyleneglycol diacrylate (PEGDA) andpolyethylene glycol 400Punctal plugs with drug-eluting capabilitiesfor sustained drug release (dexamethasone,7 days)in vitroDrug-loaded micro stents wereless cytocompatible than blankcontrols[106]3D-printed polypills by selective laser sinter(SLS) printerDeveloped a non-destructive method forquality control for 3D-printedantimetabolite drug-release implant (thedrugs loaded were amlodipine andlisinopril for preventing conjunctivalfibrosis)Prototype development andcharacterizationLack of standardization andregulatory guidelines fordrug-eluting implants[55]Biomimetics 2024, 9, 145 22 of 286. 3D Printing in Ophthalmic Prototyping and Simulation6.1. Training Model for Surgical PracticeThree-dimensional printing technology offers realistic training devices that are morecost-effective and accessible than traditional animal or cadaver models. For instance,Lichtenstein’s team developed a 3D-printed tactile and structurally mimicking model in-corporating both hard and soft tissues for orbital surgical training [109]. In a survey byRama et al., more than 84% of students taught with 3D-printed orbital fracture modelsfound them useful for enhancing visual–spatial skills, anatomy education, and surgicaltraining [110]. Beyond orbital fracture training, 3D-printed eye models prove valuable forstrabismus surgery training, with surveys confirming their fidelity compared to conven-tional rabbit head models. Silicone, identified as a better substitute material for extraocularmuscles in cadaver eye models, along with the 3D-printed silicone head faceplate, enhancesthe realistic positioning and orientation of the eyeball compared to conventional rabbithead training [111]. As 3D printing models are based on tomography scans from variouspatients, they enable the exploration of diverse scenarios and anatomical variations. Addi-tionally, 3D printing technology facilitates the fabrication of cost-effective teaching tools,including customized eye mounts for cadaveric eyes, artificial irises for wet lab trainingmodels, and an eyeball puzzle assembly toolkit, supporting personalized approaches tosurgical education [112–114].6.2. Prototyping and Simulation3D printing is widely utilized in ophthalmological surgeries to enhance preoperativesurgical planning, reduce surgical time, and improve surgical outcomes. A 1:1 patient-specific disease model can be fabricated using tomography scans, providing surgeonswith a detailed representation of the individual’s distinct pathological condition. Theserapid prototyping models allow surgeons to simulate and rehearse surgical steps, servingvital roles in surgical planning and indirectly reducing intraoperative decision-makingtime. Additionally, 3D-printed models can act as osteotomy or cutting guides and facilitatethe pre-molding and pre-fitting of implants such as titanium meshes or plates, therebyreducing surgical time and indirectly minimizing surgical risks [115–117]. For instance,surgical corrections for craniofacial deformities, known for their high patient specificityand complexity, have benefited from 3D printing technology. Ouyang et al. reported asuccessful case of orbital hypertelorism correction with the aid of a 3D-printed cuttingguide. The study created a 1:1 plaster model of the skull with a predetermined osteotomyguideline that assisted in surgical planning and served as an intraoperative guide [58].Another team conducted forty cases of computer-assisted craniofacial malformity surgeries,treating hypertelorism, craniosynostosis, and orbital trauma with the aid of 3D-printedcutting guides. A stereolithographic model was fabricated for each patient, supportingcomplex cases of craniofacial osteotomy, surgical simulation, pre-planned optimized cuttingguides, and pre-fitting of implants [118].Beyond craniofacial malformities, 3D printing technology has been applied in treatingtumor masses. For instance, performing radiosurgery for intraocular tumors, such as uvealmelanoma, requires high radiation precision. Furdova’s team 3D-printed the patient’seye model with the targeted tumor mass based on CT and MRI data to aid in planningstereotactic radiosurgery [119]. Three-dimensional printing also enables different structuresof the eye, vasculature, and tumor mass to be printed in different colors and materials, withthe model available in various scale sizes to better assist in visualizing and understandingthe pathological region. Excitingly, the incorporation of 3D printing in veterinary ophthal-mological surgeries, characterized by a more diverse anatomy and complexity, is now apossibility. Another study applied 3D printing in veterinary orbital and peri-orbital massestreatment planning and surgical planning, assisting in tumor resection, cryotherapy, andorbitotomy [120]. However, it is important to note the drawbacks of 3D printing, includingthe difficulty in simulating soft tissues and the potential for anatomical changes or tumorgrowth between the time of scanning and surgery, especially in young patients. There wereBiomimetics 2024, 9, 145 23 of 28also concerns about limited intraoperative flexibility once the implants were pre-fitted orpre-molded [118].6.3. Use in Doctor–Patient CommunicationIn addition to its clinical and surgical applications, 3D-printed patient-specific modelsplay a significant role in doctor–patient communication. Multiple studies suggest thebenefits of 3D-printed models on the doctor–patient relationship, helping the patientunderstand their disease progress, surgery expectations and risks, and preventing potentialmalpractices [121–123].7. ConclusionsIn conclusion, the vanguard of ophthalmological innovation, championed by biomimet-ics, 3D printing, and bioprinting, heralds a bright and transformative future for the field.These technologies do not just imitate the complex architecture of ocular tissues but areunlocking unprecedented opportunities in oculoplastic surgery, retinal tissue engineering,corneal transplantation, and precise glaucoma interventions. Our comprehensive reviewunderscores the significant strides made from 2014 to 2023, offering a panoramic view ofthe advances and setting a course for their clinical application.With the development of state-of-the-art surgical models, enhanced preoperativeplanning, and innovative therapeutic devices, the promise of tailored ophthalmic careis closer than ever. As we look to the future, the potential advantages of 3D printingand bioprinting suggest a promising horizon for overcoming the limitations inherent inconventional methods, and the path forward is marked by a collaborative spirit that spansdisciplines and bridges the gap between bench and bedside.This synthesis of fundamental science and clinical practice invites a future where everypatient benefits from the precision and personalization that these technologies offer. Thereis a palpable sense of optimism as we anticipate the continued evolution of these modalities,ensuring that the vision of individualized treatment becomes a reality. As we forge ahead,it is the unity of researchers, engineers, and clinicians that will illuminate the way, turningtoday’s innovations into tomorrow’s standard care in ophthalmology, enhancing lives onepatient at a time.Author Contributions: Conceptualization, K.Y.W.; writing—original draft preparation, K.Y.W. andA.T.; writing—review and editing, K.Y.W., A.T., É.M. and S.D.T.; supervision, K.Y.W. and S.D.T. Allauthors have read and agreed to the published version of the manuscript.Funding: This research received no external funding.Acknowledgments: Gurleen Nirwal contributed to the Overview section; Zhuoying Liao contributedto the section on Glaucoma; Xingao (Clara) Wang contributed to the section on Oculoplastic andOrbital Surgery; and Tony Li contributed to figure creation.Conflicts of Interest: The authors declare no conflicts of interest.References1. Moshfeghi, D.M.; Moshfeghi, A.A.; Finger, P.T. Enucleation. Surv. Ophthalmol. 2000, 44, 277–301. [CrossRef]2. Dortzbach, R.K.; Woog, J.J. Choice of Procedure: Enucleation, Evisceration, or Prosthetic Fitting Over Globes. Ophthalmology 1985,92, 1249–1255. [CrossRef] [PubMed]3. Kostick, D.A.; Linberg, J.V. Evisceration with Hydroxyapatite Implant: Surgical Technique and Review of 31 Case Reports.Ophthalmology 1995, 102, 1542–1549. [CrossRef]4. Walter, W.L. Update on Enucleation and Evisceration Surgery*. Ophthal. Plast. Reconstr. 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Faculty
biomimetics
tissue engineering
3D printing
bioprinting
ophthalmology
oculoplastic surgery
retinal tissue engineering
corneal transplantation
glaucoma
surgical simulation
clinical translation
Towards Precision Ophthalmology: The Role of 3D Printing and Bioprinting in Oculoplastic Surgery, Retinal, Corneal, and Glaucoma Treatment
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