Other UBC
Non UBC
DSpace
International Journal of Molecular Sciences 23 (2): 723 (2022)
St. Paul's Hospital (Vancouver, B.C.). Centre for Heart Valve Innovation
Zhang, Xiling
Puehler, Thomas
Seiler, Jette
Gorb, Stanislav N.
Sathananthan, Janarthanan
Sellers, Stephanie
Haneya, Assad
Hansen, Jan-Hinnerk
Uebing, Anselm
Müller, Oliver J.
Frank, Derk
Lutter, Georg
Patients with the complex congenital heart disease (CHD) are usually associated with right ventricular outflow tract dysfunction and typically require multiple surgical interventions during their lives to relieve the right ventricular outflow tract abnormality. Transcatheter pulmonary valve replacement was used as a non-surgical, less invasive alternative treatment for right ventricular outflow tract dysfunction and has been rapidly developing over the past years. Despite the current favorable results of transcatheter pulmonary valve replacement, many patients eligible for pulmonary valve replacement are still not candidates for transcatheter pulmonary valve replacement. Therefore, one of the significant future challenges is to expand transcatheter pulmonary valve replacement to a broader patient population. This review describes the limitations and problems of existing techniques and focuses on decellularized tissue engineering for pulmonary valve stenting.
Citation: Zhang, X.; Puehler, T.;Seiler, J.; Gorb, S.N.; Sathananthan, J.;Sellers, S.; Haneya, A.; Hansen, J.-H.;Uebing, A.; Müller, O.J.; et al. TissueEngineered Transcatheter PulmonaryValved Stent Implantation: CurrentState and Future Prospect. Int. J. Mol.Sci. 2022, 23, 723. https://doi.org/10.3390/ijms23020723Academic Editors: Barbara Zavan,Stefano Sivolella and Alfredo RoncaReceived: 17 December 2021Accepted: 5 January 2022Published: 10 January 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 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/). International Journal of Molecular SciencesReviewTissue Engineered Transcatheter Pulmonary Valved StentImplantation: Current State and Future ProspectXiling Zhang 1,2,†, Thomas Puehler 1,2,† , Jette Seiler 1,2, Stanislav N. Gorb 3 , Janarthanan Sathananthan 4,Stephanie Sellers 4, Assad Haneya 1, Jan-Hinnerk Hansen 5, Anselm Uebing 2,5, Oliver J. Müller 2,6 ,Derk Frank 2,6 and Georg Lutter 1,2,*1 Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein (UKSH), D-24105 Kiel,Germany; zhang_xiling@outlook.com (Z.X.); thomas.puehler@uksh.de (T.P.); jette.seiler@uksh.de (J.S.);assad.haneya@uksh.de (A.H.)2 DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, D-20251 Hamburg,Germany; anselm.uebing@uksh.de (A.U.); oliver.mueller@uksh.de (O.J.M.); derk.frank@uksh.de (D.F.)3 Department of Functional Morphology and Biomechanics, Zoological Institute,Christian-Albrecht University of Kiel, D-24105 Kiel, Germany; sgorb@zoologie.uni-kiel.de4 Department of Centre for Heart Valve Innovation, St Paul’s Hospital, University of British Columbia,Vancouver, BC V5K 0A1, Canada; jsathananthan@providencehealth.bc.ca (J.S.);SSellers@providencehealth.bc.ca (S.S.)5 Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein,Campus Kiel, D-24105 Kiel, Germany; JanHinnerk.Hansen@uksh.de6 Department of Cardiology and Angiology, University Hospital Schleswig-Holstein (UKSH),D-24105 Kiel, Germany* Correspondence: georg.lutter@uksh.de† These authors contributed equally to this work.Abstract: Patients with the complex congenital heart disease (CHD) are usually associated with rightventricular outflow tract dysfunction and typically require multiple surgical interventions duringtheir lives to relieve the right ventricular outflow tract abnormality. Transcatheter pulmonary valvereplacement was used as a non-surgical, less invasive alternative treatment for right ventricularoutflow tract dysfunction and has been rapidly developing over the past years. Despite the currentfavorable results of transcatheter pulmonary valve replacement, many patients eligible for pulmonaryvalve replacement are still not candidates for transcatheter pulmonary valve replacement. Therefore,one of the significant future challenges is to expand transcatheter pulmonary valve replacement to abroader patient population. This review describes the limitations and problems of existing techniquesand focuses on decellularized tissue engineering for pulmonary valve stenting.Keywords: tissue engineering; heart valve replacement; pulmonary; transcatheter; percutaneous;biodegradable; nitinol; stents; congenital heart disease; decellularization; recellularization1. IntroductionThe incidence of congenital heart disease (CHD) is approximately 9‰ in newborns [1].Approximately 20% of newborns with CHD have malformations of the pulmonary valveor right ventricular outflow tract (RVOT), such as tetralogy of Fallot, one common arterialtrunk, or pulmonary atresia [2]. In this patient group, surgical correction in the first monthof life improves patient prognosis [3]. Surgical strategies for RVOT reconstruction includetransannular patch enlargement, bioprosthetic valve placement, and valved conduits [4].The tolerability of surgical intervention of the RVOT for complex CHD depends on thepatient’s age and the type of tissue material used [4,5].However, multiple complications such as pulmonary regurgitation, self-growth, ex-ternal ductal stenosis, valvular stenosis, ductal distortion, sternal compression, intimalInt. J. Mol. Sci. 2022, 23, 723. https://doi.org/10.3390/ijms23020723 https://www.mdpi.com/journal/ijmsInt. J. Mol. Sci. 2022, 23, 723 2 of 19hyperplasia, external ductal calcification, and deformation of the aneurysm lead to progres-sive RVOT dysfunction in these patients [4,6].Therefore, repeated surgical interventions are required throughout their lives. Despitethe low mortality rate of surgical interventions, complications are significantly higher,especially in patients undergoing repeated procedures [7,8].In this clinical context, transcatheter pulmonary valve replacement (TPVR) has emergedas a non-surgical, less invasive alternative treatment for RVOT dysfunction.In 2000, Bonhoeffer et al. [9] successfully performed the first TPVR using a bare-metalplatinum alloy stent and a manually sewn flap bovine jugular vein [2,10]. In the decadesince then, catheter-based valve implantation has evolved rapidly. As a result of TPVR,the interval between surgical replacements has approximately doubled [11]. Although theresults are encouraging, the heterogeneity of this patient population and the diversity ofmorphology, size, and hemodynamics of the implantation site allow for TPVR in only about15% of patients, which means that surgical pulmonary valve replacement is still necessaryfor 85% of patients, limiting the applicability of TPVR [12].In addition, valve implantation is not without complications. The prosthetic valvescurrently used in clinical practice have significant deficits. Mechanical valve replacementsrequire lifelong anticoagulation therapy, with the attendant risk of bleeding and thrombo-embolism [13], while biological valves are poorly durable, with an average useful lifeof only about 7 to a maximum of 15 years, due to changes such as calcification anddecay in the distant future [14,15]. Moreover, since the allograft or homograft may nevergrow, it was a pitfall for younger patients, meaning they may have to undergo multiplesurgeries [16]. Despite the use of transcatheter valves, interventions were required every2.6 years (median) [11].Tissue engineering is a multidisciplinary field that aims to develop biological tissuesthat can be used in the clinical treatment of diseases. Tissue-engineered products haveproven to be effective in different applications, such as burn treatment or drug screening.The success of this approach in other medical fields has established the foundation for itsapplication in heart valves [17–22]. A new alternative therapy to replace faulty valve graftsis emerging—tissue-engineered heart valves. These limitations are being overcome bytissue-engineered heart valves that are living, non-cytotoxic, and mechanically analogousheart valve replacements, and can grow and remodel with the patient. However, livingvalves still have insurmountable problems, including the choice of living material, thecomplexity of in vitro culture, and how the valves are stored. All of these issues havehindered the commercialization of tissue-engineered heart valve therapies.This review discusses the applications and limitations of TPVR and the practice andprospects of tissue-engineered valved stents.2. Transcatheter Pulmonary Valve Replacement in Large Right Ventricular Outflow TractsTPVR currently has a high success rate with favorable safety and prognosis. A96.2% success rate was reported in a previous meta-analysis [23]. Data from US clini-cal trial data, the freedom from 5-year reintervention and reinsertion rates were reportedto be were 76 ± 4% and 92 ± 3%, respectively [24]. However, the current indicationsfor TPVR are limited to postsurgical RVOT dysfunction with an enlarged ductal inter-nal diameter between 16–24 mm (Melody valve, Figure 1A) and 21–27 mm (SAPIENvalve, Figure 1B) [16,25,26]. It is estimated that only 15% of patients with CHD andRVOT dysfunction meet such stringent criteria [12,27]. Most patients who would ben-efit from TPVR are those with non-indicated applications, such as native RVOT or RVOTenlarged by transannular patch, bioprosthetic valves, or small internal diameter (<16 mm)of external ducts.Int. J. Mol. Sci. 2022, 23, 723 3 of 19Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 19 addressed solely by the transcatheter aortic valve stents currently available on the market. An innovative transcatheter stent must be developed to remove surgical limitations. Figure 1. (A) Medtronic Melody Pulmonary valve, comprised of a bovine jugular vein valve sutured within a platinum iridium frame; with the permission of reproduction by Medtronic Inc. (B) Edwards SAPIEN 3 valve, made of bovine pericardial tissue attached to a balloon‐expandable, cobalt‐chromium frame for support; with the permission of reproduction by Edwards Lifesciences Inc. (C) Medtronic HARMONY Transcatheter Pulmonary Valve, comprised of porcine pericardial tissue valve and self‐expanding nitinol frame with polyester cloth covering; with the permission of reproduction by Medtronic Inc. (D) VenusP‐Valve, consisting of a self‐expanding stent made of nitinol with a tri‐leaflet porcine pericardial tissue; with the permission of reproduction by Venus Medtech Inc. (E) Edwards SAPIEN XT valve, made of bovine pericardial tissue with high radial strength cobalt‐chromium frame with low frame height design; with the permission of reproduction by Edwards Lifesciences Inc. Figure 1. ( ) edtronic Melody Pulmonary valve, comprised of a bovine jugular vein valve suturedwithin a platinum iridium frame; with the permission of reproduction by Medtronic Inc. (B) EdwardsSAPIEN 3 valve, made of bovine pericardial tissue attached to a balloon-expandable, cobalt-chromiumframe for support; with the permission of reproduction by Edwards Lifesciences Inc. (C) MedtronicHARMONY Transcatheter Pulmonary Valve, compris d of porcine pericardial tissue valve andself-expanding nitinol frame with polyester cloth covering; with the permission of reproduction byMedtronic Inc. (D) VenusP-Valve, consisting of a self-expanding stent made of nitinol with a tri-leafletporcine pericardial tissue; with the permission of reproduction by Venus Medtech Inc. (E) EdwardsSAPIEN XT valve, made of bovine pericardial tissue with high radial strength cobalt-chromium framewith low frame height design; with the permission of reproduction by Edwards Lifesciences Inc.Boshoff et al. [27] reported 23 cases of TPVR applied non-indicatively, including8 cases of enlarged RVOTs with transannular patches without external conduits, 2 cases ofpulmonary valve stenosis, and 13 cases of external conduits with small internal diameters.At a mean follow-up time of 1.2 years, the peak RVOT pressure difference was significantlylower, and no more than mild pulmonary regurgitation was present. Two patients were re-intervened for the development of restenosis. No vascular complications, stent disruption,or valve migration occurred during follow-up. Meadow et al. [28] found a solution to theright ventricle-to-pulmonary artery pressure difference, successfully following 31 patientswith TPVR for RVOT dysfunction on their own or without an external conduit. Similarencouraging results were observed in cases of percutaneous “valve in valve” after biologicvalve dysfunction. A total of 104 cases of TPVR after biologic valve dysfunction wereInt. J. Mol. Sci. 2022, 23, 723 4 of 19reported by Gillespie et al. [29] At a median follow-up of 1 year, four cases of restenosiswith no more than mild pulmonary regurgitation were observed, and at follow-up, stentdisruption was observed in two cases, none of which required further intervention. Overall,the 2-year reintervention-free rate was >90%, and no operation-related deaths occurred.There are clearly increased complications associated with non-indicated applicationscompared to strict adherence to indications as well as issues related to liability and ethicsfor non-indication applications. However, situations exist in which TPVR is clinicallyindicated in healthcare settings based on published data or standard practice, but it remainsnon-indicated if applied by regulatory agency regulations. In such cases, patients may bedeprived of effective therapeutic measures because of strictly limited indications. As TPVRtechnology evolves, more and more large clinical studies on the use of TPVR in small innerdiameter, non-tubularly placed RVOT cases will be conducted, expanding the indicationsfor TPVR in the near future.A range of innovative techniques are emerging to expand the population for TPVR,particularly in patients with dilated RVOTs.In 2010, Schievano et al. [30] reported a case of successful transcatheter self-expandingpulmonary valve expansion (Figure 2). This device was later called the Native OutflowTract device (Medtronic, Figure 1C). It has an hourglass contour line with relatively largeinternal diameters at the ends and relatively small internal diameters in the middle. Theself-expanding properties of the nitinol stent could, in theory, improve valve stability inthe presence of different RVOT morphologies. At 6-month follow-up, no stent fracture andonly trivial paravalvular leakages were observed.Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 5 of 19 Figure 2. New device: (A) An end‐on‐view of the new device showing the Nitinol stent with graft covering and the open pericardial valve leaflets. (B) The delivery system with the device crimped and loaded onto the distal end (right side of picture) [30]. 2.1. Development of Tissue‐Engineered Pulmonary Valves While pulmonary valve replacement can be lifesaving in pediatric and adolescent patients, there is a critical problem: the graft cannot grow. This means that such patients may have to undergo multiple surgeries, increasing the risk of complications and even death. To address this problem, tissue‐engineered valves can create a living heart valve with excellent self‐repair and reconstruction capabilities that can overcome the various disadvantages of current prostheses. Tissue engineering can enhance the ability of damaged, malformed, or diseased valve tissue to heal itself by guiding the reconstruction of a native extracellular matrix (ECM) bionic microenvironment with appropriate biomechanical properties, as well as providing the necessary bionic physical and biological stimuli. Synthetic resorbable valves with bionic function not only transport cells but also provide mechanical support and bio‐stimulation to promote valve regeneration, thus meeting a variety of clinical needs [38]. The construction of novel valve materials by means of tissue engineering is expected to overcome the shortcomings of current valve materials. The tissue‐engineered heart valve (TEHV) is constructed by using a combination of porous cell scaffolds, seed cells, and bioactive factors with the ultimate goals of: (1) providing excellent hemodynamics without anticoagulation therapy, (2) promoting tissue remodeling and preventing valve degradation, and (3) having regenerative characteristics to avoid reoperation. TEHV cellular scaffolds mainly include natural material stents (such as decellularized tissue or biomaterials) versus synthetic material stents (degradable polymers). 2.2. Decellularized Tissue‐Engineered Heart Valve Decellularization is removing cells (including the nucleus) from the ECM of biological tissue. After cell removal, the remaining ECM provides a cellular scaffold with voids, which not only retains the complex geometry of natural tissues but also consists of natural components that promote cell migration and differentiation, resulting in constructive remodeling. In addition, decellularized valves do not require complete degradation and can maintain their own anisotropic mechanical properties. To date, decellularized heart valves (DHVs) are more favorable than synthetic‐material valves for clinical applications, and implantation has been accomplished in animals and humans as valve replacements. Although decellularized tissues have been used clinically for many years, it was not until 2011 that generally accepted quantifiable minimum criteria for moderate decellularization was generated [39]: in samples with (1) double‐stranded DNA (dsDNA) content < 50 ng/mg ECM dry weight; (2) DNA fragment length < 200 bp; and (3) no visible nuclei in sections stained with 4′,6‐diamidino‐2‐phenylindole (DAPI) or hematoxylin‐eosin (H&E) stained tissue sections without visible nuclei. Figure 2. New device: (A) An end-on-view of the new device showing the Nitinol stent with graftcovering and the open pericardial valve leaflets. (B) The delivery system with the device crimpedand loaded onto the distal end (right side of picture) [30].The Venous P valve stent (Shanghai, China,Figure 1D) is also a novel self-expandingpercutaneous pulmonary device consisting of a three-lobed porcine pulmonary valve anda surrounding nickel-titanium metal stent frame delivered by a 14- or 22-F sheath, withvalve sizes ranging from 20 to 32 mm. Small clinical studies have confirmed the safety andefficacy of the Venous pulmonary valve stent [31,32]. Given the ability of this device tofit the enlarged RVOT via a transannular patch, this device will play an important role inwidening the indications for TPVR in the future if additional clinical studies confirm thesepositive results.Similarly, the Sapien XT (Edwards, Figure 1E) 29 mm size valve can be used as analternative treatment for larger inner diameter RVOTs; although, this valve has not beenexplicitly studied in the pulmonary artery position. A percutaneous pulmonary valvedstent designed to reduce the internal diameter of the RVOT has been successfully placed inthe RVOT of sheep, but it is still in preclinical trials [33,34]. Other advanced techniques havebeen successfully used in patients with disseminated, complex RVOT geometry, includingplacement of Melody transcatheter pulmonary valves in both pulmonary arteries [35], andthe pulmonary artery “jailing” technique in which a folded bare metal stent is bifurcatedfrom the pulmonary artery into the RVOT to distend it as an anchor for TPVR [36].Int. J. Mol. Sci. 2022, 23, 723 5 of 19However, there are still some problems to overcome, such as tricuspid valve injury,paravalvular leakages, stent migration, arrhythmia, stent fracture, etc. [37]. The stentgrafts for patients with large native or patched RVOT diameters (>30 mm) cannot beaddressed solely by the transcatheter aortic valve stents currently available on the market.An innovative transcatheter stent must be developed to remove surgical limitations.2.1. Development of Tissue-Engineered Pulmonary ValvesWhile pulmonary valve replacement can be lifesaving in pediatric and adolescentpatients, there is a critical problem: the graft cannot grow. This means that such patients mayhave to undergo multiple surgeries, increasing the risk of complications and even death. Toaddress this problem, tissue-engineered valves can create a living heart valve with excellentself-repair and reconstruction capabilities that can overcome the various disadvantages ofcurrent prostheses. Tissue engineering can enhance the ability of damaged, malformed, ordiseased valve tissue to heal itself by guiding the reconstruction of a native extracellularmatrix (ECM) bionic microenvironment with appropriate biomechanical properties, as wellas providing the necessary bionic physical and biological stimuli. Synthetic resorbablevalves with bionic function not only transport cells but also provide mechanical support andbio-stimulation to promote valve regeneration, thus meeting a variety of clinical needs [38].The construction of novel valve materials by means of tissue engineering is expected toovercome the shortcomings of current valve materials. The tissue-engineered heart valve(TEHV) is constructed by using a combination of porous cell scaffolds, seed cells, andbioactive factors with the ultimate goals of: (1) providing excellent hemodynamics withoutanticoagulation therapy, (2) promoting tissue remodeling and preventing valve degradation,and (3) having regenerative characteristics to avoid reoperation. TEHV cellular scaffoldsmainly include natural material stents (such as decellularized tissue or biomaterials) versussynthetic material stents (degradable polymers).2.2. Decellularized Tissue-Engineered Heart ValveDecellularization is removing cells (including the nucleus) from the ECM of biologicaltissue. After cell removal, the remaining ECM provides a cellular scaffold with voids,which not only retains the complex geometry of natural tissues but also consists of naturalcomponents that promote cell migration and differentiation, resulting in constructiveremodeling. In addition, decellularized valves do not require complete degradation andcan maintain their own anisotropic mechanical properties. To date, decellularized heartvalves (DHVs) are more favorable than synthetic-material valves for clinical applications,and implantation has been accomplished in animals and humans as valve replacements.Although decellularized tissues have been used clinically for many years, it wasnot until 2011 that generally accepted quantifiable minimum criteria for moderate de-cellularization was generated [39]: in samples with (1) double-stranded DNA (dsDNA)content < 50 ng/mg ECM dry weight; (2) DNA fragment length < 200 bp; and (3) no visiblenuclei in sections stained with 4′,6-diamidino-2-phenylindole (DAPI) or hematoxylin-eosin(H&E) stained tissue sections without visible nuclei.These criteria list the essential indicators to be met for clinically applicable decellular-ized tissues because incomplete decellularization can affect the human immune responseby affecting macrophage polarization and inhibiting constructive matrix remodeling. Al-though decellularization does preserve the natural tissue geometry, inappropriate decellu-larization methods can negatively affect the natural three-dimensional ultrastructure of thematrix, the surface topology, and the composition of matrix proteins.2.3. Seed Cells and Recellularization of Tissue-Engineered ValvesThe body’s heart valves consist of mainly interstitial valve cells and endothelial cells.Endothelial cells cover the valve leaflet surface and serve as an essential protective barrierbetween the interstitial cells and the extracellular matrix, while endothelial cells alsoregulate the coagulation system. The current biological valves in clinical use are pericardialInt. J. Mol. Sci. 2022, 23, 723 6 of 19membranes prepared using glutaraldehyde cross-linking. The pericardium itself has noendothelial cells, and the endothelialization, of biologic valves can effectively delay orprevent the decay and calcification of biologic valves, which may fundamentally solve theproblem of biologic valve durability, and effort is directed to develop new biologic valveswith very important clinical significance [40].There are two ways of achieving biological valve re-endothelialization [41]: in vitroand in vivo. For in vitro re-endothelialization, host endothelial cells are cultured in vitroand grown on the surface of the bioprosthetic valve. Dohmen et al. [42] isolated, cultured,expanded, and seeded human transcatheter endothelial cells on human post-decellularizedpulmonary valves with good results after surgery. In vitro re-endocytosis faces manydifficulties and challenges, including the source of seeded cells, efficiently achieving anexpansion of seeded cells, and possible immune rejection. In vivo re-endothelialization, orin situ recellularization, refers to the implantation of decellularized biologic valve scaffoldtissue directly into the body, where the host’s own endothelial cells grow and crawl. Elkinset al. [43] implanted decellularized sheep pulmonary artery valves into young sheep for6 months and found good valve recellularization. The mechanisms of in vivo endothelial-ization identified so far include: (1) crawling growth of endothelial cells from the injuredportion; and (2) deposition of seed cells onto the endothelial surface using blood circulation,also known as sedimentation healing. In vivo reendothelialization/in situ recellularizationsmay be a more suitable strategy for clinical application than in vitro recellularization.2.4. Effects of Seed Cells on RecellularizationThe recellularization process is influenced by various factors such as the characteristicsof the seed cells and the culture environment, the nature of the scaffold material itself, andthe cell–scaffold material interaction. Seed cells can generally be divided into adult cells(primary cells) and stem cells (or precursor cells that differentiate in a specific direction).Earlier, a variety of adult cells such as endothelial cells, VIC, and myofibroblasts wereused for the study of DHVs recellularization. The use of autologous endothelial cells(of vascular or stem cell origin) grown in vitro in DHVs results in a better endothelialcell layer (vWF+) on the valve surface, which provides some protection to the valvetissue [44–47]. However, in the absence of mesenchymal cells, it is challenging to keepthe formed endothelial cell layer stable in the presence of hemodynamic shock fromphysiological conditions. Other studies have attempted to implant mesenchymal typecells (cardiac mesenchymal cells) in DHVs, or endothelial and mesenchymal type cells(myofibroblasts) together [48–50], and have shown that some degree of endothelializationand infiltration of mesenchymal cells (αSMA+, VIM+) can be achieved; although, there is adisparity in cell volume and cell distribution with natural valves.In recent years, with the increasing maturity of stem cell technology, many studieshave started to use stem cells in attempts to recellularize DHVs. The potential for multidi-rectional differentiation and the ability of self-renewal of stem cells make them theoreticallyadvantageous as seed cells, and the commonly used ones are mesenchymal stem cells(MSC), endothelial progenitor cells, embryonic stem cells, and induced multifunctionalstem cells. MSCs are derived from bone marrow or adipose tissues and are most widelyused today. They can transform to endothelial cell phenotypes in the presence of vascularendothelial growth factor (VEGF) and under conditions such as higher fluid shear [51,52],and also have mesenchymal cell phenotype transformation potential [53].Vincentelli et al. [54] injected receptor-derived MSCs into the mesenchyme of porcineDHVs and then implanted them into sheep pulmonary valve sites, which resulted in theformation of an intact endothelial layer and a distribution of mesenchymal cells similarto that of natural pulmonary valves after 4 months. Endothelial progenitor cells aremainly obtained from peripheral blood or umbilical cord blood and differentiate mainly toendothelial cells during maturation, but can also exhibit a mesenchymal cell phenotypeunder certain conditions [55]. Embryonic stem cells are derived from embryonic tissuesand induced multifunctional stem cells are derived from somatic cells. Both have highInt. J. Mol. Sci. 2022, 23, 723 7 of 19differentiation potential and can be induced to transition into endothelial or mesenchymalcell types by a suitable environment, providing favorable environmental conditions for thefull recellularization of DHVs.In the process of decellularization, the ECM is inevitably destroyed. Therefore, toimprove the ability of seed cells to adhere, proliferate, migrate, and differentiate, bioactivefactors such as cytokines, antibodies, and peptides can be applied to modify and promoteendothelialization. The main growth factor commonly used is VEGF [56]. VEGF is as-sociated with the recruitment of endothelial cells or endothelial progenitor cells in thebloodstream. VEGF-based surface modification strategies can improve the endothelializa-tion of biological heart valves. Hopkins et al. [57] used bioengineered (decellularized withcollagen conditioning treatments) human and baboon heart valve scaffolds implanted inbaboons, and the treated valves were less immunogenic, had a less inflammatory response,and were well recellularized with good valve function. Jordan et al. [15] combined CD133+cells isolated from peripheral blood with the surface of porcine DHVs and achieved com-plete endothelialization 1 month after implantation into sheep, and mesenchymal cells,matrix metalloproteinases, and collagen were significantly higher after 3 months thanin both the DHVs group and the DHVs group implanted with autologous endothelialprogenitor cells in vitro. Our group [58] also demonstrated that bone marrow-derivedCD133+ cells on DHVs had better results concerning possible calcification, inflammation,and transvalvular gradients compared to autologous carotid artery cells on DHVs in vivo.2.5. Effects of Bioreactors on RecellularizationHeart valves, open and close approximately 100,000 times per day with each heartbeatin an in vivo blood flow environment. Static conditions in culture in vitro are far removedfrom the physiological environment in vivo. Many studies have attempted to simulate thedynamic environment in vivo to achieve better recellularization. Bioreactors can simulatephysiological conditions of pressure pulses and blood flow environment in vitro to pre-adapt valve tissue to the complex environmental changes in vivo before implantation andto provide more favorable conditions for seed cell proliferation and differentiation.Simulating the in vivo blood flow environment under hydrodynamic stimulationconditions can improve the success rate of re-endothelialization of stent materials. Licht-enberg et al. [59] found that complete endothelialization of DHVs could be achieved byproviding hydrodynamic stimulation through a bioreactor and stepping up the flow rateof the solution in the reactor to physiological conditions, whereas increasing the flowrate too rapidly to physiological conditions resulted in the destruction of endothelial cellsimplanted on the surface of the scaffold material, which may explain the shedding ofimplant cells when tissue-engineered valves formed under static in vitro culture enter thebody and are exposed to the physiological mechanics [60]. They further re-endothelializedDHVs using young sheep autologous endothelial cells in a bioreactor, and after 3 monthsof implantation into young sheep pulmonary valve sites, the endothelial coverage of thevalve was increased and thrombus formation on the valve surface was reduced [61]. Asimilar approach was used for the implantation of sheep aortic valves, which showed nosignificant dysfunction after 3 months, with intact endothelial coverage and no signs ofinflammation, whereas the cryopreserved implanted valves showed significant signs ofcalcification and decay [62].A dynamic culture environment that mimics physiological conditions may also in-crease infiltration of mesenchymal type cells and facilitate the preservation of valve cellfunction after implantation. Schenke-Layland et al. [63] incubated myo-fibroblasts withDHVs under static conditions for 2 d, then transferred them to a bioreactor for 9 d or16 d before implanting endothelial cells in a static environment, which resulted in a betterrecellularization of the valve compared with static culture alone, with better coverage ofthe endothelial layer and significant infiltration of mesenchymal cells.Kajbafzadeh et al. [64] grew autologous MSCs in decellularized sheep aortic valvesunder pulsed conditions in a bioreactor, cultured them, and implanted them in the thoracicInt. J. Mol. Sci. 2022, 23, 723 8 of 19descending aortic position in sheep, eight recipients survived up to 19 months with nosignificant endothelial tears on CT at 18 months, and pathological sections showed thatthe valves reached a level of α SMA+ cellularity closer to that of natural valves. Cebotariet al. [65] grew single nucleated cells isolated from human peripheral blood in a bioreactorin decellularized human pulmonary valves. After 21 d of culture, endothelial cell-specificphenotypes were seen on the surface cells, which were then implanted in the pulmonaryvalve sites of two children with preexisting heart disease. During 3.5 years of follow-up, itwas observed that the implanted pulmonary valves maintained relatively good functionand showed growth without significant failure.2.6. In Vivo In Situ Recellularization ProcedureIn contrast to in vitro recellularization, many research teams have attempted to im-plant DHVs directly into the body, hoping that it will guide specific cell aggregation,adhesion, proliferation, and differentiation in vivo to achieve in situ recellularization,which is also called “guided tissue regeneration” [66]. Compared to in vitro recellulariza-tion, this method recruits and differentiates cells in vivo without the need for autologouscell isolation, implantation, and culture processes, and the in vitro treatment process isrelatively simpler and shorter. Some studies have found that in vivo implantation in miceresults in more complete in situ recellularization [67], but most implanted valves in pigs orsheep show only endothelial coverage or infiltration of inflammatory cells [66,68–74], sug-gesting that it may be more difficult to achieve complete recellularization directly in vivo inlarger animals. Rabbit aortic valves implanted in dogs showed rapid failure [75], whereasporcine-DHVs implants in dogs or sheep developed better endothelialization [76,77], sug-gesting that small animal valves implanted in large animals may be less likely to achieverecellularization and less durable.2.7. Tissue-Engineered Pulmonary Valves in the ClinicTo date, young patients including pediatric patients undergoing pulmonary valvereplacement continue to face the dilemma that neither mechanical valves nor xenobioticvalves are ideal. Therefore, the homogeneous allogeneic pulmonary valve remains thebest option currently: cryopreserved, homogeneous valves have good hemodynamicperformance, low incidence of thromboembolism and infection, and better durabilitythan other biologic replacements. A concomitant problem, however, is the degradation ofhomograft valves over time, which is particularly evident in children and young adults [16].The results of animal trials with decellularized valves have been encouraging, withanimals surviving up to 9 months after surgery, but their clinical trial results have beenmixed: in clinical practice, the majority of decellularized valves used are xenografts ratherthan homografts due to the scarcity of human tissue, and clinical practice with xenograftdecellularized valves has not been encouraging. The SynerGraft® valve from CryoLife, adecellularize valve of porcine origin, showed good initial results in adults, but has triggereda severe immune response in pediatric patients [78].Another product, Matrix P® and Matrix P plus, required reoperation for valve failurein 52% of children after implantation, and the implanted valve leaflets showed significant thick-ening with fibrosis, and severe inflammation without significant re-endothelialization [79,80].Overall, although advances in the decellularization process or better pre-implantationconditioning may improve outcomes, the clinical performance of decellularized allogeneicvalves is not superior to that of standard cryopreserved homogeneous valves.On the other hand, human homogeneous decellularized valves have been more suc-cessful in clinical practice. Haverich et al. [81] conducted a decade-long study of decellular-ized pulmonary homografts (DPHs) valved stents. The results showed that the mid-termresults of DPHs for PVR confirm earlier results of reduced re-operation rates comparedwith cryopreserved pulmonary homografts (CHs) and bovine jugular vein (BJVs) conduits,and growth potential is one of the unique features of DHPs.Int. J. Mol. Sci. 2022, 23, 723 9 of 19Preliminary results from a recent European multicenter prospective trial show thatDPH has an appreciable safety and efficacy profile with good hemodynamics over a periodof up to 3 years [82]. Evidence from multiple centers also indicates that decellularizedallografts are consistent with conventionally cryopreserved allografts in a comparison ofearly and mid-term outcomes. Moreover, the explantation and degeneration rates are lowerthan those of conventional cryopreserved allografts [83–85].In addition, data show that the CryoValve® SG valve, a human allogeneic decellu-larized valve developed by CryoLife, did not require reoperation in 93% of patients at10 years, and was free of valve dysfunction in 85% of patients at 5 years after implantationand 75% of patients at 10 years after implantation [86]. Compared with the gold standardfrozen (cryopreserved) human-derived valve (homografts), the CryoValve® SG valve wasless likely to develop valve dysfunction and less likely to require re-intervention. However,the mean follow-up was only 5 years in this study, and more extended observation is stillneeded [86]. Table 1 demonstrates the clinical application of decellulized homogeneouspulmonary valves.The primary advantage of decellularized valves over the gold standard cryopreservedhuman-derived valves (homografts) is the reduced antigenicity. This is because endothelialcells that survive cryopreservation can still express HLA antigens intact and undergoimmune reactions that cause valve failure [87]. However, to date, complete autologousrecellularization has not been achieved in implanted DHVs. Autologous recellularizationof decellularized valves is limited to the valve wall, whereas on the leaflet surface, onlythe recellularization of endothelial cells has been observed. Although this has been signifi-cantly superior to cryopreserved valves (because of the severe degradation and leukocyteinfiltration throughout the valve after frozen valve implantation), the problem that recel-lularization of decellularized valves is limited to the valve wall still limits their clinicalapplication because the valve leaflet is the main site of dysfunction after cryopreservedvalve implantation.Without the ability to reconstitute living cell communities within the leaflet mes-enchyme that can repair and remodel the ECM, DHVs will suffer the same fate as cryop-reserved valves, i.e., gradual valve degradation after implantation. In addition, DHVsrequire human or animal tissue to manufacture, which is in limited supply and requirescryopreservation, yet freeze-drying destroys the structure of the ECM in the valve andleads to inactivation of biomolecules.In addition, we should consider the cytotoxicity of decellularized tissue-engineeredvalves. Detergents commonly used are sodium deoxycholate (SDC), sodium dodecylsulfate (SDS), and ethylenediaminetetraacetic acid (EDTA). Even after rinsing, detergentresidue will remain. After surface seeding, Rieder et al. found that SDS-decellularizedxenomatrices had a toxic effect on endothelial and myofibroblast cells [46]. Nevertheless,residue concentration (<50 mg/L) in the wash solution has not affected the receptiveness ofdecellularized matrices to human endothelial cells. Therefore, detergent concentrations lessthan 50 mg/L in the washing solution may be used as an indicator for the production ofnon-toxic tissues. Alternatively, a combination of detergents at medium concentrations canachieve good decellularization and can also be rinsed off more easily [88]. DecellularizedTEHV needs to have long-term storability. Long-term storage may result in increaseddecellularized residues due to degradation of the ECM. The goal of future research shouldbe to find optimal decellularization protocols and storage strategies since decellularizationprotocols and storage strategies still differ.Int. J. Mol. Sci. 2022, 23, 723 10 of 19Table 1. Clinical application of decellulized homogeneous pulmonary valves.Trial (Year) Type of Homograft Mean Age (Years) Main FindingsESPOIR (2019) [82] fDPVH 21.3 ± 14.4Excellent performance with freedom fromexplantation and reintervention. Better safety andeffectiveness than BJV and CH.Bobylev et al. (2018) [89] fDPVH Range 2–38Superior mid-term results in children and youngadults for PVR. fDPVH provides an alternativetherapy for young patients who require multiplevalve surgeries.Sarikouch et al.(2015) [81] fDPVH 15.8 ± 10.21One-hundred percent freedom from explantationand endocarditis for fDPVH compared with CHand BJV at 10-year follow-up, associated with noincreased valvular gradient.Cebotari et al. (2011) [83] fDPVH 12.7 ± 6.1fDPVH showed the lower mean transvalvulargradient and no cusp thickening or aneurysmaticdilatation. Plus, five-year freedom fromexplantation was 100%. fDPVH also exhibitedadaptive growth.Cebotari et al. (2006) [65] fDPVH Age 11 and 13fDPVH was feasible and safe with potential toremodel and grow (increase in annulus diameter).There was no sign of valve degeneration at3.5-year follow-up.Dohmen et al. (2011) [90] cDPVH 39.6 ± 10.3 Excellent hemodynamic performance for up to10 years with no evidence of calcification.Brown et al. (2011) [91] cDPVH 28.6 ± 16.0No patients required reoperation and valvefunction did not deteriorate. Clinical andhemodynamic performance was encouraging anddid not differ significantly from CHBurch et al. (2010) [92] cDPVH 9.95 ± 7.96There was no significant difference in the trend oflower peak valve gradient and re-interventionbetween cDVPH and CH.Dohmen et al. (2007) [93] cDPVH 44.0 ± 13.7cDVPH showed excellent hemodynamicperformance, and may prevent valve degenerationand improve valve durabilityHawkins et al.(2003) [94] cDPVH 8.5 ± 7.9After 1 year, the hemodynamic function of cDPVHwas similar to that of CH, but the levels of class Iand class II HLA antibodies were significantlylower in cDPVH than in CH.BJV: bovine jugular vein; cDPVH: cryopreserved decellularized pulmonary valve homograft; CH: cryopreservedhomograft; fDPVH: fresh decellularized pulmonary valve homograft.Despite the many advantages of allograft valves, both decellularized and conventionalcryopreserved allograft valves have associated problems. In addition to the scarcity of rawmaterials, calcification occurs. This also dramatically reduces its availability. Currently,two types of materials are being studied, biological-based materials and synthetic-basedmaterials. Decellularized valves made from collagen, elastin, fibrin, sodium alginate,chitosan, and other biomaterials have advantages in cell adhesion, migration, proliferation,and differentiation. However, their mechanical properties are fragile. Many polymericheart valves are already in use. In fact, pulmonary monocusp valve prostheses made ofpolytetrafluoroethylene have been used for more than 20 years for the surgical treatmentof RVOT abnormalities due to calcification or abnormal function in young patients withgood results [95]. However, these materials were found to degrade and thrombose at anearly stage [96]. Lutter et al. [97] described a novel low-profile self-expanding nitinol stentcarrying a dip-coated pulmonary heart valve prosthesis made of polycarbonate urethaneInt. J. Mol. Sci. 2022, 23, 723 11 of 19(PCU) and demonstrated promising results in animal experiments (Figure 3). PCU hasbeen shown to have good biocompatibility, durability, and resistance to thromboembolism.It is expected to be an alternative to allograft pulmonary valves. Seed cells were alsosuccessfully colonized on polymeric heart valves. Aleksieva et al. [98] successfully seededsaphenous vein-derived endothelial cells and fibroblasts on polyurethane scaffolds. CD133+cells were also successfully colonized on PCU [58]. Combining synthetic scaffolds withbiological scaffolds is also being explored; for example, chitosan-modified polycaprolactoneporous scaffolds can improve fibroblast adhesion on TEHV [99]. The use of synthetic heartvalves in clinical applications, however, has not yet been reported.Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 11 of 19 availability. Currently, two types of materials are being studied, biological‐based materials and synthetic‐based materials. Decellularized valves made from collagen, elastin, fibrin, sodium alginate, chitosan, and other biomaterials have advantages in cell adhesion, migration, proliferation, and differentiation. However, their mechanical properties are fragile. Many polymeric heart valves are already in use. In fact, pulmonary monocusp valve prostheses made of polytetrafluoroethylene have been used for more than 20 years for the surgical treatment of RVOT abnormalities due to calcification or abnormal function in young patients with good results [95]. However, these materials were found to degrade and thrombose at an early stage [96]. Lutter et al. [97] described a novel low‐profile self‐expanding nitinol stent carrying a dip‐coated pulmonary heart valve prosthesis made of polycarbonate urethane (PCU) and demonstrated promising results in animal experiments (Figure 3). PCU has been shown to have good biocompatibility, durability, and resistance to thromboembolism. It is expected to be an alternative to allograft pulmonary valves. Seed cells were also successfully colonized on polymeric heart valves. Aleksieva et al. [98] successfully seeded saphenous vein‐derived endothelial cells and fibroblasts on polyurethane scaffolds. CD133+ cells were also successfully colonized on PCU [58]. Combining synthetic scaffolds with biological scaffolds is also being explored; for example, chitosan‐modified polycaprolactone porous scaffolds can improve fibroblast adhesion on TEHV [99]. The use of synthetic heart valves in clinical applications, however, has not yet been reported. Figure 3. (A) Self‐expanding nitinol stent, sizes 24 mm (ventricular)/22 mm (middle)/20 mm (pulmonary) with an overall length of 35 mm. (B) Top view of tricuspid polycarbonate urethane valved stent. (C) The valved stent is crimped in a 14‐Fr delivery catheter with a smooth silicone structure at the proximal tip [97]. 3. Tissue‐Engineered Transcatheter Pulmonary Valved Stent Implantation In patients with RVOT dysfunction, TPVR offers a minimally invasive treatment option that allows such patients to avoid repeat surgery. In contrast, the bovine jugular vein valve currently used in TPVR is a glutaraldehyde fixed heterogeneous valve that is prone to degeneration. Tissue‐engineered valves offer a way to overcome the limitations of current heart valve replacements. Tissue‐engineered valves are currently being used successfully in the clinic with good results. However, the current approach to tissue‐engineered valve implantation still uses open‐heart surgery rather than transcatheter minimally invasive surgery. There are still some tissue‐engineered valve grafts in studies with stenosis and/or regurgitation, which are mainly caused by distal anastomotic Figure 3. ( ) Self-expanding nitinol stent, sizes 24 m (ventricular)/22 m (middle)/20 mm(pulmonary) with an overall length of 35 mm. (B) Top view of tricuspid polycarbonate urethanevalved stent. (C) The valved stent is crimped in a 14-Fr delivery catheter with a smooth siliconestructure at the proximal tip [97].3. Tissue-Engineered Transcatheter Pulmonary Valved Stent ImplantationIn patients with RVOT dysfunction, TPVR offers a minimally invasive treatmentoption that allows such patients to avoid repeat surgery. In contrast, the bovine jugular veinvalve currently used in TPVR is a glutaraldehyde fixed heterogeneous valve that is prone todegeneration. Tissue-engineered valves offer a way to overcome the limitations of currentheart valve replacements. Tissue-engineered valves are currently being used successfullyin the clinic with good results. However, the current approach to tissue-engineered valveimplantation still uses open-heart surgery rather than transcatheter minimally invasivesurgery. There are still some tissue-engineered valve grafts in studies with stenosis and/orregurgitation, which are mainly caused by distal anastomotic stenosis [81]. Furthermore,valve regurgitation can occur when implantation is poor because decellularized grafts aresoft. The growth potential is a unique feature of decellularized pulmonary valve grafts,but it depends on the recellularization of the graft. However, when the graft is in thesetting of severe scarring, rapid and complete recellularization seems unlikely. Therefore,how to combine TPVR with tissue-engineered valves should be a focus of future research.While avoiding repeat surgery and overcoming the disadvantages of existing xenobioticvalves, Lutter’s group [100,101] successfully performed TPVR in a sheep model usingan autologous tissue-engineered valve scaffold without regurgitation after 4 weeks, andangiography and echocardiography showed good opening and closing of the implantedheart valves. However, all animals developed arrhythmias (Figure 4).Int. J. Mol. Sci. 2022, 23, 723 12 of 19Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 12 of 19 stenosis [81]. Furthermore, valve regurgitation can occur when implantation is poor because decellularized grafts are soft. The growth potential is a unique feature of decellularized pulmonary valve grafts, but it depends on the recellularization of the graft. However, when the graft is in the setting of severe scarring, rapid and complete recellularization seems unlikely. Therefore, how to combine TPVR with tissue‐engineered valves should be a focus of future research. While avoiding repeat surgery and overcoming the disadvantages of existing xenobiotic valves, Lutter’s group [100,101] successfully performed TPVR in a sheep model using an autologous tissue‐engineered valve scaffold without regurgitation after 4 weeks, and angiography and echocardiography showed good opening and closing of the implanted heart valves. However, all animals developed arrhythmias (Figure 4). There are several issues that still need to be addressed for transcatheter tissue‐engineered pulmonary valve stenting. The first is the anchoring of the valve stent. It is essential to deliver the stent to the exact position and not displace it. A precise 3D structural design allows for better alignment of the stent and better adaptation to the RVOT and pulmonary valve annulus region at implantation. The second is the choice of the stent material. Bare metal stents are unable to follow the growth of the child and have a limited ability to expand, which means that surgical re‐intervention is required. Biodegradable stents have become an alternative to bare metal stents, with the most significant advantage of degradation leaving only endothelialized natural vessels with the potential for further growth. Teams worldwide have been working on designing biodegradable stents for children with CHD [102]. Illusicor stent (Tremedics Medical Devices LLC, Richland Hills, TX, USA) and 480 Biomedical stent (480 Biomedical Inc., Cambridge, MA, USA) have been developed as bioresorbable stents with preclinical experience for use in CHD [102–104]. The Zinc bioresorbable stent (ZeBRa stent, Pediastent LLC, Cleveland, OH, USA) is the latest biodegradable stent explicitly designed for CHD. Figure 4. (A,B) Gross morphology of tissue‐engineered pulmonary valved stent [100,101]. 4. Discussion TPVR is a safe and effective non‐surgical treatment strategy for RVOT dysfunction. However, TRVR is still not available in approximately two‐thirds of patients due to large RVOT diameters. Devices suitable for large RVOT diameters are currently under investigation and testing (Venus P valve, Medtronic Harmony). The largest transcatheter pulmonary valve prosthesis is the Edwards Sapien XT valve, a transcatheter aortic valve implant. It can be dilated to 31 mm without damaging the Sapien valve or using an Alterra Adaptive Prestent (Edwards Lifesciences, Irvine, CA, USA) [105]. In future work, an innovative valved stent must be developed to address these limitations. Until then, surgical treatment will remain the gold standard. In addition to this, the issue of valve material deserves our attention. For young patients who need to be operated, multiple surgeries are to be avoided. Therefore, tissue‐Figure 4. (A,B) Gross morphology of tissue-engineered pulmonary valved stent [100,101].There are several issues that still need to be addressed for transcatheter tissue-engineeredpulmonary v lve stenting. The first is the anchoring of the valve stent. It is essential todeli the stent o the exact pos tion and not displace it. A precis 3D structu al designallows for b tter alignment of th stent nd better adaptation to the RVOT and pulmonaryalve nnulus r gion at implantation.The second is t e choice of the stent material. Bare metal stents are unable to followthe growth of the child and have a limited ability to expand, which means that surgicalre-intervention is required. Biodegradable stents have become an alternative to bare metalstents, with the most significant advantage of degradation leaving only endothelializednatural vessels with the potential for further growth. Teams worldwide have been workingon designing biodegradable stents for children with CHD [102]. Illusicor stent (TremedicsMedical Devices LLC, Richland Hills, TX, USA) and 480 Biomedical stent (480 BiomedicalInc., Cambridge, MA, USA) have been developed as bioresorbable stents with preclinicalexperience for use in CHD [102–104]. The Zinc bioresorbable stent (ZeBRa stent, PediastentLLC, Cleveland, OH, USA) is the latest biodegradable stent explicitly designed for CHD.4. DiscussionTPVR is a safe and effective non-surgical treatment strategy for RVOT dysfunction.However, TRVR is still not available in approximately two-thirds of patients due to largeRVOT diameters. Devices suitable for large RVOT diameters are currently under investiga-tion and testing (Venus P valve, Medtronic Harmony). The largest transcatheter pulmonaryvalve prosthesis is the Edwards Sapien XT valve, a transcatheter aortic valve implant. Itcan be dilated to 31 mm without damaging the Sapien valve or using an Alterra AdaptivePrestent (Edwards Lifesciences, Irvine, CA, USA) [105]. In future work, an innovativevalved stent must be developed to address these limitations. Until then, surgical treatmentwill remain the gold standard.In addition to this, the issue of valve material deserves our attention. For youngpatients who need to be operated, multiple surgeries are to be avoided. Therefore, tissue-engineered valves have been studied for more than 20 years as a solution to this problem.DHVs are an essential component of this research. Decellularized pulmonary valve ho-mografts (DPVHs) have been used in the clinic, and the first fDPVHs have been shown toperform with spontaneous recellularization potential [65,81]. fDPVHs have demonstratedsuperior performance compared to CHs [82]. cDPVHs also showed promising results interms of immunocompatibility, performance, and durability in the short term [91,106].However, in an 8–10-year time period, it did not significantly reduce reoperation rates nordid it show better performance than CHs and was comparable to CHs in terms of fibrosis,calcification, and the degree of recellularization [79,92,106,107].In contrast, it has been shown that fresh DPVHs performed better than cryopreservedDPVHs [106], possibly because the hypothermic environment and decellularization pro-cedure affected the original tissue structure and mechanical properties, thus affectingInt. J. Mol. Sci. 2022, 23, 723 13 of 19the endothelialization procedure. In addition, it has been shown that low-dose gammaradiation can severely affect the structural integrity of ECM [108].With the development of multiphoton-induced autofluorescence and second harmonicgenerated imaging, it is possible to visualize the alterations of the ECM in frozen heartvalve tissue [109]. It is well known that the formation of extracellular ice is a hazard tostructural tissues and organs. In 1965, Farrant recommended replacing 60% of cell waterwith cryoprotectant to prevent freezing at temperatures below −70 ◦C [110]. As a result,several valve tissue preservation methods have been developed. To promote vitrification,a 55% cryoprotectant formulation can be used to avoid ice formation below the glasstransition temperature of the cryopreservation solution [111]. Brockbank et al. reported theuse of an 83% cryoprotectant formulation: 83% of cryoprotectant formulation are storedat higher temperatures than 55% cryoprotectant formulation and cut without the risk ofice formation. This method is called ice-free cryopreservation, and the study showed thatthere was no significant difference in material properties, ECM component integrity, andcell viability of porcine valve tissue stored under 83% cryoprotectant solution at −80 ◦Ccompared to −135 ◦C vitrification cryopreservation [112]. However, cryoprotectants inhigh concentrations are potentially toxic, so long-term studies are still needed to determinetheir safety.While other storage methods such as glutaraldehyde [113], glycerol [114], etc., havebeen reported, there is no consensus so far on the best storage strategies to ensure thequality of decellularized TEHV.Therefore, it is essential to investigate cryopreservation techniques and optimize thedecellularization and sterilization processes to protect homograft stability and remodelingafter this step.The lack of homografts has prompted researchers to search for new polymeric valvematerials. In preclinical studies, polymeric valves have shown promising early function,implantation remodeling, and endothelialization potential [115–117]. However, they arestill not being used in clinical applications. The reasons for this may be manifold; Firstly,their long-term safety and efficacy have not yet been established. Secondly, the wholeprocess, both technically and logistically, is complex. Finally, differences between donor-to-donor may lead to inconsistent and uncontrolled leaflet thickening and shortening of thefinal product, resulting in valve insufficiency [118]. Out of these reasons, decellularizedheart valves are more favorable than synthetic ones at the time [81,82].In situ tissue engineering has received much attention, is a simple process comparedto in vitro re-cellularization and is designed to promote host cell adhesion and tissue forma-tion. However, in situ tissue engineering is more dependent on the recipient’s regenerativepotential. The ideal in situ TEHV tissue should have the ability to selectively control hostcell aggregation and adhesion, as well as the ability to directionally differentiate whilecontrolling the onset of degradation until near-natural, functional tissue emerges [119].5. Summary and ProspectsTPVR has emerged as a safe and effective therapy for RVOT dysfunction. The devel-opment of tissue engineering has solved already some problems. Nevertheless, there arestill some issues that limit its indications and long-term prognosis.Therefore, new designs of tissue-engineered bioresorbable valved stents and the searchfor more suitable valve material and, more importantly, combining the two technologieswith each other will be the focus in the near future.Author Contributions: Conceptualization, G.L. and T.P.; methodology, Z.X., J.S. (Jette Seiler), S.N.G.,O.J.M.; validation, Z.X, G.L., T.P., and D.F.; formal analysis, Z.X.; investigation, T.P. and J.-H.H.;resources, G.L.; data curation, Z.X., J.S. (Jette Seiler); writing—original draft preparation, Z.X. andT.P.; writing—review and editing, T.P., J.S. (Janarthanan Sathananthan), S.S. and A.H.; visualization,J.-H.H.; supervision, A.U., G.L. and Z.X.; project administration, Z.X., G.L., D.F. and T.P.; funding andacquisition, G.L. All authors have read and agreed to the published version of the manuscript.Int. J. Mol. Sci. 2022, 23, 723 14 of 19Funding: Financial support was received from the German Centre for Cardiovascular Research(DZHK; 81Z07002020) and the German Foundation of Heart Research (DSHF; F/12/17).Institutional Review Board Statement: The study procedures were approved by the ethics commit-tee of the Medical Faculty of Medicine of the Kiel University, Germany (D522/16).Conflicts of Interest: All authors declare no conflicts of interest.AbbreviationsCHD Congenital heart diseaseRVOT Right ventricular outflow tractTPVR Transcatheter pulmonary valve replacementECM Extracellular matrixTEHV Tissue-engineered heart valveDHVs Decellularized heart valvesdsDNA Double-stranded DNADAPI 4′,6-diamidino-2-phenylindoleH&E Hematoxylin-eosinMSC Mesenchymal stem cellsVEGF Vascular endothelial growth factorDPHs Decellularized pulmonary homograftsCH Cryopreserved homograftBJV Bovine jugular veinSDC Sodium deoxycholateSDS Sodium dodecyl sulfateEDTA Ethylenediaminetetraacetic acidcDPVH Cryopreserved decellularized pulmonary valve homograftfDPVH Fresh decellularized pulmonary valve homograftPCU Polycarbonate urethaneDPVHs Decellularized pulmonary valve homograftsReferences1. Baumgartner, H.; De Backer, J.; Babu-Narayan, S.V.; Budts, W.; Chessa, M.; Diller, G.P.; Lung, B.; Kluin, J.; Lang, I.M.; Meijboom,F.; et al. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur. Heart J. 2021, 42, 563–645. [CrossRef]2. McElhinney, D.B.; Hennesen, J.T. The Melody(R) valve and Ensemble(R) delivery system for transcatheter pulmonary valvereplacement. Ann. N. Y. Acad. Sci. 2013, 1291, 77–85. [CrossRef] [PubMed]3. Murphy, J.G.; Gersh, B.J.; Mair, D.D.; Fuster, V.; McGoon, M.D.; Ilstrup, D.M.; McGoon, D.C.; Kirklin, J.W.; Danielson, G.K.Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N. Engl. J. Med. 1993, 329, 593–599. [CrossRef][PubMed]4. Yuan, S.-M.; Mishaly, D.; Shinfeld, A.; Raanani, E. Right ventricular outflow tract reconstruction: Valved conduit of choice andclinical outcomes. J. Cardiovasc. Med. 2008, 9, 327–337. [CrossRef] [PubMed]5. Brown, J.W.; Ruzmetov, M.; Rodefeld, M.D.; Vijay, P.; Turrentine, M.W. Right ventricular outflow tract reconstruction with anallograft conduit in non-ross patients: Risk factors for allograft dysfunction and failure. Ann. Thorac. Surg. 2005, 80, 655–663,discussion 663–654. [CrossRef]6. Wells, W.J.; Arroyo, H., Jr.; Bremner, R.M.; Wood, J.; Starnes, V.A. Homograft conduit failure in infants is not due to somaticoutgrowth. J. Thorac. Cardiovasc. Surg. 2002, 124, 88–96. [CrossRef]7. Lange, R.; Weipert, J.; Homann, M.; Mendler, N.; Paek, S.-U.; Holper, K.; Meisner, H. Performance of allografts and xenografts forright ventricular outflow tract reconstruction. Ann. Thorac. Surg. 2001, 71, S365–S367. [CrossRef]8. Kanter, K.R.; Budde, J.M.; Parks, W.J.; Tam, V.K.; Sharma, S.; Williams, W.H.; Fyfe, D.A. One hundred pulmonary valvereplacements in children after relief of right ventricular outflow tract obstruction. Ann. Thorac. Surg. 2002, 73, 1801–1807.[CrossRef]9. Bonhoeffer, P.; Boudjemline, Y.; Saliba, Z.; Merckx, J.; Aggoun, Y.; Bonnet, D.; Acar, P.; Le Bidois, J.; Sidi, D.; Kachaner, J.Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction.Lancet 2000, 356, 1403–1405. [CrossRef]10. Zahn, E.M.; Hellenbrand, W.E.; Lock, J.E.; McElhinney, D.B. Implantation of the Melody transcatheter pulmonary valve in patientswith a dysfunctional right ventricular outflow tract conduit: Early results from the US clinical trial. J. Am. Coll. Cardiol. 2009, 54,1722–1729. [CrossRef]Int. J. Mol. Sci. 2022, 23, 723 15 of 1911. Boethig, D.; Avsar, M.; Bauer, U.M.; Sarikouch, S.; Beerbaum, P.; Berger, F.; Cesnjevar, R.; Dähnert, I.; Dittrich, S.; Ewert, P.Pulmonary valve prostheses: Patient’s lifetime procedure load and durability. Evaluation of the German National Register forCongenital Heart Defects. Interact. CardioVasc. Thorac. Surg. 2021, ivab233. [CrossRef]12. Schievano, S.; Coats, L.; Migliavacca, F.; Norman, W.; Frigiola, A.; Deanfield, J.; Bonhoeffer, P.; Taylor, A.M. Variations in rightventricular outflow tract morphology following repair of congenital heart disease: Implications for percutaneous pulmonaryvalve implantation. J. Cardiovasc. Magn. Reson. 2007, 9, 687–695. [CrossRef] [PubMed]13. Basude, S.; Hein, C.; Curtis, S.; Clark, A.; Trinder, J. Low-molecular-weight heparin or warfarin for anticoagulation in pregnantwomen with mechanical heart valves: What are the risks? A retrospective observational study. BJOG Int. J. Obstet. Gynaecol. 2012,119, 1008–1013. [CrossRef] [PubMed]14. Schoen, F.J.; Levy, R.J. Calcification of tissue heart valve substitutes: Progress toward understanding and prevention. Ann. Thorac.Surg. 2005, 79, 1072–1080. [CrossRef]15. Jordan, J.E.; Williams, J.K.; Lee, S.-J.; Raghavan, D.; Atala, A.; Yoo, J.J. Bioengineered self-seeding heart valves. J. Thorac. Cardiovasc.Surg. 2012, 143, 201–208. [CrossRef]16. Stassen, O.; Muylaert, D.; Bouten, C.V.; Hjortnaes, J. Current challenges in translating tissue-engineered heart valves. Curr. Treat.Options Cardiovasc. Med. 2017, 19, 71. [CrossRef] [PubMed]17. Nii, T.; Katayama, Y. Biomaterial-Assisted regenerative medicine. Int. J. Mol. Sci. 2021, 22, 8657. [CrossRef] [PubMed]18. Yue, S.; He, H.; Li, B.; Hou, T. Hydrogel as a biomaterial for bone tissue engineering: A review. Nanomaterials 2020, 10, 1511.[CrossRef]19. Groeber, F.; Holeiter, M.; Hampel, M.; Hinderer, S.; Schenke-Layland, K. Skin tissue engineering—in vivo and in vitro applications.Adv. Drug Deliv. Rev. 2011, 63, 352–366. [CrossRef]20. Nii, T.; Makino, K.; Tabata, Y. Three-dimensional culture system of cancer cells combined with biomaterials for drug screening.Cancers 2020, 12, 2754. [CrossRef]21. Peña, B.; Laughter, M.; Jett, S.; Rowland, T.J.; Taylor, M.R.; Mestroni, L.; Park, D. Injectable hydrogels for cardiac tissue engineering.Macromol. Biosci. 2018, 18, 1800079. [CrossRef]22. Mitsui, R.; Matsukawa, M.; Nakagawa, K.; Isomura, E.; Kuwahara, T.; Nii, T.; Tanaka, S.; Tabata, Y. Efficient cell transplantationcombining injectable hydrogels with control release of growth factors. Regen. Ther. 2021, 18, 372–383. [CrossRef]23. Alkashkari, W.; Albugami, S.; Abbadi, M.; Niyazi, A.; Alsubei, A.; Hijazi, Z.M. Transcatheter pulmonary valve replacement inpediatric patients. Expert Rev. Med. Devices 2020, 17, 541–554. [CrossRef] [PubMed]24. Cheatham, J.P.; Hellenbrand, W.E.; Zahn, E.M.; Jones, T.K.; Berman, D.P.; Vincent, J.A.; McElhinney, D.B. Clinical and hemody-namic outcomes up to 7 years after transcatheter pulmonary valve replacement in the US melody valve investigational deviceexemption trial. Circulation 2015, 131, 1960–1970. [CrossRef] [PubMed]25. Kenny, D.; Hijazi, Z.M.; Kar, S.; Rhodes, J.; Mullen, M.; Makkar, R.; Shirali, G.; Fogel, M.; Fahey, J.; Heitschmidt, M.G. Percutaneousimplantation of the Edwards SAPIEN transcatheter heart valve for conduit failure in the pulmonary position: Early phase 1results from an international multicenter clinical trial. J. Am. Coll. Cardiol. 2011, 58, 2248–2256. [CrossRef]26. Odemis, E.; Guzeltas, A.; Saygi, M.; Ozyilmaz, I.; Momenah, T.; Bakir, I. Percutaneous Pulmonary Valve Implantation UsingE dwards SAPIEN T ranscatheter H eart V alve in Different Types of Conduits: Initial Results of a Single Center Experience.Congenit. Heart Dis. 2013, 8, 411–417.27. Boshoff, D.E.; Cools, B.L.; Heying, R.; Troost, E.; Kefer, J.; Budts, W.; Gewillig, M. Off-label use of percutaneous pulmonary valvedstents in the right ventricular outflow tract: Time to rewrite the label? Catheter. Cardiovasc. Interv. 2013, 81, 987–995. [CrossRef][PubMed]28. Meadows, J.J.; Moore, P.M.; Berman, D.P.; Cheatham, J.P.; Cheatham, S.L.; Porras, D.; Gillespie, M.J.; Rome, J.J.; Zahn, E.M.;McElhinney, D.B. Use and performance of the Melody Transcatheter Pulmonary Valve in native and postsurgical, nonconduitright ventricular outflow tracts. Circ. Cardiovasc. Interv. 2014, 7, 374–380. [CrossRef]29. Gillespie, M.J.; Rome, J.J.; Levi, D.S.; Williams, R.J.; Rhodes, J.F.; Cheatham, J.P.; Hellenbrand, W.E.; Jones, T.K.; Vincent, J.A.;Zahn, E.M. Melody valve implant within failed bioprosthetic valves in the pulmonary position: A multicenter experience. Circ.Cardiovasc. Interv. 2012, 5, 862–870. [CrossRef]30. Schievano, S.; Taylor, A.M.; Capelli, C.; Coats, L.; Walker, F.; Lurz, P.; Nordmeyer, J.; Wright, S.; Khambadkone, S.; Tsang, V.First-in-man implantation of a novel percutaneous valve: A new approach to medical device development. EuroInterv. J. EuroPCRCollab. Work. Group Interv. Cardiol. Eur. Soc. Cardiol. 2010, 5, 745–750. [CrossRef]31. Cao, Q.L.; Kenny, D.; Zhou, D.; Pan, W.; Guan, L.; Ge, J.; Hijazi, Z.M. Early clinical experience with a novel self-expandingpercutaneous stent-valve in the native right ventricular outflow tract. Catheter. Cardiovasc. Interv. 2014, 84, 1131–1137. [CrossRef]32. Promphan, W.; Prachasilchai, P.; Siripornpitak, S.; Qureshi, S.A.; Layangool, T. Percutaneous pulmonary valve implantation withthe Venus P-valve: Clinical experience and early results. Cardiol. Young 2016, 26, 698–710. [CrossRef]33. Basquin, A.; Pineau, E.; Galmiche, L.; Bonnet, D.; Sidi, D.; Boudjemline, Y. Transcatheter valve insertion in a model of enlargedright ventricular outflow tracts. J. Thorac. Cardiovasc. Surg. 2010, 139, 198–208. [CrossRef]34. Amahzoune, B.; Szymansky, C.; Fabiani, J.-N.; Zegdi, R. A new endovascular size reducer for large pulmonary outflow tract. Eur.J. Cardio-Thorac. Surg. 2010, 37, 730–732. [CrossRef]Int. J. Mol. Sci. 2022, 23, 723 16 of 1935. Gillespie, M.J.; Dori, Y.; Harris, M.A.; Sathanandam, S.; Glatz, A.C.; Rome, J.J. Bilateral branch pulmonary artery melody valveimplantation for treatment of complex right ventricular outflow tract dysfunction in a high-risk patient. Circ. Cardiovasc. Interv.2011, 4, e21–e23. [CrossRef] [PubMed]36. Boudjemline, Y.; Legendre, A.; Ladouceur, M.; Boughenou, M.-F.; Patel, M.; Bonnet, D.; Iserin, L. Branch pulmonary artery jailingwith a bare metal stent to anchor a transcatheter pulmonary valve in patients with patched large right ventricular outflow tract.Circ. Cardiovasc. Interv. 2012, 5, e22–e25. [CrossRef] [PubMed]37. Ruiz, C.E.; Pasala, T.K. Are We Ready for Transcatheter Pulmonary Valve Replacement in Native Right Ventricular Outflow Tract?American College of Cardiology Foundation: Washington, DC, USA, 2018.38. Masoumi, N.; Annabi, N.; Assmann, A.; Larson, B.L.; Hjortnaes, J.; Alemdar, N.; Kharaziha, M.; Manning, K.B.; Mayer, J.E.,Jr.; Khademhosseini, A. Tri-layered elastomeric scaffolds for engineering heart valve leaflets. Biomaterials 2014, 35, 7774–7785.[CrossRef]39. Crapo, P.M.; Gilbert, T.W.; Badylak, S.F. An overview of tissue and whole organ decellularization processes. Biomaterials 2011, 32,3233–3243. [CrossRef]40. Koolbergen, D.R.; Hazekamp, M.G.; Kurvers, M.; de Heer, E.; Cornelisse, C.J.; Huysmans, H.A.; Bruijn, J.A. Tissue chimerism inhuman cryopreserved homograft valve explants demonstrated by in situ hybridization. Ann. Thorac. Surg. 1998, 66, S225–S232.[CrossRef]41. Lehner, G.; Fischlein, T.; Baretton, G.; Murphy, J.; Reichart, B. Endothelialized biological heart valve prostheses in the non-humanprimate model. Eur. J. Cardio-Thorac. Surg. 1997, 11, 498–504. [CrossRef]42. Dohmen, P.M.; Lembcke, A.; Hotz, H.; Kivelitz, D.; Konertz, W.F. Ross operation with a tissue-engineered heart valve. The Ann.Thorac. Surg. 2002, 74, 1438–1442. [CrossRef]43. Elkins, R.C.; Dawson, P.E.; Goldstein, S.; Walsh, S.P.; Black, K.S. Decellularized human valve allografts. Ann. Thorac. Surg. 2001,71, S428–S432. [CrossRef]44. Grauss, R.W.; Hazekamp, M.G.; Oppenhuizen, F.; van Munsteren, C.J.; Gittenberger-de Groot, A.C.; DeRuiter, M.C. Histologicalevaluation of decellularised porcine aortic valves: Matrix changes due to different decellularisation methods. Eur. J. Cardio-Thorac.Surg. 2005, 27, 566–571. [CrossRef] [PubMed]45. Bin, F.; Yinglong, L.; Nin, X.; Kai, F.; Laifeng, S.; Xiaodong, Z. Construction of tissue-engineered homograft bioprosthetic heartvalves in vitro. ASAIO J. 2006, 52, 303–309. [CrossRef] [PubMed]46. Rieder, E.; Kasimir, M.-T.; Silberhumer, G.; Seebacher, G.; Wolner, E.; Simon, P.; Weigel, G. Decellularization protocols of porcineheart valves differ importantly in efficiency of cell removal and susceptibility of the matrix to recellularization with humanvascular cells. J. Thorac. Cardiovasc. Surg. 2004, 127, 399–405. [CrossRef]47. Rieder, E.; Seebacher, G.; Kasimir, M.-T.; Eichmair, E.; Winter, B.; Dekan, B.; Wolner, E.; Simon, P.; Weigel, G. Tissue engineering ofheart valves: Decellularized porcine and human valve scaffolds differ importantly in residual potential to attract monocytic cells.Circulation 2005, 111, 2792–2797. [CrossRef]48. Dainese, L.; Guarino, A.; Burba, I.; Esposito, G.; Pompilio, G.; Polvani, G.; Rossini, A. Heart valve engineering: Decellularizedaortic homograft seeded with human cardiac stromal cells. J. Heart Valve Dis. 2012, 21, 125.49. Knight, R.L.; Booth, C.; Wilcox, H.E.; Fisher, J.; Ingham, E. Tissue engineering of cardiac valves: Re-seeding of acellular porcineaortic valve matrices with human mesenchymal progenitor cells. J. Heart Valve Dis. 2005, 14, 806–813. [PubMed]50. Zeltinger, J.; Landeen, L.K.; Alexander, H.G.; Kidd, I.D.; Sibanda, B. Development and characterization of tissue-engineered aorticvalves. Tissue Eng. 2001, 7, 9–22. [CrossRef]51. Yuan, L.; Sakamoto, N.; Song, G.; Sato, M. High-level shear stress stimulates endothelial differentiation and VEGF secretion byhuman mesenchymal stem cells. Cell. Mol. Bioeng. 2013, 6, 220–229. [CrossRef]52. Pankajakshan, D.; Kansal, V.; Agrawal, D.K. In vitro differentiation of bone marrow derived porcine mesenchymal stem cells toendothelial cells. J. Tissue Eng. Regen. Med. 2013, 7, 911–920. [CrossRef] [PubMed]53. Converse, G.L.; Buse, E.E.; Neill, K.R.; McFall, C.R.; Lewis, H.N.; VeDepo, M.C.; Quinn, R.W.; Hopkins, R.A. Design and efficacyof a single-use bioreactor for heart valve tissue engineering. J. Biomed. Mater. Res. Part B Appl. Biomater. 2017, 105, 249–259.[CrossRef] [PubMed]54. Vincentelli, A.; Wautot, F.; Juthier, F.; Fouquet, O.; Corseaux, D.; Marechaux, S.; Le Tourneau, T.; Fabre, O.; Susen, S.; Van Belle,E. In vivo autologous recellularization of a tissue-engineered heart valve: Are bone marrow mesenchymal stem cells the bestcandidates? J. Thorac. Cardiovasc. Surg. 2007, 134, 424–432. [CrossRef]55. Sales, V.L.; Mettler, B.A.; Engelmayr, G.C., Jr.; Aikawa, E.; Bischoff, J.; Martin, D.P.; Exarhopoulos, A.; Moses, M.A.; Schoen, F.J.;Sacks, M.S. Endothelial progenitor cells as a sole source for ex vivo seeding of tissue-engineered heart valves. Tissue Eng. Part A2010, 16, 257–267. [CrossRef]56. Frid, M.G.; Kale, V.A.; Stenmark, K.R. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: In vitro analysis. Circ. Res. 2002, 90, 1189–1196. [CrossRef]57. Hopkins, R.A.; Bert, A.A.; Hilbert, S.L.; Quinn, R.W.; Brasky, K.M.; Drake, W.B.; Lofland, G.K. Bioengineered human and allogeneicpulmonary valve conduits chronically implanted orthotopically in baboons: Hemodynamic performance and immunologicconsequences. J. Thorac. Cardiovasc. Surg. 2013, 145, 1098–1107.e1093. [CrossRef] [PubMed]Int. J. Mol. Sci. 2022, 23, 723 17 of 1958. Boldt, J.; Lutter, G.; Pohanke, J.; Fischer, G.; Schoettler, J.; Cremer, J.; Metzner, A. Percutaneous tissue-engineered pulmonaryvalved stent implantation: Comparison of bone marrow-derived CD133+-cells and cells obtained from carotid artery. Tissue Eng.Part C Methods 2013, 19, 363–374. [CrossRef]59. Lichtenberg, A.; Tudorache, I.; Cebotari, S.; Ringes-Lichtenberg, S.; Sturz, G.; Hoeffler, K.; Hurscheler, C.; Brandes, G.; Hilfiker,A.; Haverich, A. In vitro re-endothelialization of detergent decellularized heart valves under simulated physiological dynamicconditions. Biomaterials 2006, 27, 4221–4229. [CrossRef]60. Lichtenberg, A.; Cebotari, S.; Tudorache, I.; Sturz, G.; Winterhalter, M.; Hilfiker, A.; Haverich, A. Flow-dependent re-endothelialization of tissue-engineered heart valves. J. Heart Valve Dis. 2006, 15, 287.61. Lichtenberg, A.; Tudorache, I.; Cebotari, S.; Suprunov, M.; Tudorache, G.; Goerler, H.; Park, J.-K.; Hilfiker-Kleiner, D.; Ringes-Lichtenberg, S.; Karck, M. Preclinical testing of tissue-engineered heart valves re-endothelialized under simulated physiologicalconditions. Circulation 2006, 114, I-559–I-565. [CrossRef]62. Tudorache, I.; Calistru, A.; Baraki, H.; Meyer, T.; Höffler, K.; Sarikouch, S.; Bara, C.; Görler, A.; Hartung, D.; Hilfiker, A. Orthotopicreplacement of aortic heart valves with tissue-engineered grafts. Tissue Eng. Part A 2013, 19, 1686–1694. [CrossRef]63. Schenke-Layland, K.; Opitz, F.; Gross, M.; Döring, C.; Halbhuber, K.; Schirrmeister, F.; Wahlers, T.; Stock, U. Complete dynamicrepopulation of decellularized heart valves by application of defined physical signals—An in vitro study. Cardiovasc. Res. 2003,60, 497–509. [CrossRef]64. Kajbafzadeh, A.-M.; Tafti, S.H.A.; Mokhber-Dezfooli, M.-R.; Khorramirouz, R.; Sabetkish, S.; Sabetkish, N.; Rabbani, S.; Tavana, H.;Mohseni, M.J. Aortic valve conduit implantation in the descending thoracic aorta in a sheep model: The outcomes of pre-seededscaffold. Int. J. Surg. 2016, 28, 97–105. [CrossRef]65. Cebotari, S.; Lichtenberg, A.; Tudorache, I.; Hilfiker, A.; Mertsching, H.; Leyh, R.; Breymann, T.; Kallenbach, K.; Maniuc, L.;Batrinac, A. Clinical application of tissue engineered human heart valves using autologous progenitor cells. Circulation 2006, 114,I-132–I-137. [CrossRef]66. Iop, L.; Gerosa, G. Guided tissue regeneration in heart valve replacement: From preclinical research to first-in-human trials.BioMed Res. Int. 2015, 2015, 432901. [CrossRef]67. James, I.A.; Yi, T.; Tara, S.; Best, C.A.; Stuber, A.J.; Shah, K.V.; Austin, B.F.; Sugiura, T.; Lee, Y.-U.; Lincoln, J. Hemodynamiccharacterization of a mouse model for investigating the cellular and molecular mechanisms of neotissue formation in tissue-engineered heart valves. Tissue Eng. Part C Methods 2015, 21, 987–994. [CrossRef]68. Baraki, H.; Tudorache, I.; Braun, M.; Höffler, K.; Görler, A.; Lichtenberg, A.; Bara, C.; Calistru, A.; Brandes, G.; Hewicker-Trautwein, M. Orthotopic replacement of the aortic valve with decellularized allograft in a sheep model. Biomaterials 2009, 30,6240–6246. [CrossRef] [PubMed]69. Hopkins, R.A.; Jones, A.L.; Wolfinbarger, L.; Moore, M.A.; Bert, A.A.; Lofland, G.K. Decellularization reduces calcification whileimproving both durability and 1-year functional results of pulmonary homograft valves in juvenile sheep. J. Thorac. Cardiovasc.Surg. 2009, 137, 907–913.e904. [CrossRef]70. Quinn, R.W.; Hilbert, S.L.; Bert, A.A.; Drake, B.W.; Bustamante, J.A.; Fenton, J.E.; Moriarty, S.J.; Neighbors, S.L.; Lofland, G.K.;Hopkins, R.A. Performance and morphology of decellularized pulmonary valves implanted in juvenile sheep. Ann. Thorac. Surg.2011, 92, 131–137. [CrossRef] [PubMed]71. Leyh, R.G.; Wilhelmi, M.; Rebe, P.; Fischer, S.; Kofidis, T.; Haverich, A.; Mertsching, H. In vivo repopulation of xenogeneic andallogeneic acellular valve matrix conduits in the pulmonary circulation. Ann. Thorac. Surg. 2003, 75, 1457–1463. [CrossRef]72. Paniagua Gutierrez, J.R.; Berry, H.; Korossis, S.; Mirsadraee, S.; Lopes, S.V.; da Costa, F.; Kearney, J.; Watterson, K.; Fisher, J.;Ingham, E. Regenerative potential of low-concentration SDS-decellularized porcine aortic valved conduits in vivo. Tissue Eng.Part A 2015, 21, 332–342. [CrossRef]73. Juthier, F.; Vincentelli, A.; Gaudric, J.; Corseaux, D.; Fouquet, O.; Calet, C.; Le Tourneau, T.; Soenen, V.; Zawadzki, C.; Fabre, O.Decellularized heart valve as a scaffold for in vivo recellularization: Deleterious effects of granulocyte colony-stimulating factor.J. Thorac. Cardiovasc. Surg. 2006, 131, 843–852. [CrossRef]74. Honge, J.L.; Funder, J.; Hansen, E.; Dohmen, P.M.; Konertz, W.; Hasenkam, J.M. Recellularization of aortic valves in pigs. Eur. J.Cardio-Thorac. Surg. 2011, 39, 829–834. [CrossRef]75. Takagi, K.; Fukunaga, S.; Nishi, A.; Shojima, T.; Yoshikawa, K.; Hori, H.; Akashi, H.; Aoyagi, S. In vivo recellularization of plaindecellularized xenografts with specific cell characterization in the systemic circulation: Histological and immunohistochemicalstudy. Artif. Organs 2006, 30, 233–241. [CrossRef]76. Goldstein, S.; Clarke, D.R.; Walsh, S.P.; Black, K.S.; O’Brien, M.F. Transpecies heart valve transplant: Advanced studies of abioengineered xeno-autograft. Ann. Thorac. Surg. 2000, 70, 1962–1969. [CrossRef]77. Iwai, S.; Torikai, K.; Coppin, C.M.; Sawa, Y. Minimally immunogenic decellularized porcine valve provides in situ recellularizationas a stentless bioprosthetic valve. J. Artif. Organs 2007, 10, 29–35. [CrossRef] [PubMed]78. Simon, P.; Kasimir, M.; Seebacher, G.; Weigel, G.; Ullrich, R.; Salzer-Muhar, U.; Rieder, E.; Wolner, E. Early failure of the tissueengineered porcine heart valve SYNERGRAFT®in pediatric patients. Eur. J. Cardio-Thorac. Surg. 2003, 23, 1002–1006. [CrossRef]79. Konertz, W.; Angeli, E.; Tarusinov, G.; Christ, T.; Kroll, J.; Dohmen, P.M.; Krogmann, O.; Franzbach, B.; Pace Napoleone, C.;Gargiulo, G. Right ventricular outflow tract reconstruction with decellularized porcine xenografts in patients with congenitalheart disease. J. Heart Valve Dis. 2011, 20, 341.Int. J. Mol. Sci. 2022, 23, 723 18 of 1980. Voges, I.; Bräsen, J.H.; Entenmann, A.; Scheid, M.; Scheewe, J.; Fischer, G.; Hart, C.; Andrade, A.; Pham, H.M.; Kramer, H.-H.Adverse results of a decellularized tissue-engineered pulmonary valve in humans assessed with magnetic resonance imaging.Eur. J. Cardio-Thorac. Surg. 2013, 44, e272–e279. [CrossRef]81. Sarikouch, S.; Horke, A.; Tudorache, I.; Beerbaum, P.; Westhoff-Bleck, M.; Boethig, D.; Repin, O.; Maniuc, L.; Ciubotaru,A.; Haverich, A. Decellularized fresh homografts for pulmonary valve replacement: A decade of clinical experience. Eur. J.Cardio-Thorac. Surg. 2016, 50, 281–290. [CrossRef] [PubMed]82. Boethig, D.; Horke, A.; Hazekamp, M.; Meyns, B.; Rega, F.; Van Puyvelde, J.; Hübler, M.; Schmiady, M.; Ciubotaru, A.; Stellin, G.A European study on decellularized homografts for pulmonary valve replacement: Initial results from the prospective ESPOIRTrial and ESPOIR Registry data. Eur. J. Cardio-Thorac. Surg. 2019, 56, 503–509. [CrossRef] [PubMed]83. Cebotari, S.; Tudorache, I.; Ciubotaru, A.; Boethig, D.; Sarikouch, S.; Goerler, A.; Lichtenberg, A.; Cheptanaru, E.; Barnaciuc, S.;Cazacu, A. Use of fresh decellularized allografts for pulmonary valve replacement may reduce the reoperation rate in childrenand young adults: Early report. Circulation 2011, 124, S115–S123. [CrossRef] [PubMed]84. Ruzmetov, M.; Shah, J.J.; Geiss, D.M.; Fortuna, R.S. Decellularized versus standard cryopreserved valve allografts for rightventricular outflow tract reconstruction: A single-institution comparison. J. Thorac. Cardiovasc. Surg. 2012, 143, 543–549.[CrossRef]85. Brown, J.W.; Elkins, R.C.; Clarke, D.R.; Tweddell, J.S.; Huddleston, C.B.; Doty, J.R.; Fehrenbacher, J.W.; Takkenberg, J.J. Performanceof the CryoValve SG human decellularized pulmonary valve in 342 patients relative to the conventional CryoValve at a meanfollow-up of four years. J. Thorac. Cardiovasc. Surg. 2010, 139, 339–348. [CrossRef]86. Bibevski, S.; Ruzmetov, M.; Fortuna, R.S.; Turrentine, M.W.; Brown, J.W.; Ohye, R.G. Performance of SynerGraft decellularizedpulmonary allografts compared with standard cryopreserved allografts: Results from multiinstitutional data. Ann. Thorac. Surg.2017, 103, 869–874. [CrossRef]87. Yankah, A.; Wottge, H.-U.; Muller-Hermelink, H.; Feller, A.; Lange, P.; Wessel, U.; Dreyer, H.; Bernhard, A.; Müller-Ruchholtz, W.Transplantation of aortic and pulmonary allografts, enhanced viability of endothelial cells by cryopreservation, importance ofhistocompatibility. J. Card. Surg. 1987, 2, 209–220. [CrossRef]88. Cebotari, S.; Tudorache, I.; Jaekel, T.; Hilfiker, A.; Dorfman, S.; Ternes, W.; Haverich, A.; Lichtenberg, A. Detergent decellularizationof heart valves for tissue engineering: Toxicological effects of residual detergents on human endothelial cells. Artif. Organs 2010,34, 206–210. [CrossRef]89. Bobylev, D.; Sarikouch, S.; Tudorache, I.; Cvitkovic, T.; Söylen, B.; Boethig, D.; Theodoridis, K.; Bertram, H.; Beerbaum, P.;Haverich, A. Double semilunar valve replacement in complex congenital heart disease using decellularized homografts. Interact.Cardiovasc. Thorac. Surg. 2019, 28, 151–157. [CrossRef]90. Dohmen, P.M.; Lembcke, A.; Holinski, S.; Pruss, A.; Konertz, W. Ten years of clinical results with a tissue-engineered pulmonaryvalve. Ann. Thorac. Surg. 2011, 92, 1308–1314. [CrossRef]91. Brown, J.W.; Ruzmetov, M.; Eltayeb, O.; Rodefeld, M.D.; Turrentine, M.W. Performance of SynerGraft decellularized pulmonaryhomograft in patients undergoing a Ross procedure. Ann. Thorac. Surg. 2011, 91, 416–423. [CrossRef]92. Burch, P.T.; Kaza, A.K.; Lambert, L.M.; Holubkov, R.; Shaddy, R.E.; Hawkins, J.A. Clinical performance of decellularizedcryopreserved valved allografts compared with standard allografts in the right ventricular outflow tract. Ann. Thorac. Surg. 2010,90, 1301–1306. [CrossRef] [PubMed]93. Dohmen, P.M.; Lembcke, A.; Holinski, S.; Kivelitz, D.; Braun, J.P.; Pruss, A.; Konertz, W. Mid-term clinical results using atissue-engineered pulmonary valve to reconstruct the right ventricular outflow tract during the Ross procedure. Ann. Thorac.Surg. 2007, 84, 729–736. [CrossRef] [PubMed]94. Hawkins, J.A.; Hillman, N.D.; Lambert, L.M.; Jones, J.; Di Russo, G.B.; Profaizer, T.; Fuller, T.C.; Minich, L.L.; Williams, R.V.;Shaddy, R.E. Immunogenicity of decellularized cryopreserved allografts in pediatric cardiac surgery: Comparison with standardcryopreserved allografts. J. Thorac. Cardiovasc. Surg. 2003, 126, 247–252. [CrossRef]95. Kumar, M.; Turrentine, M.W.; Rodefeld, M.D.; Bell, T.; Brown, J.W. Right ventricular outflow tract reconstruction with apolytetrafluoroethylene monocusp valve: A 20-year experience. Semin. Thorac. Cardiovasc. Surg. 2016, 28, 463–470. [CrossRef]96. Nistal, F.; García-Martínez, V.; Arbe, E.; Fernàndez, D.; Artiñano, E.; Mazorra, F.; Gallo, I. In vivo experimental assessment ofpolytetrafluoroethylene trileaflet heart valve prosthesis. J. Thorac. Cardiovasc. Surg. 1990, 99, 1074–1081. [CrossRef]97. Lutter, G.; Topal, A.; Hansen, J.H.; Haneya, A.; Santhanthan, J.; Freitag-Wolf, S.; Frank, D.; Puehler, T. Transcatheter pulmonaryvalve replacement: A new polycarbonate urethane valve. Eur. J. Cardio-Thorac. Surg. 2021, 59, 1048–1056. [CrossRef]98. Aleksieva, G.; Hollweck, T.; Thierfelder, N.; Haas, U.; Koenig, F.; Fano, C.; Dauner, M.; Wintermantel, E.; Reichart, B.; Schmitz, C.Use of a special bioreactor for the cultivation of a new flexible polyurethane scaffold for aortic valve tissue engineering. Biomed.Eng. Online 2012, 11, 92. [CrossRef]99. Mei, N.; Chen, G.; Zhou, P.; Chen, X.; Shao, Z.-Z.; Pan, L.-F.; Wu, C.-G. Biocompatibility of poly (ε-caprolactone) scaffold modifiedby chitosan—The fibroblasts proliferation in vitro. J. Biomater. Appl. 2005, 19, 323–339. [CrossRef]100. Lutter, G.; Metzner, A.; Jahnke, T.; Bombien, R.; Boldt, J.; Iino, K.; Cremer, J.; Stock, U.A. Percutaneous tissue-engineeredpulmonary valved stent implantation. Ann. Thorac. Surg. 2010, 89, 259–263. [CrossRef]101. Metzner, A.; Stock, U.A.; Iino, K.; Fischer, G.; Huemme, T.; Boldt, J.; Braesen, J.H.; Bein, B.; Renner, J.; Cremer, J. Percutaneouspulmonary valve replacement: Autologous tissue-engineered valved stents. Cardiovasc. Res. 2010, 88, 453–461. [CrossRef]Int. J. Mol. Sci. 2022, 23, 723 19 of 19102. Welch, T.R.; Nugent, A.; Veeram, S. Biodegradable stents for congenital heart disease. Interv. Cardiol. Clin. 2019, 8, 81–94.[CrossRef]103. Herbert, C.E.; Veeram Reddy, S.; Welch, T.R.; Wang, J.; Richardson, J.A.; Forbess, J.M.; Nugent, A.W. Bench and initial preclinicalresults of a novel 8 mm diameter double opposed helical biodegradable stent. Catheter. Cardiovasc. Interv. 2016, 88, 902–911.[CrossRef]104. Nugent, A.W.; Welch, T. Development of large diameter bioresorbable stents for congenital heart disease. J. Am. Coll. Cardiol.2018, 71, A1353. [CrossRef]105. Sathananthan, J.; Sellers, S.; Barlow, A.; Fraser, R.; Stanová, V.; Cheung, A.; Ye, J.; Alenezi, A.; Murdoch, D.J.; Hensey, M.Overexpansion of the SAPIEN 3 transcatheter heart valve: An ex vivo bench study. JACC Cardiovasc. Interv. 2018, 11, 1696–1705.[CrossRef]106. Helder, M.R.; Kouchoukos, N.T.; Zehr, K.; Dearani, J.A.; Maleszewski, J.J.; Leduc, C.; Heins, C.N.; Schaff, H.V. Late durabilityof decellularized allografts for aortic valve replacement: A word of caution. J. Thorac. Cardiovasc. Surg. 2016, 152, 1197–1199.[CrossRef]107. Sayk, F.; Bos, I.; Schubert, U.; Wedel, T.; Sievers, H.-H. Histopathologic findings in a novel decellularized pulmonary homograft:An autopsy study. Ann. Thorac. Surg. 2005, 79, 1755–1758. [CrossRef] [PubMed]108. Helder, M.R.; Hennessy, R.S.; Spoon, D.B.; Tefft, B.J.; Witt, T.A.; Marler, R.J.; Pislaru, S.V.; Simari, R.D.; Stulak, J.M.; Lerman, A.Low-dose gamma irradiation of decellularized heart valves results in tissue injury in vitro and in vivo. Ann. Thorac. Surg. 2016,101, 667–674. [CrossRef]109. Schenke-Layland, K.; Xie, J.; Heydarkhan-Hagvall, S.; Hamm-Alvarez, S.F.; Stock, U.A.; Brockbank, K.G.; MacLellan, W.R.Optimized preservation of extracellular matrix in cardiac tissues: Implications for long-term graft durability. Ann. Thorac. Surg.2007, 83, 1641–1650. [CrossRef] [PubMed]110. Farrant, J. Mechanism of cell damage during freezing and thawing and its prevention. Nature 1965, 205, 1284–1287. [CrossRef]111. Song, Y.C.; Khirabadi, B.S.; Lightfoot, F.; Brockbank, K.G.; Taylor, M.J. Vitreous cryopreservation maintains the function ofvascular grafts. Nat. Biotechnol. 2000, 18, 296–299. [CrossRef]112. Brockbank, K.G.; Wright, G.J.; Yao, H.; Greene, E.D.; Chen, Z.Z.; Schenke-Layland, K. Allogeneic heart valve storage above theglass transition at −80 ◦C. Ann. Thorac. Surg. 2011, 91, 1829–1835. [CrossRef] [PubMed]113. Salles, C.A.; Buffolo, E.; Andrade, J.C.; Palma, J.H.; Silva, R.R.; Santiago, R.; Casagrande, I.S.; Moreira, M.C.V. Mitral valvereplacement with glutaraldehyde preserved aortic allografts. Eur. J. Cardio-Thorac. Surg. 1998, 13, 135–143. [CrossRef]114. Parker, R.; Randev, R.; Wain, W.; Ross, D. Storage of heart valve allografts in glycerol with subsequent antibiotic sterilisation.Thorax 1978, 33, 638–645. [CrossRef]115. Hoerstrup, S.P.; Sodian, R.; Daebritz, S.; Wang, J.; Bacha, E.A.; Martin, D.P.; Moran, A.M.; Guleserian, K.J.; Sperling, J.S.; Kaushal,S. Functional living trileaflet heart valves grown in vitro. Circulation 2000, 102, Iii-44–Iii-49. [CrossRef]116. Gottlieb, D.; Kunal, T.; Emani, S.; Aikawa, E.; Brown, D.W.; Powell, A.J.; Nedder, A.; Engelmayr, G.C., Jr.; Melero-Martin, J.M.;Sacks, M.S. In vivo monitoring of function of autologous engineered pulmonary valve. J. Thorac. Cardiovasc. Surg. 2010, 139,723–731. [CrossRef]117. Dijkman, P.E.; Driessen-Mol, A.; de Heer, L.M.; Kluin, J.; van Herwerden, L.A.; Odermatt, B.; Baaijens, F.; Hoerstrup, S.P.Trans-apical versus surgical implantation of autologous ovine tissue-engineered heart valves. J. Heart Valve Dis. 2012, 21, 670–678.118. Beachy, S.H.; Wizemann, T.; Hackmann, M. Exploring Sources of Variability Related to the Clinical Translation of RegenerativeEngineering Products: Proceedings of a Workshop; The National Academies Press: Washington, DC, USA, 2019.119. Wissing, T.B.; Bonito, V.; Bouten, C.V.; Smits, A.I. Biomaterial-driven in situ cardiovascular tissue engineering—A multi-disciplinary perspective. NPJ Regen. Med. 2017, 2, 18. [CrossRef] [PubMed]
Article
eng
Reviewed
Vancouver : University of British Columbia Library
Multidisciplinary Digital Publishing Institute
CC BY 4.0
Faculty
Researcher
Other
tissue engineering
heart valve replacement
pulmonary
transcatheter
percutaneous
biodegradable
nitinol
stents
congenital heart disease
decellularization
recellularization
Tissue Engineered Transcatheter Pulmonary Valved Stent Implantation: Current State and Future Prospect
Text