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Biofunctionalization of the Tissue Engineered Heart Valves
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Valve replacement is the mainstay of treatment for end-stage valvular heart disease, but varying degrees of defects exist in clinically applied valve implants. A mechanical heart valve requires long-term anti-coagulation, but the formation of blood clots is still inevitable. A biological heart valve eventually decays following calcification due to glutaraldehyde cross-linking toxicity and a lack of regenerative capacity. The goal of tissue-engineered heart valves is to replace normal heart valves and overcome the shortcomings of heart valve replacement commonly used in clinical practice. Surface biofunctionalization has been widely used in various fields of research to achieve functionalization and optimize mechanical properties.

surface biofunctionalization tissue engineering valve implants
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Table of Contents

    1. Introduction

    Valvular replacement is the most important treatment for patients with end-stage valvular disease [1]. More than 200,000 heart valve replacement surgeries are performed worldwide every year, and the number is expected to increase to 850,000 per year by 2050 [2]. During surgery, a natural valve that has lost its function is replaced with an artificial valve, either a mechanical heart valve (MHV) or a biological heart valve (BHV). MHV is generally made of pyrolyzed carbon, various polymers, and metal alloys, whereas BHV is generally composed of three types: (1) Chemically stable animal-derived tissue, (2) valve transplantation from cadaveric or living donors in the heart, or (3) patients’ own valve transplantation from one location to another. Both MHV and BHV have their advantages and disadvantages [3][4][5]. Patients using mechanical valves require lifelong anticoagulation, which can lead to severe thromboembolism or bleeding complications. While the biorepairing of heart valves has achieved clinical success in the short to medium term, calcification leads to their eventual decay [6][7][8][9]. In addition, none of the heart valve replacements currently in use have shown the ability to grow or regenerate, which puts pediatric patients at risk of multiple surgeries. Therefore, creating a valve substitute with the ability to grow, repair, and regenerate using engineered tissue seems to be the best way to overcome many limitations at present.
    The concept of tissue-engineered heart valves (TEHV) is described as the development of a heart valve with mechanical function and bioactivity under physiological conditions that facilitate the repair and reshaping of the scaffold [10]. TEHV generally addresses defects in implants by causing biomaterials to interact with autologous cells to achieve growth and biointegration. An ideal heart valve prosthesis should be biocompatible and durable with antithrombotic and anticalcification effects and a physiologically hemodynamic profile [11].

    2. Biofunctionalization of the Tissue Engineered Heart Valves

    2.1. Non-Glutaraldehyde Cross-Linking

    Glutaraldehyde (GLUT) is an aliphatic dialdehyde that can be attached to an amine functional group on collagen by the Schiff alkali reaction [12]; it has been shown to be reversible with easy hydrolysis [12][13]. GLUT or the presence of some groups such as aldehyde groups are highly cytotoxic and do not facilitate cell adhesion and growth on the valve, further leading to valve calcification [14][15]. In addition, GLUT can cause a strong immune response in the body, which leads to valve degeneration through the activation of macrophages, phagocytes, and T lymphocytes, and the aggregation of platelets [16][17][18]. Due to the defects in GLUT cross-linking, the implanted BHV is susceptible to structural damage and loss of function, resulting in a reduction in its durability and the need for reoperation in approximately only 15 years [19][20].
    An ideal biomaterial cross-linker should be cytotoxic and less expensive. It can improve the mechanical properties of the material and inhibit calcification. Many fixed ECM-derived scaffolds of cross-linking agents are available, which can be divided into (1) chemical cross-linking agents and (2) natural cross-linking agents. Chemical cross-linkers include carbodiimide [1-ethyl-3-(3-dimethylaminopropyl)-carbondiimide (EDC)], epoxy compounds, six methylene diisocyanates, glycerin, and alginate [21][22][23][24]. Natural cross-linkers mainly include genipin, nordihydroguaiaretic acid, tannic acid, and proanthocyanidins [25]. Besides the aforementioned cross-linking agents, researchers have developed many uncommon cross-linking agents, and their effect is also worth looking forward to. Guo et al. [26][27] and Xu et al. [28] explored the comprehensive properties of the prepared BHV by radical polymerization and cross-linking, respectively. The results showed that the free radical polymerization cross-linking treatment had similar ECM stability and biaxial mechanical properties to the GLUT treatment. Furthermore, the samples showed better cytocompatibility, endothelialization potential, and anti-calcification potential and lower immune response in vivo after the free radical polymerization cross-linking treatment (Figure 1). Curcumin, quercetin, and other polyphenols have calcification inhibition potential similar to that of proanthocyanidins in cross-linked collagen and elastin scaffolds [29][30]. Curcumin [31] and quercetin [32] were developed as cross-linking reagents for valve materials. The cross-linked samples were superior to GLUT in terms of mechanical properties, blood compatibility, and cell compatibility.
    Figure 1. Schematic illustrations of the presumable cross-linking mechanism for RPC-PP. (A) Synthesis of PPMA. (B) Cross-linking of PPMA. PP, porcine pericardium; PPMA, porcine pericardium methacryloyl; RPC-PP, radical polymerization cross-linking-treated PP (adapted from Ref. [27]).
    The focus of research on the bioprocessing of BHV involves the improvement of traditional GLUT cross-linking methods and the design of novel cross-linking methods. The special treatment employed by some researchers of BHVs cross-linked with ethanol, metal ions, -amino-oleic acid, and some other substances has effectively delayed the calcification of BHVs [33][34][35][36][37]. However, these methods still have many shortcomings. For example, epoxy cross-linked ECM-derived scaffolds are white, soft, and nonshrinking, with collagen remaining loose and natural [38]. Linear epoxy compounds exhibit low cross-linking and are also poorly stable due to their resistance to the degradability of collagen [38]. In addition, the epoxy compounds in the cross-linked extracellular matrix-derived scaffolds showed a degree of toxicity, leading to an immune response and eventual calcification failure [37][39][40]. The scaffold obtained by EDC cross-linking does not effectively inhibit calcification, which determines whether it can be used in the field of cardiovascular grafts [35]. The current substitution effect of cross-linkers has not been verified in the clinical stage. Therefore, although the development results of many cross-linkers are exciting, the ultimate success is yet to be achieved. Table 1 shows the basic research on non-glutaraldehyde cross-linking in the past 20 years.
    Table 1. Application of different cross-linking agents in the study of tissue-engineered heart valves.

    2.2. Modification Strategies after Decellularization

    The decellularized porcine aortic valve is a promising alternative to the ideal tissue-engineered valve scaffold [50][51][52][53]. Pretreatment of the porcine aortic valve with fixatives and detergents can greatly stabilize xenografts, improve their persistence, and reduce immunogenic updates. However, biofunctionalized decellularized porcine valves, such as Synerggraft, have failed due to decreased mechanical properties and poor cell aggregation [54]. Therefore, surface biofunction has attracted widespread attention as an important means to improve the performance of decellularized valves.

    2.2.1. Hydrogel Coating

    Physical coatings can give the substrate an ideal morphology and corresponding biological function, which is simple, fast, and efficient compared with chemical modification. In recent years, hydrogels have been widely used in engineered tissue due to their good biocompatibility and adjustable mechanical properties, but their application has been limited due to poor mechanical durability. Therefore, hydrogel coatings based on decellularized scaffolds have been developed by many researchers. These coatings provide good biocompatibility and function as carriers for decellularized scaffolds, while decellularized scaffolds provide sufficient mechanical properties. A variety of hydrogels, including natural (e.g., collagen [35], fibrin [55][56], and hyaluronic acid [56][57]), synthetic (e.g., polyethylene glycol [58][59] and polyvinyl alcohol [60]), and composite hydrogels (e.g., type I collagen with chondroitin sulfate [61]), have been developed, which provide good biocompatibility and bioactivity for engineered tissue applications. Synthetic hydrogels are composed of synthetic polymers, which have the advantages of adjustable mechanical properties and structure and easy control of chemical composition compared with natural hydrogels. Taking enhanced endothelialization as an example, the researchers seemed to prefer to load vascular endothelial growth factor (VEGF) into hydrogels as a core factor and coat decellularized scaffolds using natural hydrogels such as hyaluronic acid [62], elastin [63], and alginate [64]. The types and functions of synthetic hydrogels are much more complex. They not only focus on solving the side effects of heart valve implants but also make more detailed adjustments to the mechanical properties and fatigue resistance of the hybrid scaffold. Luo et al. used methacrylic anhydride to modify the decellularized heart valves and applied a mixed hydrogel made of sulfa methacrylate and hyaluronic acid methacrylate to the surface to improve the anti-calcification performance of BHVs. This strategy could achieve both endothelialization and anti-calcification, thus helping improve the main drawbacks of the existing commercial BHV products [65]. In addition, Jahnavi et al. [66] developed a biological hybrid scaffold with a natural structure of non-cross-linked decellularized bovine pericardium coated with a layer of polycaprolactone-chitosan nanofibers, showing superior mechanical properties. These synthetic hydrogels solved individual problems to varying degrees, but for hydrogels, most of the studies did not take into account their own problems, that is, poor fatigue resistance, which leads to rapid damage during circulating hydrodynamic stress. Strengthening the mechanical properties of the overmolded hydrogel is a necessary condition for long-term protection. A dual-network hard hydrogel was developed in response to the anti-fatigue properties of single-mesh hydrogels. This gel penetrated and anchored the matrix of the decellularized porcine pericardium to form a strong and stable conformal coating, reduce immunogenicity, improve antithrombosis, and accelerate endothelialization (a schematic diagram is shown in Figure 2) [67]. In the last decade, researchers seem to have focused on the use of hydrogels in tissue-engineered heart valves, and as research continues to grow, various potential hydrogels have been proposed (Table 2). Hydrogel coatings are now gaining attention in this field, but most of these studies are currently in the initial research phase and have not reached the clinical stage. Hydrogel coatings still have a long way to go in this field, but the proposal of many research concepts has provided more ideas and perspectives for future researchers.
    Figure 2. A schematic overview presenting the fabrication process, structure, and function of the decellularized porcine pericardium coated with polyacrylamide/hyaluronic acid dual-network hydrogel (adapted from Ref. [67]).
    Table 2. Application of hydrogels in the study of tissue-engineered heart valves.

    2.2.2. Cross-Linked with Nanocomposite

    The advent of nanotechnology has made anti-tumor interventions possible. It also provides new ideas for TEHV. The nanoparticles have good biocompatibility. Furthermore, their surfaces have a variety of active groups, and researchers can modify them according to their purpose [71]. Common nanoparticles include lipids [72][73], polymers [74], inorganics [75][76], metals [77], and so forth. Nanoparticles are used in tissue-engineered heart valves mainly for gene transmission or the transmission of biologically active factors. This can effectively solve the limitation of cell seeding before TEHV implantation. A polyethylene glycol nanoparticle containing transforming growth factor-β1 was developed through a carbon diimide-modified fibrous valve scaffold that improved the ECM microenvironment of the tissue-engineered heart valves [78]. Based on this concept, researchers encapsulated VEGF in polycaprolactone (PCL) nanoparticles (Figure 3). Then, using the Michael addition reaction, PCL nanoparticles were introduced to the decellularized aortic valve, and a hybrid valve was prepared. The results showed that the mixed valve could effectively accelerate endothelialization [79]. A large number of nanoparticles used in tissue-engineered heart valves in recent years are biocompatible polymers, such as PEGs, PCL, and so forth. Recently, Hu et al. [80] were inspired by the natural biological systems and reported a new approach for cross-linking amino and carboxyl groups. The heart valves with erythrocyte membrane bionic drug-carrier nanoparticles were modified using amino and carboxyl groups remaining after GLUT cross-linking. This modified heart valve not only preserved the structural integrity, stability, and mechanical properties of GLUT-treated BHV but also significantly improved anticoagulation, anti-inflammatory, anti-calcification, and endothelialization properties.
    Figure 3. Preparation scheme of VEGF-loaded nanoparticles and endothelialization of the hybrid valve (adapted from [79]).
    An inorganic nanoparticle, mesoporous silica, has attracted much attention because of its advantages of good compatibility and adjustable particle size, pore size, and structure [81][82]. Pinese et al. [83] applied MSNs to tissue engineering and prepared siRNA/MSNPEI complexes for siRNA delivery. The results showed that siRNA/MSNPEI complexes were more efficient and less toxic than the traditional silencing methods. However, MSN has not been used in decellularized tissue engineering so far. Hence, this may be one of the key directions to be explored by researchers. Many metal nanoparticles, such as gold, silver, and titanium nanoparticles, have been widely examined in other fields. Their future performance in TEHV based on their basic properties is also worth examining. These nanoparticles can be used as a functional platform to achieve the transmission of a certain substance (Table 3 lists the basic research of nanocomplexes applied to tissue-engineered heart valves in the last 15 years). However, they seem to be more flexible in terms of modification and function and can even be used as a cross-linking agent to make the structure more stable.
    Table 3. Application of different nanocomposites in the study of tissue-engineered heart valves.


    1. Lindroos, M.; Kupari, M.; Heikkilä, J.; Tilvis, R. Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample. J. Am. Coll. Cardiol. 1993, 21, 1220–1225.
    2. Lim, W.Y.; Lloyd, G.; Bhattacharyya, S. Mechanical and surgical bioprosthetic valve thrombosis. Heart 2017, 103, 1934–1941.
    3. Vahanian, A.; Beyersdorf, F.; Praz, F.; Milojevic, M.; Baldus, S.; Bauersachs, J.; Capodanno, D.; Conradi, L.; De Bonis, M.; De Paulis, R.; et al. Corrigendum to: 2021 ESC/EACTS Guidelines for the management of valvular heart disease: Developed by the Task Force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2022, 43, 561–632.
    4. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2022, 79, e263–e421.
    5. Tasoudis, P.T.; Varvoglis, D.N.; Vitkos, E.; Mylonas, K.S.; Sá, M.P.; Ikonomidis, J.S.; Caranasos, T.G.; Athanasiou, T. Mechanical versus bioprosthetic valve for aortic valve replacement: Systematic review and meta-analysis of reconstructed individual participant data. Eur. J. Cardio-Thorac. Surg. 2022, 62, ezac268.
    6. Sewell-Loftin, M.K.; Chun, Y.W.; Khademhosseini, A.; Merryman, W.D. EMT-Inducing Biomaterials for Heart Valve Engineering: Taking Cues from Developmental Biology. J. Cardiovasc. Transl. Res. 2011, 4, 658–671.
    7. Sacks, M.S.; Schoen, F.J.; Mayer, J.E. Bioengineering Challenges for Heart Valve Tissue Engineering. Annu. Rev. Biomed. Eng. 2009, 11, 289–313.
    8. Cannegieter, S.C.; Rosendaal, F.R.; Briët, E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994, 89, 635–641.
    9. Schoen, F.J.; Levy, R.J. Calcification of Tissue Heart Valve Substitutes: Progress Toward Understanding and Prevention. Ann. Thorac. Surg. 2005, 79, 1072–1080.
    10. Boroumand, S.; Asadpour, S.; Akbarzadeh, A.; Faridi-Majidi, R.; Ghanbari, H. Heart valve tissue engineering: An overview of heart valve decellularization processes. Regen. Med. 2018, 13, 41–54.
    11. Nachlas, A.L.; Li, S.; Davis, M.E. Developing a Clinically Relevant Tissue Engineered Heart Valve—A Review of Current Approaches. Adv. Healthc. Mater. 2017, 6, 1700918.
    12. Bezuidenhout, D.; Oosthuysen, A.; Human, P.; Weissenstein, C.; Zilla, P. The effects of cross-link density and chemistry on the calcification potential of diamine-extended glutaraldehyde-fixed bioprosthetic heart-valve materials. Biotechnol. Appl. Biochem. 2009, 54, 133–140.
    13. Nimni, M.E.; Deshmukh, A.; Deshmukh, K. Synthesis of aldehydes and their interactions during the in vitro aging of collagen. Biochemistry 1971, 10, 2337–2342.
    14. Carpentier, A.; Lemaigre, G.; Robert, L.; Carpentier, S.; Dubost, C. Biological factors affecting long-term results of valvular heterografts. J. Thorac. Cardiovasc. Surg. 1969, 58, 467–483.
    15. Golomb, G.; Schoen, F.J.; Smith, M.S.; Linden, J.; Dixon, M.; Levy, R.J. The role of glutaraldehyde-induced cross-links in calcification of bovine pericardium used in cardiac valve bioprostheses. Am. J. Pathol. 1987, 127, 122–130.
    16. Dahm, M.; Lyman, W.D.; Schwell, A.B.; Factor, S.M.; Frater, R.W. Immunogenicity of glutaraldehyde-tanned bovine pericardium. J. Thorac. Cardiovasc. Surg. 1990, 99, 1082–1090.
    17. Everts, V.; van der Zee, E.; Creemers, L.; Beertsen, W. Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. Histochem. J. 1996, 28, 229–245.
    18. Stein, P.D.; Wang, C.H.; Riddle, J.M.; Magilligan, D.J., Jr. Leukocytes, platelets, and surface microstructure of spontaneously degen-erated porcine bioprosthetic valves. J. Card. Surg. 1988, 3, 253–261.
    19. Siddiqui, R.F.; Abraham, J.R.; Butany, J. Bioprosthetic heart valves: Modes of failure. Histopathology 2009, 55, 135–144.
    20. Manji, R.A.; Menkis, A.H.; Ekser, B.; Cooper, D.K. Porcine bioprosthetic heart valves: The next generation. Am. Heart J. 2012, 164, 177–185.
    21. Sung, H.-W.; Hsu, C.-S.; Lee, Y.-S. Physical properties of a porcine internal thoracic artery fixed with an epoxy compound. Biomaterials 1996, 17, 2357–2365.
    22. Jorge-Herrero, E.; Fonseca, C.; Barge, A.; Turnay, J.; Olmo, N.; Fernández, P.; Lizarbe, M.; García-Páez, J. Biocompatibility and calcification of bovine pericardium employed for the construction of cardiac bioprostheses treated with different chemical crosslink methods. Artif Organs. 2010, 34, E168–E176.
    23. Damink, L.O.; Dijkstra, P.J.; Van Luyn, M.J.A.; Van Wachem, P.B.; Nieuwenhuis, P.; Feijen, J. In vitro degradation of dermal sheep collagen cross-linked using a water-soluble carbodiimide. Biomaterials 1996, 17, 679–684.
    24. Cao, H.; Xu, S.Y. EDC/NHS-crosslinked type II collagen-chondroitin sulfate scaffold: Characterization and in vitro evaluation. J. Mater. Sci. Mater. Med. 2008, 19, 567–575.
    25. Ma, B.; Wang, X.; Wu, C.; Chang, J. Crosslinking strategies for preparation of extracellular matrix-derived cardiovascular scaffolds. Regen. Biomater. 2014, 1, 81–89.
    26. Jin, L.; Guo, G.; Jin, W.; Lei, Y.; Wang, Y. Cross-Linking Methacrylated Porcine Pericardium by Radical Polymerization Confers Enhanced Extracellular Matrix Stability, Reduced Calcification, and Mitigated Immune Response to Bioprosthetic Heart Valves. ACS Biomater. Sci. Eng. 2019, 5, 1822–1832.
    27. Guo, G.; Jin, L.; Jin, W.; Chen, L.; Lei, Y.; Wang, Y. Radical polymerization-crosslinking method for improving extracellular matrix stability in bioprosthetic heart valves with reduced potential for calcification and inflammatory response. Acta Biomater. 2018, 82, 44–55.
    28. Xu, L.; Yang, F.; Ge, Y.; Guo, G.; Wang, Y. Crosslinking porcine aortic valve by radical polymerization for the preparation of BHVs with improved cytocompatibility, mild immune response, and reduced calcification. J. Biomater. Appl. 2021, 35, 1218–1232.
    29. Zhai, W.; Chang, J.; Lü, X.; Wang, Z. Procyanidins-crosslinked heart valve matrix: Anticalcification effect. J. Biomed. Mater. Res. Part B Appl. Biomater. 2009, 90, 913–921.
    30. Zhai, W.; Chang, J.; Lin, K.; Wang, J.; Zhao, Q.; Sun, X. Crosslinking of decellularized porcine heart valve matrix by procyanidins. Biomaterials 2006, 27, 3684–3690.
    31. Liu, J.; Li, B.; Jing, H.; Qin, Y.; Wu, Y.; Kong, D.; Leng, X.; Wang, Z. Curcumin-crosslinked acellular bovine pericardium for the application of calcification inhibition heart valves. Biomed. Mater. 2020, 15, 045002.
    32. Zhai, W.; Lü, X.; Chang, J.; Zhou, Y.; Zhang, H. Quercetin-crosslinked porcine heart valve matrix: Mechanical properties, stability, anticalcification and cytocompatibility. Acta Biomater. 2010, 6, 389–395.
    33. Calero, P.; Jorge-Herrero, E.; Turnay, J.; Olmo, N.; de Silanes, I.L.; Lizarbe, M.; Maestro, M.; Arenaz, B.; Castillo-Olivares, J. Gelatinases in soft tissue biomaterials. Analysis of different crosslinking agents. Biomaterials 2002, 23, 3473–3478.
    34. Dewanjee, M.K.; Solis, E.; Lanker, J.; Mackey, S.T.; Lombardo, G.M.; Tidwell, C.; Ellefsen, R.D.; Kaye, M.P. Effect of diphosphonate binding to collagen upon inhibition of calcification and pro-motion of spontaneous endothelial cell coverage on tissue valve prostheses. ASAIO Trans. 1986, 32, 24–29.
    35. Jorge-Herrero, E.; Fernández, P.; Turnay, J.; Olmo, N.; Calero, P.; García, R.; Freile, I.; Castillo-Olivares, J. Influence of different chemical cross-linking treatments on the properties of bovine pericardium and collagen. Biomaterials 1999, 20, 539–545.
    36. Lovekamp, J.; Vyavahare, N. Periodate-mediated glycosaminoglycan stabilization in bioprosthetic heart valves. J. Biomed. Mater. Res. 2001, 56, 478–486.
    37. Sung, H.W.; Hsu, H.L.; Shih, C.C.; Lin, D.S. Cross-linking characteristics of biological tissues fixed with monofunctional or multi-functional epoxy compounds. Biomaterials 1996, 17, 1405–1410.
    38. Sung, H.W.; Chang, Y.; Chiu, C.T.; Chen, C.N.; Liang, H.C. Crosslinking characteristics and mechanical properties of a bovine peri-cardium fixed with a naturally occurring crosslinking agent. J. Biomed. Mater. Res. 1999, 47, 116–126.
    39. Jayakrishnan, A.; Jameela, S. Glutaraldehyde as a fixative in bioprostheses and drug delivery matrices. Biomaterials 1996, 17, 471–484.
    40. Van Wachem, P.B.; Brouwer, L.A.; Zeeman, R.; Dijkstra, P.J.; Feijen, J.; Hendriks, M.; Cahalan, P.T.; van Luyn, M.J. In vivo behavior of epoxy-crosslinked porcine heart valve cusps and walls. J. Biomed. Mater. Res. 2000, 53, 18–27.
    41. Park, S.-N.; Park, J.-C.; Kim, H.O.; Song, M.J.; Suh, H. Characterization of porous collagen/hyaluronic acid scaffold modified by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide cross-linking. Biomaterials 2001, 23, 1205–1212.
    42. Yang, F.; He, H.; Xu, L.; Jin, L.; Guo, G.; Wang, Y. Inorganic-polymerization crosslinked tissue-siloxane hybrid as potential biomaterial for bioprosthetic heart valves. J. Biomed. Mater. Res. Part A 2020, 109, 754–765.
    43. Hu, M.; Peng, X.; Zhao, Y.; Yu, X.; Cheng, C.; Yu, X. Dialdehyde pectin-crosslinked and hirudin-loaded decellularized porcine pericardium with improved matrix stability, enhanced anti-calcification and anticoagulant for bioprosthetic heart valves. Biomater. Sci. 2021, 9, 7617–7635.
    44. Liu, J.; Jing, H.; Qin, Y.; Li, B.; Sun, Z.; Kong, D.; Leng, X.; Wang, Z. Nonglutaraldehyde Fixation for off the Shelf Decellularized Bovine Pericardium in Anticalcification Cardiac Valve Applications. ACS Biomater. Sci. Eng. 2019, 5, 1452–1461.
    45. Yang, F.; Xu, L.; Guo, G.; Wang, Y. Visible light-induced cross-linking of porcine pericardium for the improvement of endotheli-alization, anti-tearing, and anticalcification properties. J. Biomed. Mater. Res. Part A 2022, 110, 31–42.
    46. Sacks, M.S.; Hamamoto, H.; Connolly, J.M.; Gorman, R.C.; Gorman, J.H., 3rd; Levy, R.J. In vivo biomechanical assessment of triglyc-idylamine crosslinked pericardium. Biomaterials 2007, 28, 5390–5398.
    47. Connolly, J.M.; Bakay, M.A.; Alferiev, I.S.; Gorman, R.C.; Gorman, J.H.; Kruth, H.S.; Ashworth, P.E.; Kutty, J.K.; Schoen, F.J.; Bianco, R.W.; et al. Triglycidyl Amine Crosslinking Combined with Ethanol Inhibits Bioprosthetic Heart Valve Calcification. Ann. Thorac. Surg. 2011, 92, 858–865.
    48. Rapoport, H.S.; Connolly, J.M.; Fulmer, J.; Dai, N.; Murti, B.H.; Gorman, R.C.; Gorman, J.H.; Alferiev, I.; Levy, R.J. Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate. Biomaterials 2007, 28, 690–699.
    49. Connolly, J.M.; Alferiev, I.; Eidelman, N.; Sacks, M.; Palmatory, E.; Kronsteiner, A.; DeFelice, S.; Xu, J.; Ohri, R.; Narula, N.; et al. Triglycidylamine Crosslinking of Porcine Aortic Valve Cusps or Bovine Pericardium Results in Improved Biocompatibility, Biomechanics, and Calcification Resistance: Chemical and Biological Mechanisms. Am. J. Pathol. 2005, 166, 1–13.
    50. Steinhoff, G.; Stock, U.; Karim, N.; Mertsching, H.; Timke, A.; Meliss, R.R.; Pethig, K.; Haverich, A.; Bader, A. Tissue Engineering of Pulmonary Heart Valves on Allogenic Acellular Matrix Conduits: In Vivo Restoration of Valve Tissue. Circulation 2000, 102, Iii-50–Iii-55.
    51. Booth, C.; Korossis, S.A.; Wilcox, H.E.; Watterson, K.G.; Kearney, J.N.; Fisher, J.; Ingham, E. Tissue engineering of cardiac valve prostheses I: Development and histological char-acterization of an acellular porcine scaffold. J. Heart Valve Dis. 2002, 11, 457–462.
    52. Korossis, S.A.; Booth, C.; Wilcox, H.E.; Watterson, K.G.; Kearney, J.N.; Fisher, J.; Ingham, E. Tissue engineering of cardiac valve prostheses II: Biomechanical characterization of decellularized porcine aortic heart valves. J. Heart Valve Dis. 2002, 11, 463–471.
    53. Cebotari, S.; Mertsching, H.; Kallenbach, K.; Kostin, S.; Repin, O.; Batrinac, A.; Ciubotaru, A.; Haverich, A. Construction of autologous human heart valves based on an acellular allograft matrix. Circulation 2002, 106 (Suppl. 1), I-63–I-68.
    54. Simon, P.; Kasimir, M.; Seebacher, G.; Weigel, G.; Ullrich, R.; Salzer-Muhar, U.; Rieder, E.; Wolner, E. Early failure of the tissue engineered porcine heart valve SYNERGRAFT™ in pediatric patients. Eur. J. Cardio-Thorac. Surg. 2003, 23, 1002–1006.
    55. Mol, A.; van Lieshout, M.I.; Veen, C.G.D.-D.; Neuenschwander, S.; Hoerstrup, S.P.; Baaijens, F.P.; Bouten, C.V. Fibrin as a cell carrier in cardiovascular tissue engineering applications. Biomaterials 2005, 26, 3113–3121.
    56. Flanagan, T.C.; Sachweh, J.S.; Frese, J.; Schnöring, H.; Gronloh, N.; Koch, S.; Tolba, R.H.; Schmitz-Rode, T.; Jockenhoevel, S. In Vivo Remodeling and Structural Characterization of Fibrin-Based Tissue-Engineered Heart Valves in the Adult Sheep Model. Tissue Eng. Part A 2009, 15, 2965–2976.
    57. Masters, K.S.; Shah, D.N.; Leinwand, L.A.; Anseth, K.S. Crosslinked hyaluronan scaffolds as a biologically active carrier for valvular interstitial cells. Biomaterials 2005, 26, 2517–2525.
    58. Durst, C.A.; Cuchiara, M.P.; Mansfield, E.G.; West, J.L.; Grande-Allen, K.J. Flexural characterization of cell encapsulated PEGDA hydrogels with applications for tissue engineered heart valves. Acta Biomater. 2011, 7, 2467–2476.
    59. Tseng, H.; Cuchiara, M.L.; Durst, C.A.; Cuchiara, M.P.; Lin, C.J.; West, J.L.; Grande-Allen, K.J. Fabrication and Mechanical Evaluation of Anatomically-Inspirei Quasilaminate Hydrogel Structures with Layer-Specific Formulations. Ann. Biomed. Eng. 2013, 41, 398–407.
    60. Jiang, H.; Campbell, G.; Boughner, D.; Wan, W.-K.; Quantz, M. Design and manufacture of a polyvinyl alcohol (PVA) cryogel tri-leaflet heart valve prosthesis. Med. Eng. Phys. 2004, 26, 269–277.
    61. Flanagan, T.C.; Wilkins, B.; Black, A.; Jockenhoevel, S.; Smith, T.J.; Pandit, A.S. A collagen-glycosaminoglycan co-culture model for heart valve tissue engineering applications. Biomaterials 2006, 27, 2233–2246.
    62. Lei, Y.; Deng, L.; Tang, Y.; Ning, Q.; Lan, X.; Wang, Y. Hybrid Pericardium with VEGF-Loaded Hyaluronic Acid Hydrogel Coating to Improve the Biological Properties of Bioprosthetic Heart Valves. Macromol. Biosci. 2019, 19, e1800390.
    63. Lei, L.; Tao, X.; Xie, L.; Hong, Z. Vascular endothelial growth factor-loaded elastin-hydrogel modification of the pericardium im-proves endothelialization potential of bioprosthetic heart valves. J. Biomater. Appl. 2019, 34, 451–459.
    64. Marinval, N.; Morenc, M.; Labour, M.-N.; Samotus, A.; Mzyk, A.; Ollivier, V.; Maire, M.; Jesse, K.; Bassand, K.; Niemiec-Cyganek, A.; et al. Fucoidan/VEGF-based surface modification of decellularized pulmonary heart valve improves the antithrombotic and re-endothelialization potential of bioprostheses. Biomaterials 2018, 172, 14–29.
    65. Luo, Y.; Huang, S.; Ma, L. Zwitterionic hydrogel-coated heart valves with improved endothelialization and anti-calcification properties. Mater. Sci. Eng. C 2021, 128, 112329.
    66. Jahnavi, S.; Kumary, T.; Bhuvaneshwar, G.; Natarajan, T.; Verma, R. Engineering of a polymer layered bio-hybrid heart valve scaffold. Mater. Sci. Eng. C 2015, 51, 263–273.
    67. Cheng, S.; Liu, X.; Qian, Y.; Maitusong, M.; Yu, K.; Cao, N.; Fang, J.; Liu, F.; Chen, J.; Xu, D.; et al. Double-Network Hydrogel Armored Decellularized Porcine Pericardium as Durable Bioprosthetic Heart Valves. Adv. Healthc. Mater. 2021, 11, 2102059.
    68. Dai, J.; Qiao, W.; Shi, J.; Liu, C.; Hu, X.; Dong, N. Modifying decellularized aortic valve scaffolds with stromal cell-derived factor-1α loaded proteolytically degradable hydrogel for recellularization and remodeling. Acta Biomater. 2019, 88, 280–292.
    69. Guo, R.; Zhou, Y.; Liu, S.; Li, C.; Lu, C.; Yang, G.; Nie, J.; Wang, F.; Dong, N.-G.; Shi, J. Anticalcification Potential of POSS-PEG Hybrid Hydrogel as a Scaffold Material for the Devel-opment of Synthetic Heart Valve Leaflets. ACS Appl. Bio Mater. 2021, 4, 2534–2543.
    70. Lopez-Moya, M.; Melgar-Lesmes, P.; Kolandaivelu, K.; de la Torre Hernández, J.M.; Edelman, E.R.; Balcells, M. Optimizing Glutaralde-hyde-Fixed Tissue Heart Valves with Chondroitin Sulfate Hydrogel for Endothelialization and Shielding against Deterioration. Biomacromolecules 2018, 19, 1234–1244.
    71. Paris, J.L.; Vallet-Regí, M. Mesoporous Silica Nanoparticles for Co-Delivery of Drugs and Nucleic Acids in Oncology: A Review. Pharmaceutics 2020, 12, 526.
    72. Morrison, C. Alnylam prepares to land first RNAi drug approval. Nat. Rev. Drug Discov. 2018, 17, 156–157.
    73. Mayer, L.D.; Tardi, P.; Louie, A.C. CPX-351: A nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties. Int. J. Nanomed. 2019, 14, 3819–3830.
    74. Lu, X.Y.; Wu, D.C.; Li, Z.J.; Chen, G.Q. Polymer nanoparticles. Prog. Mol. Biol. Transl. Sci. 2011, 104, 299–323.
    75. Zhou, Y.; Quan, G.; Wu, Q.; Zhang, X.; Niu, B.; Wu, B.; Huang, Y.; Pan, X.; Wu, C. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharm. Sin. B 2018, 8, 165–177.
    76. Vallet-Regí, M.; Colilla, M.; Izquierdo-Barba, I.; Manzano, M. Mesoporous Silica Nanoparticles for Drug Delivery: Current Insights. Molecules 2018, 23, 47.
    77. Arisawa, M. Development of Metal Nanoparticle Catalysis toward Drug Discovery. Chem. Pharm. Bull. 2019, 67, 733–771.
    78. Deng, C.; Dong, N.; Shi, J.; Chen, S.; Xu, L.; Shi, F.; Hu, X.; Zhang, X. Application of decellularized scaffold combined with loaded nanoparticles for heart valve tissue engineering in vitro. J. Huazhong Univ. Sci. Technol. 2011, 31, 88–93.
    79. Zhou, J.; Ding, J.; Zhu, Z.; Xu, J.; Yi, Y.; Li, Y.; Fan, H.; Bai, S.; Yang, J.; Tang, Y.; et al. Surface biofunctionalization of the decellularized porcine aortic valve with VEGF-loaded nano-particles for accelerating endothelialization. Mater. Sci. Eng. C 2019, 97, 632–643.
    80. Hu, C.; Luo, R.; Wang, Y. Heart Valves Cross-Linked with Erythrocyte Membrane Drug-Loaded Nanoparticles as a Biomimetic Strategy for Anti-coagulation, Anti-inflammation, Anti-calcification, and Endothelialization. ACS Appl. Mater. Interfaces 2020, 12, 41113–41126.
    81. Manzano, M.; Colilla, M.; Vallet-Regí, M. Drug delivery from ordered mesoporous matrices. Expert Opin. Drug Deliv. 2009, 6, 1383–1400.
    82. Manzano, M.; Vallet-Regí, M. New developments in ordered mesoporous materials for drug delivery. J. Mater. Chem. 2010, 20, 5593–5604.
    83. Pinese, C.; Lin, J.; Milbreta, U.; Li, M.; Wang, Y.; Leong, K.W.; Chew, S.Y. Sustained delivery of siRNA/mesoporous silica nanoparticle complexes from nanofiber scaf-folds for long-term gene silencing. Acta Biomater. 2018, 76, 164–177.
    84. Li, Y.; Zhang, Y.; Ding, J.-L.; Liu, J.-C.; Xu, J.-J.; Tang, Y.-H.; Yi, Y.-P.; Xu, W.-C.; Yu, W.-P.; Lu, C.; et al. Biofunctionalization of decellularized porcine aortic valve with OPG-loaded PCL nanoparticles for anti-calcification. RSC Adv. 2019, 9, 11882–11893.
    85. Wang, Y.; Ma, B.; Liu, K.; Luo, R.; Wang, Y. A multi-in-one strategy with glucose-triggered long-term antithrombogenicity and sequentially enhanced endothelialization for biological valve leaflets. Biomaterials 2021, 275, 120981.
    86. Ghanbari, H.; Radenkovic, D.; Marashi, S.M.; Parsno, S.; Roohpour, N.; Burriesci, G.; Seifalian, A. Novel heart valve prosthesis with self-endothelialization potential made of modified polyhedral oligomeric silsesquioxane-nanocomposite material. Biointerphases 2016, 11, 029801.
    87. Kidane, A.G.; Burriesci, G.; Edirisinghe, M.; Ghanbari, H.; Bonhoeffer, P.; Seifalian, A.M. A novel nanocomposite polymer for devel-opment of synthetic heart valve leaflets. Acta Biomater. 2009, 5, 2409–2417.
    88. Ghanbari, H.; Kidane, A.G.; Burriesci, G.; Ramesh, B.; Darbyshire, A.; Seifalian, A. The anti-calcification potential of a silsesquioxane nanocomposite polymer under in vitro conditions: Potential material for synthetic leaflet heart valve. Acta Biomater. 2010, 6, 4249–4260.
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      Yu, W.; Jiang, Y.; Lin, F.; Liu, J.; Zhou, J. Biofunctionalization of the Tissue Engineered Heart Valves. Encyclopedia. Available online: (accessed on 02 February 2023).
      Yu W, Jiang Y, Lin F, Liu J, Zhou J. Biofunctionalization of the Tissue Engineered Heart Valves. Encyclopedia. Available at: Accessed February 02, 2023.
      Yu, Wenpeng, Ying Jiang, Feng Lin, Jichun Liu, Jianliang Zhou. "Biofunctionalization of the Tissue Engineered Heart Valves," Encyclopedia, (accessed February 02, 2023).
      Yu, W., Jiang, Y., Lin, F., Liu, J., & Zhou, J. (2022, September 27). Biofunctionalization of the Tissue Engineered Heart Valves. In Encyclopedia.
      Yu, Wenpeng, et al. ''Biofunctionalization of the Tissue Engineered Heart Valves.'' Encyclopedia. Web. 27 September, 2022.