Hydrogels, Bio-ceramics, and Polymeric Biomaterials in Regenerative Medicine: Chemical Design, Functionalization, and Biomedical Applications
DOI:
https://doi.org/10.67364/k92x0z23Keywords:
Regenerative medicine, Biomaterials, Bioceramics, Polymeric biomaterialsAbstract
Abstract
Regenerative medicine is an inter-disciplinary scientific field that combines biomaterials science, tissue engineering, biotechnology, stem cell biology, and nanotechnology to promote repair and regeneration of injured tissues. Within the broad class of biomaterials being explored for their regenerative properties, hydrogels, bioceramics, and polymeric materials can be highlighted due to their excellent biocompatibility, physicochemical properties, structural diversity, and capacity to mimic the extracellular matrix. Hydrogels represent hydrated three-dimensional networks useful for encapsulation of cells and delivery of therapeutic agents, while bioceramics, which include hydroxyapatite, tricalcium phosphate, calcium silicate, and bioactive glasses represent bioactive materials capable of interfacing with bone and dental tissue. Polymers, natural or synthetic, complement their mechanical, degradation, and functionalization properties by facilitating the fabrication of composite materials. Recent developments in nanotechnology, stem cell engineering, gene delivery, smart biomaterials, immunomodulation, and three-dimensional bioprinting of biomaterials have further broadened the possibilities of use of these materials for tissue regeneration purposes. In this review, particular attention will be paid to chemical design and functionalization of biomaterials, cross-linking chemistry, chemical structure-property relationship, degradation processes, ion substitution and surface chemistry of bioceramics, and molecular interactions controlling the loading and release of therapeutic molecules from biomaterials.
References
1. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–926.
2. Vacanti CA, Langer R. Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet. 1999;354(Suppl 1):SI32–SI34.
3. Atala A. Engineering organs. Current Opinion in Biotechnology. 2009;20:575–592.
4. O'Brien FJ. Biomaterials & scaffolds for tissue engineering. Materials Today. 2011;14:88–95.
5. Place ES, Evans ND, Stevens MM. Complexity in biomaterials for tissue engineering. Nature Materials. 2009;8:457–470.
6. Hollister SJ. Porous scaffold design for tissue engineering. Nature Materials. 2005;4:518–524.
7. Khademhosseini A, Langer R. A decade of progress in tissue engineering. Nature Protocols. 2016;11:1775–1781.
8. Mao AS, Mooney DJ. Regenerative medicine: current therapies and future directions. Proceedings of the National Academy of Sciences USA. 2015;112:14452–14459.
9. Gaharwar AK, Singh V, Chang LY, et al. Engineering of multi-functional materials for regenerative medicine. Advanced Materials. 2014;26:341–352.
10. Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nature Biotechnology. 2014;32:773–785.
11. Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chemical Reviews. 2001;101:1869–1879.
12. Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Advanced Materials. 2006;18:1345–1360.
13. Hoffman AS. Hydrogels for biomedical applications. Advanced Drug Delivery Reviews. 2012;64:18–23.
14. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nature Reviews Materials. 2016;1:16071.
15. Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels: a review of patents and commercial products. European Polymer Journal. 2015;65:252–267.
16. Li Y, Rodrigues J, Tomás H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chemical Society Reviews. 2012;41:2193–2221.
17. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24:4337–4351.
18. Seliktar D. Designing cell-compatible hydrogels for biomedical applications. Science. 2012;336:1124–1128.
19. Ahmed EM. Hydrogel: Preparation, characterization, and applications: A review. Journal of Advanced Research. 2015;6:105–121.
20. Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49:1993–2007.
21. Omidian H, Dey Chowdhury S, Wilson RL. Advancements and challenges in hydrogel engineering for regenerative medicine. Gels. 2024;10:238.
22. Carton F, Rizzi M, Canciani E, et al. Use of hydrogels in regenerative medicine: focus on mechanical properties. International Journal of Molecular Sciences. 2024;25:11426.
23. Xie C, Xu J, Wang X, et al. Smart hydrogels for tissue regeneration. Macromolecular Bioscience. 2024;24:e2300339.
24. Zhang Y, Xu Y, Gao J. The engineering and application of extracellular matrix hydrogels: a review. Biomaterials Science. 2023;11:3784–3799.
25. Zhu W, Zhang J, Wei Z, Zhang B, Weng X. Advances and progress in self-healing hydrogel and its application in regenerative medicine. Materials. 2023;16:1215.
26. Li S, Yu Q, Li H, et al. Self-assembled peptide hydrogels in regenerative medicine. Gels. 2023;9:653.
27. Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics. 2000;50:27–46.
28. Tibbitt MW, Anseth KS. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnology and Bioengineering. 2009;103:655–663.
29. Annabi N, Tamayol A, Uquillas JA, et al. 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Advanced Materials. 2014;26:85–124.
30. Li Y, Wang J, Mooney DJ. Designing biomaterials for regenerative medicine. Nature Reviews Materials. 2020;5:1–16.
31. Lu L, Yuan S, Wang J, et al. The formation mechanism of hydrogels. Current Stem Cell Research & Therapy. 2018;13:490–496.
32. Dragan ES. Design and applications of interpenetrating polymer network hydrogels. Chemical Engineering Journal. 2014;243:572–590.
33. Hoffman AS. Hydrogels for biomedical applications. Advanced Drug Delivery Reviews. 2012;64:18–23.
34. Koetting MC, Peters JT, Steichen SD, Peppas NA. Stimulus-responsive hydrogels: theory, modern advances, and applications. Materials Science and Engineering: R. 2015;93:1–49.
35. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Advanced Drug Delivery Reviews. 2001;53:321–339.
36. Kloxin AM, Kasko AM, Salinas CN, Anseth KS. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science. 2009;324:59–63.
37. Ifkovits JL, Burdick JA. Review: photopolymerizable and degradable biomaterials for tissue engineering applications. Tissue Engineering. 2007;13:2369–2385.
38. Nguyen KT, West JL. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials. 2002;23:4307–4314.
39. Li Y, Yang HY, Hsu YH, et al. Biodegradable and injectable hydrogels for tissue engineering. Advanced Healthcare Materials. 2019.
40. Wei Z, Yang JH, Zhou J, Xu F, Zrínyi M, Dussault PH, Osada Y, Chen YM. Self-healing gels based on constitutional dynamic chemistry and their potential applications. Chemical Society Reviews. 2014;43:8114–8131.
41. Hench LL. Bioceramics: from concept to clinic. Journal of the American Ceramic Society. 1991;74:1487–1510.
42. Hench LL. The story of Bioglass®. Journal of Materials Science: Materials in Medicine. 2006;17:967–978.
43. Vallet-Regí M. Evolution of bioceramics within the field of biomaterials. Journal of Materials Chemistry. 2006;16:26–31.
44. Bose S, Roy M, Bandyopadhyay A. Recent advances in bone tissue engineering scaffolds. Trends in Biotechnology. 2012;30:546–554.
45. Dorozhkin SV. Calcium orthophosphate bioceramics. Materials. 2013;6:3840–3942.
46. LeGeros RZ. Properties of osteoconductive biomaterials: calcium phosphates. Clinical Orthopaedics and Related Research. 2002;395:81–98.
47. Jones JR. Review of bioactive glass: from Hench to hybrids. Acta Biomaterialia. 2013;9:4457–4486.
48. El-Rashidy AA, Roether JA, Harhaus L, et al. Regenerating bone with bioactive glass scaffolds. International Journal of Molecular Sciences. 2017;18:116.
49. Kargozar S, Mozafari M, Ghodrat S, Fiume E, Baino F. Bioglass®-based composites for bone tissue engineering. Materials. 2019;12:3362.
50. Fiume E, Barberi J, Verné E, Baino F. Bioactive glasses: from parent 45S5 composition to scaffold-assisted tissue-healing therapies. Journal of Functional Biomaterials. 2018;9:24.
51. Fendi F, Abdullah B, Suryani S, Usman AN, Tahir D. Development and application of hydroxyapatite-based scaffolds for bone tissue regeneration: a systematic literature review. Bone. 2024;183:117075.
52. Amiryaghoubi N, Jahanban Esfahlan R. Applications of hydroxyapatite-based polymeric scaffolds in bone tissue engineering: an update. Advanced Pharmaceutical Bulletin. 2024;14:794–806.
53. Bose S, Vahabzadeh S, Bandyopadhyay A. Bone tissue engineering using 3D printing. Materials Today. 2013;16:496–504.
54. O'Brien FJ. Biomaterials & scaffolds for tissue engineering. Materials Today. 2011;14:88–95.
55. Zhang Y, Wu C, Chang J. Bioactive inorganic biomaterials for bone regeneration. Materials Science and Engineering C. 2018;88:100–113.
56. Dash M, Chiellini F, Ottenbrite RM, Chiellini E. Chitosan—a versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science. 2011;36:981–1014.
57. Jayakumar R, Prabaharan M, Sudheesh Kumar PT, Nair SV, Tamura H. Biomaterials based on chitin and chitosan in wound dressing applications. Biotechnology Advances. 2011;29:322–337.
58. Mano JF, Silva GA, Azevedo HS, et al. Natural origin biodegradable systems in tissue engineering and regenerative medicine. Chemical Society Reviews. 2007;36:562–579.
59. Silva GA, Coutinho OP, Ducheyne P, Reis RL. Materials in particulate form for tissue engineering. Current Topics in Developmental Biology. 2005;65:1–36.
60. Lee KY, Silva EA, Mooney DJ. Controlled growth factor delivery from a self-assembling peptide. Nature Materials. 2009;8:731–736.
61. Van Vlierberghe S, Dubruel P, Schacht E. Biopolymer-based hydrogels as scaffolds for tissue engineering applications. Biomacromolecules. 2011;12:1387–1408.
62. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24:4337–4351.
63. George M, Abraham TE. Polyionic hydrocolloids for the intestinal delivery of protein drugs. Journal of Controlled Release. 2006;114:1–14.
64. Boateng J, Catanzano O. Advanced therapeutic dressings for effective wound healing. Journal of Pharmaceutical Sciences. 2015;104:3653–3680.
65. Chattopadhyay S, Raines RT. Collagen-based biomaterials for wound healing. Biopolymers. 2014;101:821–833.
66. Middleton JC, Tipton AJ. Synthetic biodegradable polymers as orthopedic devices. Biomaterials. 2000;21:2335–2346.
67. Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Progress in Polymer Science. 2007;32:762–798.
68. Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers. 2011;3:1377–1397.
69. Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres. Advanced Drug Delivery Reviews. 1997;28:5–24.
70. Gentile P, Chiono V, Carmagnola I, Hatton PV. An overview of poly(lactic-co-glycolic acid) biomaterials for bone tissue engineering. International Journal of Molecular Sciences. 2014;15:3640–3659.
71. Lyu S, Untereker D. Degradability of polymers for implantable biomedical devices. International Journal of Molecular Sciences. 2009;10:4033–4065.
72. Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. European Cells and Materials. 2003;5:1–16.
73. Puppi D, Chiellini F, Piras AM, Chiellini E. Polymeric materials for bone and cartilage regeneration. Progress in Polymer Science. 2010;35:403–440.
74. Zhu Y, Mao Z, Gao C. Control over the distribution of electrospun fibers and its application in tissue engineering. Biomaterials. 2013;34:3467–3478.
75. Xie J, MacEwan MR, Schwartz AG, Xia Y. Electrospun nanofibers for neural tissue engineering. Nanoscale. 2010;2:35–44.
76. Gaharwar AK, Peppas NA, Khademhosseini A. Nanocomposite hydrogels for biomedical applications. Biotechnology and Bioengineering. 2014;111:441–453.
77. Thakur VK, Thakur MK. Recent advances in hydrogels based on natural polymers. International Journal of Biological Macromolecules. 2015;72:1191–1201.
78. Dash R, Foston M, Ragauskas AJ. Improving nanocellulose composites for biomedical applications. Cellulose. 2013;20:2837–2848.
79. Zhang Y, Rhee KY, Hui D, Park SJ. A critical review of nanodiamond based nanocomposites. Composites Part B. 2018;143:22–31.
80. Li Y, Xiao Y, Liu C. The horizon of biomedical nanomaterials and implants for tissue engineering. Chemical Reviews. 2017;117:4376–4421.
81. Kargozar S, Mozafari M. Nanotechnology and nanomedicine: start small, think big. Materials Today. 2018;21:303–307.
82. Han F, Wang J, Ding L, et al. Tissue engineering and regenerative medicine: achievements, future, and sustainability. Advanced Materials. 2020;32:e1906738.
83. Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nature Biotechnology. 2014;32:773–785.
84. Jose RR, Rodriguez MJ, Dixon TA, Omenetto F, Kaplan DL. Evolution of bioinks and additive manufacturing technologies for 3D bioprinting. ACS Biomaterials Science & Engineering. 2016;2:1662–1678.
85. Bishop ES, Mostafa S, Pakvasa M, et al. 3-D bioprinting technologies in tissue engineering and regenerative medicine: current and future trends. Genes & Diseases. 2017;4:185–195.
86. Zhang YS, Yue K, Aleman J, et al. 3D bioprinting for tissue and organ fabrication. Annals of Biomedical Engineering. 2017;45:148–163.
87. Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnology Advances. 2016;34:422–434.
88. Groll J, Burdick JA, Cho DW, et al. A definition of bioinks and their distinction from biomaterial inks. Biofabrication. 2019;11:013001.
89. Hospodiuk M, Dey M, Sosnoski D, Ozbolat IT. The bioink: a comprehensive review on bioprintable materials. Biotechnology Advances. 2017;35:217–239.
90. Derakhshanfar S, Mbeleck R, Xu K, Zhang X, Zhong W, Xing M. 3D bioprinting for biomedical devices and tissue engineering: a review of recent trends and advances. Bioactive Materials. 2018;3:144–156.
91. Ng WL, Chua CK, Shen YF. Print me an organ: why are we not there yet? Progress in Polymer Science. 2019;97:101145.
92. Ozbolat IT, Hospodiuk M. Current advances and future perspectives in extrusion-based bioprinting. Biomaterials. 2016;76:321–343.
93. Loukelis K, Koutsomarkos N, Mikos AG, Chatzinikolaidou M. Advances in 3D bioprinting for regenerative medicine applications. Regenerative Biomaterials. 2024;11:rbae033.
94. Mirsky NA, Ehlen QT, Greenfield JA, et al. Three-dimensional bioprinting: a comprehensive review for applications in tissue engineering and regenerative medicine. Bioengineering. 2024;11:777.
95. Sabetkish S, Currie P, Meagher L. Recent trends in 3D bioprinting technology for skeletal muscle regeneration. Acta Biomaterialia. 2024;181:46–66.
96. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regenerative Medicine. 2019;4:22.
97. Li Y, Liu W, Liu F, et al. Primed 3D-exercise of mesenchymal stem cells in hydrogel microenvironments. Advanced Healthcare Materials. 2015.
98. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–689.
99. Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310:1139–1143.
100. Guilak F, Cohen DM, Estes BT, et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell. 2009;5:17–26.
101. Daley GQ. The promise and perils of stem cell therapeutics. Cell Stem Cell. 2012;10:740–749.
103. Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018). Journal of Extracellular Vesicles. 2018;7:1535750.
104. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.
105. Yáñez-Mó M, Siljander PRM, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles. 2015;4:27066.
106. Tkach M, Théry C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–1232.
107. El Andaloussi S, Mäger I, Breakefield XO, Wood MJA. Extracellular vesicles: biology and emerging therapeutic opportunities. Nature Reviews Drug Discovery. 2013;12:347–357.
108. Liu L, Liu W, Han Z, et al. Extracellular vesicles-in-hydrogel targeting pathophysiology for tissue repair. Bioactive Materials. 2024.
109. Hashemi A, Ezati M, Partovi Nasr M, et al. Extracellular vesicles and hydrogels: an innovative approach to tissue regeneration. ACS Omega. 2024;9:6184–6218.
110. Zheng Y, Pan C, Xu P, Liu K. Hydrogel-mediated extracellular vesicles for enhanced wound healing: the latest progress, and their prospects for 3D bioprinting. Journal of Nanobiotechnology. 2024;22:57.
111. Zhang Y, Wu D, Zhou C, et al. Engineered extracellular vesicles for tissue repair and regeneration. Burns & Trauma. 2024;12:tkae062.
112. Li Z, Liu J, Song J, et al. Multifunctional hydrogel-based engineered extracellular vesicles delivery for complicated wound healing. Theranostics. 2024;14:4198–4217.
113. Exosome-integrated hydrogels for bone tissue engineering. Gels. 2024;10:762.
114. Anitua E, Troya M, Falcon-Pérez JM, et al. Advances in platelet rich plasma-derived extracellular vesicles for regenerative medicine: a systematic-narrative review. International Journal of Molecular Sciences. 2023;24:13043.
115. Extracellular vesicles: emerged as a promising strategy for regenerative medicine. World Journal of Stem Cells. 2023.
116. Huebsch N, Mooney DJ. Inspiration and application in the evolution of biomaterials. Nature. 2009;462:426–432.
117. Stevens MM. Biomaterials for bone tissue engineering. Materials Today. 2008;11:18–25.
118. O'Brien FJ. Materials and devices for bone tissue engineering. Materials Today. 2011;14:88–95.
119. Langer R, Tirrell DA. Designing materials for biology and medicine. Nature. 2004;428:487–492.
120. Freed LE, Vunjak-Novakovic G, Biron RJ, et al. Biodegradable polymer scaffolds for tissue engineering. Bio/Technology. 1994;12:689–693.
121. Place ES, George JH, Williams CK, Stevens MM. Synthetic polymer scaffolds for tissue engineering. Chemical Society Reviews. 2009;38:1139–1151.
122. Khademhosseini A, Eng G, Yeh J, Fukuda J, Burdick JA, Langer R. Microfluidic platforms for generating and patterning cell-laden hydrogels. Lab on a Chip. 2006;6:107–110.
123. Bae H, Puranik AS, Gauvin R, et al. Building vascular networks. Science Translational Medicine. 2012;4:160ps23.
124. Novosel EC, Kleinhans C, Kluger PJ. Vascularization is the key challenge in tissue engineering. Advanced Drug Delivery Reviews. 2011;63:300–311.
125. Rouwkema J, Rivron NC, van Blitterswijk CA. Vascularization in tissue engineering. Trends in Biotechnology. 2008;26:434–441.
126. Laschke MW, Menger MD. Prevascularization in tissue engineering: current concepts and future directions. Biotechnology Advances. 2016;34:112–121.
127. Place ES, Evans ND, Stevens MM. Complexity in biomaterials for tissue engineering. Nature Materials. 2009;8:457–470.
128. Kuo CK, Li WJ, Mauck RL, Tuan RS. Cartilage tissue engineering: its potential and uses. Current Opinion in Rheumatology. 2006;18:64–73.
129. Chung C, Burdick JA. Engineering cartilage tissue interfaces. Advanced Materials. 2008;20:1–14.
130. Langer R, Peppas NA. Advances in biomaterials, drug delivery, and bionanotechnology. AIChE Journal. 2003;49:2990–3006.
131. Zhang Z, Zhou X, Fang Y, Xiong Z, Zhang T. AI-driven 3D bioprinting for regenerative medicine: from bench to bedside. Bioactive Materials. 2024;45:201–230. doi:10.1016/j.bioactmat.2024.11.021.
132. Lee JM, Yeong WY. Design and printing strategies for pharmaceutical 3D printing. International Journal of Bioprinting. 2015;1:23–31.
133. Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnology Advances. 2016;34:422–434.
134. Cui H, Nowicki M, Fisher JP, Zhang LG. 3D bioprinting for organ regeneration. Advanced Healthcare Materials. 2017;6:1601118.
135. Hospodiuk M, Dey M, Sosnoski D, Ozbolat IT. The bioink: a comprehensive review on bioprintable materials. Biotechnology Advances. 2017;35:217–239.
136. Zhang YS, Khademhosseini A. Advances in engineering hydrogels. Science. 2017;356:eaaf3627.
137. Burdick JA, Murphy WL. Moving from static to dynamic complexity in hydrogel design. Nature Communications. 2012;3:1269.
138. Gjorevski N, Sachs N, Manfrin A, et al. Designer matrices for intestinal stem cell and organoid culture. Nature. 2016;539:560–564.
139. Lutolf MP, Blau HM. Artificial stem cell niches. Advances in Materials. 2009;21:3255–3268.
140. Li Y, Rodrigues J, Tomás H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chemical Society Reviews. 2012;41:2193–2221.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Advanced Journal of Scientific Research
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
