Smart Hydrogels Empowering Tissue Repair: Material Design, Emerging Applications, Repair Mechanisms, and Future Challenges

Abstract

Smart hydrogels are attracting considerable interest in the biomedical field, because of their high water content, excellent biocompatibility and biodegradability, and distinctive properties in response to stimuli. Their three-dimensional mesh structure effectively mimics the microenvironment of human tissue, by maintaining moist conditions conducive to wound healing while also serving as a support for active ingredients, thus ensuring their precise and controlled release. Consequently, these materials have excellent potential for use in tissue regeneration. This article first classifies smart hydrogels according to their response mechanisms, specifically systems that respond to temperature, pH, light, and magnetic fields. It then systematically examines potential applications of smart hydrogels in tissue regeneration, according to their ability to dynamically adapt to different tissue microenvironments, particularly the regeneration of skin, bone and cartilage, nerve tissue, and internal organs. Despite their promising potential, smart hydrogels still face several challenges, including imbalances in the rates of tissue degradation and regeneration, insufficient mechanical properties, and relatively limited functionality. Future research should focus on material modification and optimization, AI-assisted design, and interdisciplinary collaboration between medicine and engineering to develop hydrogels’ multifunctional, personalized integration and clinical application, and ultimately enable smarter, more effective solutions for tissue engineering and regenerative medicine.

Keywords

Drug delivery / mechanism of action / smart hydrogels / stimuli responsive / tissue regeneration

References

[1] Guo P, Lei P, Luo L, Yang Q, Yang Q, et al. Microfluidic-engineered Chinese herbal nanocomposite hydrogel microspheres for diabetic wound tissue regeneration. J Nanobiotechnol 2024; 22(1): 724. [PMID: 39568066 DOI: 10.1186/s12951-024-02998-0]

[2] Zhao Z, Zhang Y, Meng C, Xie X, Cui W, et al. Tissue-penetrating ultrasound-triggered hydrogel for promoting microvascular network reconstruction. Adv Sci (Weinh) 2024; 11(23): e2401368. [PMID: 38600702 DOI: 10.1002/advs.202401368]

[3] Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024; 25(8): 599-616. [PMID: 38528155 DOI: 10.1038/s41580-024-00715-1]

[4] Nie R, Zhang QY, Feng ZY, Huang K, Zou CY, et al. Hydrogel-based immunoregulation of macrophages for tissue repair and regeneration. Int J Biol Macromol 2024; 268(Pt 1): 131643. [PMID: 38643918 DOI: 10.1016/j.ijbiomac.2024.131643]

[5] Nii T, Katayama Y. Biomaterial-assisted regenerative medicine. Int J Mol Sci 2021; 22(16): 8657. [PMID: 34445363 DOI: 10.3390/ijms22168657]

[6] Maurya PK, Hazarika K, Bandyopadhyay-Ghosh S, Nandi SK, Ghosh SB. From water to medicine: the transformative role of hydrogels in diabetic wound healing. J Biomater Sci Polym Ed 2025; 1-26. [PMID: 41359509 DOI: 10.1080/09205063.2025.2599294]

[7] Qing X, He G, Liu Z, Yin Y, Cai W, et al. Preparation and properties of polyvinyl alcohol/ N-succinyl chitosan/lincomycin composite antibacterial hydrogels for wound dressing. Carbohydr Polym 2021; 261: 117875. [PMID: 33766362 DOI: 10.1016/j.carbpol.2021.117875]

[8] Hao R, Cui Z, Zhang X, Tian M, Zhang L, et al. Rational design and preparation of functional hydrogels for skin wound healing. Front Chem 2022; 9: 839055. [PMID: 35141209 DOI: 10.3389/fchem.2021.839055]

[9] Delanne-Cumémal A, Verney V, Portanguen S, Fadhlaoui K, Chalancon S, et al. Polysaccharides from Adansonia digitata combined with whey protein and alginate enhance the viscosity, swelling, controlled release, and mucoadhesion properties of hydrogels for oral drug delivery. Int J Pharm 2026; 692: 126624. [PMID: 41592628 DOI: 10.1016/j.ijpharm.2026.126624]

[10] Pavithra B, Singh P, Ramesh Kumar V, Durairaj S, Hassan S. Advances in polymeric nanoparticles and hydrogels in 3D bioprinting: enhancing bioinks for tissue engineering and regenerative medicine. Bioprinting 2025; 51: e00438. [DOI: 10.1016/j.bprint.2025.e00438]

[11] Shen F, Ding X, Wang G, Chen M, Shi H, et al. Dextran based hydrogel wound dressing with cytocompatible, anti-protein and antibacterial properties for infected wound healing. Int J Biol Macromol 2025; 334(Pt 1): 148709. [PMID: 41207592 DOI: 10.1016/j.ijbiomac.2025.148709]

[12] Hamidi M, Azadi A, Rafiei P. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev 2008; 60(15): 1638-49. [PMID: 18840488 DOI: 10.1016/j.addr.2008.08.002]

[13] Kass LE, Nguyen J. Nanocarrier-hydrogel composite delivery systems for precision drug release. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2022; 14(2): e1756. [PMID: 34532989 DOI: 10.1002/wnan.1756]

[14] He Q, Ding X, Deng J, Zhang Y, Wang X, et al. Fabrication of injectable, adhesive, self-healing, superabsorbent hydrogels based on quaternary ammonium chitosan and oxidized pullulan. Heliyon 2024; 10(19): e38577. [PMID: 39435091 DOI: 10.1016/j.heliyon.2024.e38577]

[15] Rafati F, Johari N, Nokhbedehghan Z, Samadikuchaksaraei A, Razavi M, et al. Innovative silk fibroin-flax nanocomposite hydrogels: a drug-loaded system for potential wound dressing applications. Mater Today Commun 2025; 49: 113973. [DOI: 10.1016/j.mtcomm.2025.113973]

[16] Yu H, Zhang J, Yang L, Tian Y, Milne C, et al. MSC-derived exosomes injectable hyaluronic acid hydrogel for enhanced chronic wound healing. J Control Release 2025; 385: 113985. [PMID: 40581219 DOI: 10.1016/j.jconrel.2025.113985]

[17] Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev 2002; 54(1): 3-12. [PMID: 11755703 DOI: 10.1016/s0169-409x(01)00239-3]

[18] Arguchinskaya NV, Isaeva EV, Kisel AA, Beketov EE, Lagoda TS, et al. Properties and printability of the synthesized hydrogel based on GelMA. Int J Mol Sci 2023; 24(3): 2121. [PMID: 36768446 DOI: 10.3390/ijms24032121]

[19] Duan Y, Jiang F, Li Q, McDowell A, Li Y, et al. Multifunctional polysaccharide/metal/polyphenol double-crosslinked hydrogel for infected wound. Carbohydr Polym 2024; 332: 121912. [PMID: 38431415 DOI: 10.1016/j.carbpol.2024.121912]

[20] Zhao J, Jia F, Li J, Tao YC, Hu JY, et al. Sprayable reactive oxygen species-responsive hydrogel coatings restore endothelial barrier integrity for functional vascular healing. ACS Nano 2025; 19(23): 21757-74. [PMID: 40457543 DOI: 10.1021/acsnano.5c05477]

[21] Lin X, Liu R, Zhou Y, Beitzel J, Noguchi A, et al. Injectable biodegradable polysaccharide-based hydrogels for stem cell delivery and cartilage regeneration. J Mater Chem B 2025; 13(26): 7838-53. [PMID: 40485218 DOI: 10.1039/d5tb00287g]

[22] Wang Z, Liu J, Deng R, Yang Y, Fangfang C, et al. Bioactive and biodegradable hydrogel based on the dermal matrix loaded with microspheres containing vascular endothelial growth factor (VEGF) and interleukin (IL)-10 accelerated the healing of diabetic wounds in rats. Regen Ther 2025; 29: 575-86. [PMID: 40475694 DOI: 10.1016/j.reth.2025.04.017]

[23] Guo L, Fu Z, Li H, Wei R, Guo J, et al. Smart hydrogel: a new platform for cancer therapy. Adv Colloid Interface Sci 2025; 340: 103470. [PMID: 40086017 DOI: 10.1016/j.cis.2025.103470]

[24] Jiang Y, Zhu C, Ma X, Fan D. Smart hydrogel-based trends in future tendon injury repair: a review. Int J Biol Macromol 2024; 282(Pt 5): 137092. [PMID: 39489238 DOI: 10.1016/j.ijbiomac.2024.137092]

[25] Cai J, Guo J, Wang S. Application of polymer hydrogels in the prevention of postoperative adhesion: a review. Gels 2023; 9(2): 98. [PMID: 36826268 DOI: 10.3390/gels9020098]

[26] Ghanbari M, Salavati-Niasari M, Mohandes F, Firouzi Z. Modified silicon carbide NPs reinforced nanocomposite hydrogels based on alginate-gelatin by with high mechanical properties for tissue engineering. Arab J Chem 2022; 15(1): 103520. [DOI: 10.1016/j.arabjc.2021.103520]

[27] Zhang X, Liang Y, Huang S, Guo B. Chitosan-based self-healing hydrogel dressing for wound healing. Adv Colloid Interface Sci 2024; 332: 103267. [PMID: 39121832 DOI: 10.1016/j.cis.2024.103267]

[28] He J, Sun Y, Gao Q, He C, Yao K, et al. Gelatin methacryloyl hydrogel, from standardization, performance, to biomedical application. Adv Healthc Mater 2023; 12(23): e2300395. [PMID: 37115708 DOI: 10.1002/adhm.202300395]

[29] Hong SB, Jeong JO, Choi H. Hydrogels in cardiac surgery: versatile platforms for tissue repair, adhesion prevention, and localized therapeutics. Gels 2025; 11(7): 564. [PMID: 40710725 DOI: 10.3390/gels11070564]

[30] Dobner S, Bezuidenhout D, Govender P, Zilla P, Davies N. A synthetic non-degradable polyethylene glycol hydrogel retards adverse post-infarct left ventricular remodeling. J Card Fail 2009; 15(7): 629-36. [PMID: 19700140 DOI: 10.1016/j.cardfail.2009.03.003]

[31] Gong D, Wu N, Chen H, Zhang W, Yan C, et al. Phytic acid-loaded polyvinyl alcohol hydrogel promotes wound healing of injured corneal epithelium through inhibiting ferroptosis. Redox Biol 2024; 76: 103354. [PMID: 39298836 DOI: 10.1016/j.redox.2024.103354]

[32] Visan AI, Negut I. Sustainable hydrogels in water treatment-a short review. Gels 2025; 11(10): 812. [PMID: 41149418 DOI: 10.3390/gels11100812]

[33] Parvin N, Kumar V, Joo SW, Mandal TK. Cutting-edge hydrogel technologies in tissue engineering and biosensing: an updated review. Materials (Basel) 2024; 17(19): 4792. [PMID: 39410363 DOI: 10.3390/ma17194792]

[34] Segneanu AE, Bejenaru LE, Bejenaru C, Blendea A, Mogoşanu GD, et al. Advancements in hydrogels: a comprehensive review of natural and synthetic innovations for biomedical applications. Polymers (Basel) 2025; 17(15): 2026. [PMID: 40808075 DOI: 10.3390/polym17152026]

[35] Liu Z, Ma X, Liu J, Zhang H, Fu D. Advances in the application of natural/synthetic hybrid hydrogels in tissue engineering and delivery systems: a comprehensive review. Int J Pharm 2025; 672: 125323. [PMID: 39923883 DOI: 10.1016/j.ijpharm.2025.125323]

[36] Bustamante-Torres M, Romero-Fierro D, Arcentales-Vera B, Palomino K, Magana H, et al. Hydrogels classification according to the physical or chemical interactions and as stimuli-sensitive materials. Gels 2021; 7(4): 182. [PMID: 34842654 DOI: 10.3390/gels7040182]

[37] Potaś J, Szymańska E, Winnicka K. Challenges in developing of chitosan-based polyelectrolyte complexes as a platform for mucosal and skin drug delivery. Eur Polym J 2020; 140: 110020. [DOI: 10.1016/j.eurpolymj.2020.110020]

[38] Li H, Peng M, Li J, Wang L, Do H, et al. SO₂F₂ mediated click chemistry enables modular disulfide formation in diverse reaction media. Nat Commun 2024; 15(1): 8325. [PMID: 39333088 DOI: 10.1038/s41467-024-52606-w]

[39] Kim SH, Kim K, Kim BS, An YH, Lee UJ, et al. Fabrication of polyphenol-incorporated anti-inflammatory hydrogel via high-affinity enzymatic crosslinking for wet tissue adhesion. Biomaterials 2020; 242: 119905. [PMID: 32145505 DOI: 10.1016/j.biomaterials.2020.119905]

[40] Wei L, Yang Y, Qiu X, Shen J, Zhao Y, et al. Self-polymerized tough and high-entanglement zwitterionic functional hydrogels. Small 2024; 20(50): e2405789. [PMID: 39319480 DOI: 10.1002/smll.202405789]

[41] Feng Q, Zhang M, Zhang G, Mei H, Su C, et al. A whole-course-repair system based on ROS/glucose stimuli-responsive EGCG release and tunable mechanical property for efficient treatment of chronic periodontitis in diabetic rats. J Mater Chem B 2024; 12(15): 3719-40. [PMID: 38529844 DOI: 10.1039/d3tb02898d]

[42] Li X, Xiong Y. Application of “click” chemistry in biomedical hydrogels. ACS Omega 2022; 7(42): 36918-28. [PMID: 36312409 DOI: 10.1021/acsomega.2c03931]

[43] Zhang Z, Tao ZZ, Du R, Huo R, Zheng X. Artificial intelligence informed hydrogel biomaterials in additive manufacturing. Gels 2025; 11(12): 981. [PMID: 41441137 DOI: 10.3390/gels11120981]

[44] Sokmen S, Cakmak S, Oksuz I. 3D printing of an artificial intelligence-generated patient-specific coronary artery segmentation in a support bath. Biomed Mater 2024; 19(3): 035038. [PMID: 38626778 DOI: 10.1088/1748-605X/ad3f60]

[45] Li Z, Song P, Li G, Han Y, Ren X, et al. AI energized hydrogel design, optimization and application in biomedicine. Mater Today Bio 2024; 25: 101014. [PMID: 38464497 DOI: 10.1016/j.mtbio.2024.101014]

[46] Hill H, Roadevin C, Duffy S, Mandrik O, Brentnall A. Cost-effectiveness of AI for risk-stratified breast cancer screening. JAMA Netw Open 2024; 7(9): e2431715. [PMID: 39235813 DOI: 10.1001/jamanetworkopen.2024.31715]

[47] Yu Y, Liang X, Ruan H, Wang T, Li Y, et al. Hydrogel-based sensors for multimodal health monitoring: from material design to intelligent sensing. Nanoscale 2025; 17(43): 24805-29. [PMID: 41144230 DOI: 10.1039/d5nr03553h]

[48] Liao H, Hu S, Yang H, Wang L, Tanaka S, et al. Data-driven de novo design of super-adhesive hydrogels. Nature 2025; 644(8075): 89-95. [PMID: 40770436 DOI: 10.1038/s41586-025-09269-4]

[49] Salehi S, Naghib SM, Garshasbi HR, Ghorbanzadeh S, Zhang W. Smart stimuli-responsive injectable gels and hydrogels for drug delivery and tissue engineering applications: a review. Front Bioeng Biotechnol 2023; 11: 1104126. [PMID: 36911200 DOI: 10.3389/fbioe.2023.1104126]

[50] Cai Y, Xin L, Sun P, Li H, Liu C, et al. Temperature-sensitive multifunctional intelligent responsive hydrogel based on carboxymethyl agarose and N-isopropylacrylamide: controlled drug release and accelerated wound healing. Carbohydr Polym 2023; 322: 121327. [PMID: 37839839 DOI: 10.1016/j.carbpol.2023.121327]

[51] Zhang Y, Shi K, Yang X, Chen W, Wang T, et al. Sustained release of levobupivacaine from temperature-sensitive injectable hydrogel for long-term local anesthesia in postoperative pain management. Biomaterials 2023; 299: 122129. [PMID: 37167892 DOI: 10.1016/j.biomaterials.2023.122129]

[52] Gui H, Yang T, Li LL, Liang F, Yang Z. Temperature-sensitive anti-inflammatory organohydrogels containing Janus particle stabilized phase-change microinclusions. ACS Nano 2022; 16(6): 9859-70. [PMID: 35699249 DOI: 10.1021/acsnano.2c03940]

[53] Wang R, Yang Z, Luo J, Hsing IM, Sun F. B12-dependent photoresponsive protein hydrogels for controlled stem cell/protein release. Proc Natl Acad Sci U S A 2017; 114(23): 5912-7. [PMID: 28533376 DOI: 10.1073/pnas.1621350114]

[54] Wang H, Morales RT, Cui X, Huang J, Qian W, et al. A photoresponsive hyaluronan hydrogel nanocomposite for dynamic macrophage immunomodulation. Adv Healthc Mater 2019; 8(4): e1801234. [PMID: 30537061 DOI: 10.1002/adhm.201801234]

[55] Fan L, Zhang X, Liu X, Sun B, Li L, et al. Responsive hydrogel microcarrier-integrated microneedles for versatile and controllable drug delivery. Adv Healthc Mater 2021; 10(9): e2002249. [PMID: 33690992 DOI: 10.1002/adhm.202002249]

[56] Chen Y, Wang X, Tao S, Wang Q, Ma PQ, et al. Research advances in smart responsive-hydrogel dressings with potential clinical diabetic wound healing properties. Mil Med Res 2023; 10(1): 37. [PMID: 37608335 DOI: 10.1186/s40779-023-00473-9]

[57] Long J, Zhou G, Yu X, Xu J, Hu L, et al. Harnessing chemical functionality of xylan hemicellulose towards carbohydrate polymer-based pH/magnetic dual-responsive nanocomposite hydrogel for drug delivery. Carbohydr Polym 2024; 343: 122461. [PMID: 39174134 DOI: 10.1016/j.carbpol.2024.122461]

[58] Park SH, Shin HS, Park SN. A novel pH-responsive hydrogel based on carboxymethyl cellulose/2-hydroxyethyl acrylate for transdermal delivery of naringenin. Carbohydr Polym 2018; 200: 341-52. [PMID: 30177174 DOI: 10.1016/j.carbpol.2018.08.011]

[59] Wu Y, Wang Y, Long L, Hu C, Kong Q, et al. A spatiotemporal release platform based on pH/ROS stimuli-responsive hydrogel in wound repairing. J Control Release 2022; 341: 147-65. [PMID: 34813880 DOI: 10.1016/j.jconrel.2021.11.027]

[60] Yi M, Jin W, Li H, Niu X, Wang J, et al. pH-responsive bilayer hydrogel with sequential release of morin-based nanoparticles and bFGF for the treatment of the “ice and fire” wounds. Materials Today Bio 2025; 35: 102519. [PMID: 41356418 DOI: 10.1016/j.mtbio.2025.102519]

[61] Hia EM, Suh IW, Jang SR, Park CH. Magnetically responsive micro-clustered calcium phosphate-reinforced cell-laden microbead sodium alginate hydrogel for accelerated osteogenic tissue regeneration. Carbohydr Polym 2024; 346: 122666. [PMID: 39245476 DOI: 10.1016/j.carbpol.2024.122666]

[62] Xue B, Peng Y, Zhang Y, Yang S, Zheng Y, et al. A novel superparamagnetic-responsive hydrogel facilitates disc regeneration by orchestrating cell recruitment, proliferation, and differentiation within hostile inflammatory niche. Adv Sci (Weinh) 2024; 11(44): e2408093. [PMID: 39373392 DOI: 10.1002/advs.202408093]

[63] Manescu Paltanea V, Dumitru AV, Antoniac A, Antoniac I, Paltanea G, et al. Magnetic hydrogels as a treatment for oncological pathologies. J Funct Biomater 2025; 16(11): 414. [PMID: 41295069 DOI: 10.3390/jfb16110414]

[64] Qiao L, Liang Y, Chen J, Huang Y, Alsareii SA, et al. Antibacterial conductive self-healing hydrogel wound dressing with dual dynamic bonds promotes infected wound healing. Bioact Mater 2023; 30: 129-41. [PMID: 37554541 DOI: 10.1016/j.bioactmat.2023.07.015]

[65] Yao WD, Zhou JN, Tang C, Zhang JL, Chen ZY, et al. Hydrogel microneedle patches loaded with stem cell mitochondria-enriched microvesicles boost the chronic wound healing. ACS Nano 2024; 18(39): 26733-50. [PMID: 39238258 DOI: 10.1021/acsnano.4c06921]

[66] He Y, Li Y, Sun Y, Zhao S, Feng M, et al. A double-network polysaccharide-based composite hydrogel for skin wound healing. Carbohydr Polym 2021; 261: 117870. [PMID: 33766357 DOI: 10.1016/j.carbpol.2021.117870]

[67] Zhang H, Zhou W, Wang H, Zhang J, Yang H, et al. Hydrogel-based bioactive synthetic skin stimulates regenerative gas signaling and eliminates interfacial pathogens to promote burn wound healing. ACS Nano 2025; 19(15): 15002-17. [PMID: 40205977 DOI: 10.1021/acsnano.5c01134]

[68] Chen S, Xiong Y, Yang F, Hu Y, Feng J, et al. Approaches to scarless burn wound healing: application of 3D printed skin substitutes with dual properties of anti-infection and balancing wound hydration levels. EBioMedicine 2024; 106: 105258. [PMID: 39068733 DOI: 10.1016/j.ebiom.2024.105258]

[69] Zhang T, Sheng S, Cai W, Yang H, Li J, et al. 3-D bioprinted human-derived skin organoids accelerate full-thickness skin defects repair. Bioact Mater 2024; 42: 257-69. [PMID: 39285913 DOI: 10.1016/j.bioactmat.2024.08.036]

[70] Tedesco DJ, Hutter MF, Khalaf F, Ricciuti Z, Jeschke MG. Sepsis in burn care: incidence and outcomes. Mil Med Res 2025; 12(1): 55. [PMID: 40890875 DOI: 10.1186/s40779-025-00643-x]

[71] Gong Y, Wang P, Cao R, Wu J, Ji H, et al. Exudate absorbing and antimicrobial hydrogel integrated with multifunctional curcumin-loaded magnesium polyphenol network for facilitating burn wound healing. ACS Nano 2023; 17(22): 22355-70. [PMID: 37930078 DOI: 10.1021/acsnano.3c04556]

[72] Sun J, Jia W, Qi H, Huo J, Liao X, et al. An antioxidative and active shrinkage hydrogel integratedly promotes re-epithelialization and skin constriction for enhancing wound closure. Adv Mater 2024; 36(21): e2312440. [PMID: 38332741 DOI: 10.1002/adma.202312440]

[73] Zhang F, Zhang H, Wang S, Gao M, Du K, et al. A dynamically phase-adaptive regulating hydrogel promotes ultrafast anti-fibrotic wound healing. Nat Commun 2025; 16(1): 3738. [PMID: 40254609 DOI: 10.1038/s41467-025-58987-w]

[74] Zhang M, Xiang C, Zhen X, Luo W, He X, et al. Natural polymer based drug-loaded hydrogel platform for comprehensive care of acute spinal cord injury. Mater Today Bio 2025; 31: 101464. [PMID: 39896281 DOI: 10.1016/j.mtbio.2025.101464]

[75] Wang S, Wang R, Chen J, Yang B, Shu J, et al. Controlled extracellular vesicles release from aminoguanidine nanoparticle-loaded polylysine hydrogel for synergistic treatment of spinal cord injury. J Control Release 2023; 363: 27-42. [PMID: 37722419 DOI: 10.1016/j.jconrel.2023.09.026]

[76] Liu M, Wang Y, Wang H, Qi L, Shang Y, et al. Electret-inspired charge-injected hydrogel for scar-free healing of bacterially infected burns through bioelectrical stimulation and immune modulation. Adv Sci (Weinh) 2025; 12(13): e2411889. [PMID: 39951351 DOI: 10.1002/advs.202411889]

[77] Su Y, Zhang M, Yu B, Tian F, Zhu D, et al. Temperature-programmable deformable microneedles for scar-free healing of infective wounds via sensory nerve regeneration. Small 2025; 21(20): e2501491. [PMID: 40178015 DOI: 10.1002/smll.202501491]

[78] Xiong M, Yang X, Shi Z, Xiang J, Gao H, et al. Programmable artificial skins accomplish antiscar healing with multiple appendage regeneration. Adv Mater 2024; 36(50): e2407322. [PMID: 39460410 DOI: 10.1002/adma.202407322]

[79] Yang Y, Zhang J, Wu S, Deng Y, Wang S, et al. Exosome/antimicrobial peptide laden hydrogel wound dressings promote scarless wound healing through miR-21-5p-mediated multiple functions. Biomaterials 2024; 308: 122558. [PMID: 38581764 DOI: 10.1016/j.biomaterials.2024.122558]

[80] Zhao X, Luo J, Huang Y, Mu L, Chen J, et al. Injectable antiswelling and high-strength bioactive hydrogels with a wet adhesion and rapid gelling process to promote sutureless wound closure and scar-free repair of infectious wounds. ACS Nano 2023; 17(21): 22015-34. [PMID: 37862553 DOI: 10.1021/acsnano.3c08625]

[81] Park J, Kim TY, Kim Y, An S, Kim KS, et al. A mechanically resilient and tissue-conformable hydrogel with hemostatic and antibacterial capabilities for wound care. Adv Sci (Weinh) 2023; 10(30): e2303651. [PMID: 37705116 DOI: 10.1002/advs.202303651]

[82] Sun H, Wang S, Yang F, Tan M, Bai L, et al. Conductive and antibacterial dual-network hydrogel for soft bioelectronics. Mater Horiz 2023; 10(12): 5805-21. [PMID: 37817573 DOI: 10.1039/d3mh00813d]

[83] Guo S, Ren Y, Chang R, He Y, Zhang D, et al. Injectable self-healing adhesive chitosan hydrogel with antioxidative, antibacterial, and hemostatic activities for rapid hemostasis and skin wound healing. ACS Appl Mater Interfaces 2022; 14(30): 34455-69. [PMID: 35857973 DOI: 10.1021/acsami.2c08870]

[84] Xu Z, Liu G, Liu P, Hu Y, Chen Y, et al. Hyaluronic acid-based glucose-responsive antioxidant hydrogel platform for enhanced diabetic wound repair. Acta Biomater 2022; 147: 147-57. [PMID: 35649507 DOI: 10.1016/j.actbio.2022.05.047]

[85] Song Y, You Y, Xu X, Lu J, Huang X, et al. Adipose-derived mesenchymal stem cell-derived exosomes biopotentiated extracellular matrix hydrogels accelerate diabetic wound healing and skin regeneration. Adv Sci (Weinh) 2023; 10(30): e2304023. [PMID: 37712174 DOI: 10.1002/advs.202304023]

[86] Liu W, Gao R, Yang C, Feng Z, Ou-Yang W, et al. ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus-infected chronic skin wound healing. Sci Adv 2022; 8(27): eabn7006. [PMID: 35857459 DOI: 10.1126/sciadv.abn7006]

[87] Jin E, Yang Y, Cong S, Chen D, Chen R, et al. Lemon-derived nanoparticle-functionalized hydrogels regulate macrophage reprogramming to promote diabetic wound healing. J Nanobiotechnol 2025; 23(1): 68. [PMID: 39891270 DOI: 10.1186/s12951-025-03138-y]

[88] Chu Z, Liu X, Zhao T, Jiang D, Zhao J, et al. Self-healing Ppy-hydrogel promotes diabetic skin wound healing through enhanced sterilization and macrophage orchestration triggered by NIR. Biomaterials 2025; 315: 122964. [PMID: 39550986 DOI: 10.1016/j.biomaterials.2024.122964]

[89] Zhang J, Tong D, Song H, Ruan R, Sun Y, et al. Osteoimmunity-regulating biomimetically hierarchical scaffold for augmented bone regeneration. Adv Mater 2022; 34(36): e2202044. [PMID: 35785450 DOI: 10.1002/adma.202202044]

[90] Ji X, Lei Z, Yuan M, Zhu H, Yuan X, et al. Cartilage repair mediated by thermosensitive photocrosslinkable TGFβ1-loaded GM-HPCH via immunomodulating macrophages, recruiting MSCs and promoting chondrogenesis. Theranostics 2020; 10(6): 2872-87. [PMID: 32194841 DOI: 10.7150/thno.41622]

[91] Fang Z, Liu G, Wang B, Meng H, Bahatibieke A, et al. An injectable self-healing alginate hydrogel with desirable mechanical and degradation properties for enhancing osteochondral regeneration. Carbohydr Polym 2024; 343: 122424. [PMID: 39174114 DOI: 10.1016/j.carbpol.2024.122424]

[92] Wang N, Chen J, Chen Y, Chen L, Bao L, et al. Kneadable dough-type hydrogel transforming from dynamic to rigid network to repair irregular bone defects. Bioact Mater 2024; 40: 430-44. [PMID: 39007059 DOI: 10.1016/j.bioactmat.2024.06.021]

[93] Zhou S, Xiao C, Fan L, Yang J, Ge R, et al. Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing. J Nanobiotechnol 2024; 22(1): 54. [PMID: 38326903 DOI: 10.1186/s12951-024-02320-y]

[94] Wang L, Wu Z, Chen X, Bai J, Li W, et al. A multifunctional self-assembled hydrogel with bactericidal activity and macrophage metabolic reprogramming for diabetic bone defect repair. Mater Today Bio 2025; 34: 102162. [PMID: 40809348 DOI: 10.1016/j.mtbio.2025.102162]

[95] Zhang Q, Chen W, Li G, Ma Z, Zhu M, et al. A factor-free hydrogel with ROS scavenging and responsive degradation for enhanced diabetic bone healing. Small 2024; 20(24): e2306389. [PMID: 38168513 DOI: 10.1002/smll.202306389]

[96] Li J, Wei G, Liu G, Du Y, Zhang R, et al. Regulating type H vessel formation and bone metabolism via bone-targeting oral micro/nano-hydrogel microspheres to prevent bone loss. Adv Sci (Weinh) 2023; 10(15): e2207381. [PMID: 36967561 DOI: 10.1002/advs.202207381]

[97] Wei FL, Zhai Y, Wang TF, Zhao JW, Wang CL, et al. Stem cell-homing biomimetic hydrogel promotes the repair of osteoporotic bone defects through osteogenic and angiogenic coupling. Sci Adv 2024; 10(44): eadq6700. [PMID: 39485837 DOI: 10.1126/sciadv.adq6700]

[98] Zhang FX, Liu P, Ding W, Meng QB, Su DH, et al. Injectable mussel-inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials 2021; 278: 121169. [PMID: 34626937 DOI: 10.1016/j.biomaterials.2021.121169]

[99] Zuo G, Zhuang P, Yang X, Jia Q, Cai Z, et al. Regulating chondro-bone metabolism for treatment of osteoarthritis via high-permeability micro/nano hydrogel microspheres. Adv Sci (Weinh) 2024; 11(5): e2305023. [PMID: 38084002 DOI: 10.1002/advs.202305023]

[100] Yang Y, Zhao X, Wang S, Zhang Y, Yang A, et al. Ultra-durable cell-free bioactive hydrogel with fast shape memory and on-demand drug release for cartilage regeneration. Nat Commun 2023; 14(1): 7771. [PMID: 38012159 DOI: 10.1038/s41467-023-43334-8]

[101] Xie D, Hu C, Zhu Y, Yao J, Li J, et al. Sequential therapy for osteosarcoma and bone regeneration via chemodynamic effect and cuproptosis using a 3D-printed scaffold with TME-responsive hydrogel. Small 2025; 21(5): e2406639. [PMID: 39908123 DOI: 10.1002/smll.202406639]

[102] Jing Z, Yuan W, Wang J, Ni R, Qin Y, et al. Simvastatin/hydrogel-loaded 3D-printed titanium alloy scaffolds suppress osteosarcoma via TF/NOX2-associated ferroptosis while repairing bone defects. Bioact Mater 2024; 33: 223-41. [PMID: 38045570 DOI: 10.1016/j.bioactmat.2023.11.001]

[103] Chu X, Mi B, Xiong Y, Wang R, Liu T, et al. Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment. Biomaterials 2025; 312: 122714. [PMID: 39079462 DOI: 10.1016/j.biomaterials.2024.122714]

[104] Zhu M, Zhang H, Zhou Q, Sheng S, Gao Q, et al. Dynamic GelMA/DNA dual-network hydrogels promote woven bone organoid formation and enhance bone regeneration. Adv Mater 2025; 37(24): e2501254. [PMID: 40123197 DOI: 10.1002/adma.202501254]

[105] Wang Y, Chen Y, Zhou T, Li J, Zhang N, et al. A novel multifunctional nanocomposite hydrogel orchestrates the macrophage reprogramming-osteogenesis crosstalk to boost bone defect repair. J Nanobiotechnol 2024; 22(1): 702. [PMID: 39533396 DOI: 10.1186/s12951-024-02996-2]

[106] Bai L, Zhang X, Shen W, Wang P, Yin X, et al. Multifunctional scaffold comprising metal-organic framework, hydrogel, and demineralized bone matrix for the treatment of steroid-induced femoral head necrosis. Small 2025; 21(3): e2407758. [PMID: 39575484 DOI: 10.1002/smll.202407758]

[107] Lu W, Zeng M, Liu W, Ma T, Fan X, et al. Human urine-derived stem cell exosomes delivered via injectable GelMA templated hydrogel accelerate bone regeneration. Mater Today Bio 2023; 19: 100569. [PMID: 36846309 DOI: 10.1016/j.mtbio.2023.100569]

[108] Chen B, Liang Y, Zhang J, Bai L, Xu M, et al. Synergistic enhancement of tendon-to-bone healing via anti-inflammatory and pro-differentiation effects caused by sustained release of Mg²⁺/curcumin from injectable self-healing hydrogels. Theranostics 2021; 11(12): 5911-25. [PMID: 33897889 DOI: 10.7150/thno.56266]

[109] Lao A, Wu J, Li D, Shen A, Li Y, et al. Functionalized metal-organic framework-modified hydrogel that breaks the vicious cycle of inflammation and ROS for repairing of diabetic bone defects. Small 2023; 19(36): e2206919. [PMID: 37183293 DOI: 10.1002/smll.202206919]

[110] Luo Q, Yang Y, Ho C, Li Z, Chiu W, et al. Dynamic hydrogel-metal-organic framework system promotes bone regeneration in periodontitis through controlled drug delivery. J Nanobiotechnol 2024; 22(1): 287. [PMID: 38797862 DOI: 10.1186/s12951-024-02555-9]

[111] Walter J, Zweckberger K . Traumatische Verletzungen des zentralen Nervensystems. Fortschr Neurol Psychiatr 2019; 87(1): 57-69. [PMID: 30802926 DOI: 10.1055/a-0822-7071]

[112] Li Z, Zhao T, Ding J, Gu H, Wang Q, et al. A reactive oxygen species-responsive hydrogel encapsulated with bone marrow derived stem cells promotes repair and regeneration of spinal cord injury. Bioact Mater 2023; 19: 550-68. [PMID: 35600969 DOI: 10.1016/j.bioactmat.2022.04.029]

[113] Zhang D, Chen J, Lin H, Zhou M, Hou J, et al. A cocktail hydrogel promoting the functional interneurons regeneration of human neural progenitor cells for brain injury therapy. J Adv Res 2026; 81: 657-72. [PMID: 40460940 DOI: 10.1016/j.jare.2025.05.063]

[114] Khan WU, Shen Z, Mugo SM, Wang H, Zhang Q. Implantable hydrogels as pioneering materials for next-generation brain-computer interfaces. Chem Soc Rev 2025; 54(6): 2832-80. [PMID: 40035554 DOI: 10.1039/d4cs01074d]

[115] Ricci C. Neurodegenerative disease: from molecular basis to therapy. Int J Mol Sci 2024; 25(2): 967. [PMID: 38256040 DOI: 10.3390/ijms25020967]

[116] Kim S, Kim MK, Oh D, Lee SH, Kim B. Induced pluripotent stem cells as a novel tool in psychiatric research. Psychiatry Investig 2016; 13(1): 8-17. [PMID: 26766942 DOI: 10.4306/pi.2016.13.1.8]

[117] Liu Y, Tan Y, Cheng G, Ni Y, Xie A, et al. Customized intranasal hydrogel delivering methylene blue ameliorates cognitive dysfunction against Alzheimer’s disease. Adv Mater 2024; 36(19): e2307081. [PMID: 38395039 DOI: 10.1002/adma.202307081]

[118] Dickson DW. Neuropathology of Parkinson’s disease and Parkinsonism. Cold Spring Harb Perspect Med 2025; a041610. [PMID: 40324812 DOI: 10.1101/cshperspect.a041610]

[119] Chen TY, Xu J, Tai CH, Wen TK, Hsu SH. Biodegradable, electroconductive self-healing hydrogel based on polydopamine-coated polyurethane nano-crosslinker for Parkinson’s disease therapy. Biomaterials 2025; 320: 123268. [PMID: 40121830 DOI: 10.1016/j.biomaterials.2025.123268]

[120] Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 2004; 16(5): 1-7. [PMID: 15174821 DOI: 10.3171/foc.2004.16.5.2]

[121] Xu D, Fu S, Zhang H, Lu W, Xie J, et al. Ultrasound-responsive aligned piezoelectric nanofibers derived hydrogel conduits for peripheral nerve regeneration. Adv Mater 2024; 36(28): e2307896. [PMID: 38744452 DOI: 10.1002/adma.202307896]

[122] Lee HS, Jeon EY, Nam JJ, Park JH, Choi IC, et al. Development of a regenerative porous PLCL nerve guidance conduit with swellable hydrogel-based microgrooved surface pattern via 3D printing. Acta Biomater 2022; 141: 219-32. [PMID: 35081432 DOI: 10.1016/j.actbio.2022.01.042]

[123] Yu F, Wang Y, Stetler AR, Leak RK, Hu X, et al. Phagocytic microglia and macrophages in brain injury and repair. CNS Neurosci Ther 2022; 28(9): 1279-93. [PMID: 35751629 DOI: 10.1111/cns.13899]

[124] Zhang W, Liu Y, Wang Z, He S, Liu W, et al. Remodeling brain pathological microenvironment to lessen cerebral ischemia injury by multifunctional injectable hydrogels. J Control Release 2024; 369: 591-603. [PMID: 38582336 DOI: 10.1016/j.jconrel.2024.03.050]

[125] Behun MN, Kulkarni M, Nolfi AL, France CT, Skillen CD, et al. Porcine acellular nerve-derived hydrogel improves outcomes of direct muscle neurotization in rats. Tissue Eng Part A 2024; 30(1-2): 84-93. [PMID: 37917102 DOI: 10.1089/ten.TEA.2023.0191]

[126] Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006; 7(8): 617-27. [PMID: 16858390 DOI: 10.1038/nrn1956]

[127] He X, Lei M, Chen X, Xu F, Liu H, et al. Dynamic hydrogel-based strategy for traumatic brain Injury modeling and therapy. CNS Neurosci Ther 2025; 31(1): e70148. [PMID: 39788897 DOI: 10.1111/cns.70148]

[128] Cook DJ, Nguyen C, Chun HN, Llorente IL, Chiu AS, et al. Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke. J Cereb Blood Flow Metab 2017; 37(3): 1030-45. [PMID: 27174996 DOI: 10.1177/0271678X16649964]

[129] Wang W, Yao H, Xia J, Wan X, Wu J. Chitosan-based immunomodulatory bioadhesive hydrogel promotes liver hemostasis and repair. Carbohydr Polym 2025; 353: 123268. [PMID: 39914958 DOI: 10.1016/j.carbpol.2025.123268]

[130] Qin J, Wu Z, Ma S, Wu Y, Chen Y, et al. Hierarchical structures of protein-fiber-infused aminoglycan hydrogels to promote myocardial repair. ACS Nano 2025; 19(36): 32254-69. [PMID: 40910166 DOI: 10.1021/acsnano.5c07064]

[131] Yang Y, He G, Pan Z, Zhang K, Xian Y, et al. An injectable hydrogel with ultrahigh burst pressure and innate antibacterial activity for emergency hemostasis and wound repair. Adv Mater 2024; 36(33): e2404811. [PMID: 38875445 DOI: 10.1002/adma.202404811]

[132] Chen Z, Wu H, Wang H, Zaldivar-Silva D, Agüero L, et al. An injectable anti-microbial and adhesive hydrogel for the effective noncompressible visceral hemostasis and wound repair. Mater Sci Eng C Mater Biol Appl 2021; 129: 112422. [PMID: 34579930 DOI: 10.1016/j.msec.2021.112422]

[133] Wang X, Liu X, Li K, Liu W, Wang Y, et al. A microgel-hydrogel hybrid for functional compensation and mechanical stability in 3D printed cell-dense vascularized liver tissue. Adv Mater 2025; 37(28): e2413940. [PMID: 40223341 DOI: 10.1002/adma.202413940]

[134] Chou XY, Cheng KY, Yin WR, Cheng TJ, Chen RLC, et al. Self-healing hydrogel containing decellularized liver matrix and endothelial cell-covered hepatocyte spheroids for rescue of injured hepatocytes. Macromol Biosci 2024; 24(5): e2300411. [PMID: 38326219 DOI: 10.1002/mabi.202300411]

[135] Zhao M, Zhou Y, Liu S, Li L, Chen Y, et al. Control release of mitochondria-targeted antioxidant by injectable self-assembling peptide hydrogel ameliorated persistent mitochondrial dysfunction and inflammation after acute kidney injury. Drug Deliv 2018; 25(1): 546-54. [PMID: 29451033 DOI: 10.1080/10717544.2018.1440445]

[136] Garreta E, Moya-Rull D, Marco A, Amato G, Ullate-Agote A, et al. Natural hydrogels support kidney organoid generation and promote in vitro angiogenesis. Adv Mater 2024; 36(34): e2400306. [PMID: 38762768 DOI: 10.1002/adma.202400306]

[137] Khunmanee S, Chun SY, Ha YS, Lee JN, Kim BS, et al. Improvement of IgA nephropathy and kidney regeneration by functionalized hyaluronic acid and gelatin hydrogel. Tissue Eng Regen Med 2022; 19(3): 643-58. [PMID: 35325404 DOI: 10.1007/s13770-022-00442-8]

[138] Lin J, Liu S, Xue X, Lv J, Zhao L, et al. Injectable genetic engineering hydrogel for promoting spatial tolerance of transplanted kidney in situ. Adv Sci (Weinh) 2024; 11(48): e2408631. [PMID: 39498870 DOI: 10.1002/advs.202408631]

[139] Zhang J, Guo Y, Bai Y, Wei Y. Application of biomedical materials in the diagnosis and treatment of myocardial infarction. J Nanobiotechnol 2023; 21(1): 298. [PMID: 37626396 DOI: 10.1186/s12951-023-02063-2]

[140] Zhao C, Wang H, Sun X, Liu Y, Chen J, et al. Non-covalent cross-linking hydrogel: a new method for visceral hemostasis. Gels 2024; 10(5): 326. [PMID: 38786243 DOI: 10.3390/gels10050326]

[141] Li H, Zhou X, Luo L, Ding Q, Tang S. Bio-orthogonally crosslinked catechol-chitosan hydrogel for effective hemostasis and wound healing. Carbohydr Polym 2022; 281: 119039. [PMID: 35074104 DOI: 10.1016/j.carbpol.2021.119039]

[142] Gong J, Qiu Y, Yu C, Cao C, Li X, et al. Injectable hydrogel for cardiac repair via dual inhibition of ferroptosis and oxidative stress. ACS Appl Mater Interfaces 2025; 17(19): 27906-22. [PMID: 40326674 DOI: 10.1021/acsami.5c02666]

[143] Butenko S, Nagalla RR, Guerrero-Juarez CF, Palomba F, David LM, et al. Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing. Nat Commun 2024; 15(1): 6820. [PMID: 39122702 DOI: 10.1038/s41467-024-50072-y]

[144] Zhang Y, Yu L, Qiu R, Cao L, Ye G, et al. 3D hypoxia-mimicking and anti-synechia hydrogel enabling promoted neovascularization for renal injury repair and regeneration. Mater Today Bio 2023; 21: 100694. [PMID: 37346780 DOI: 10.1016/j.mtbio.2023.100694]

[145] Jiang S, Kim TM, Park SY, Jin EJ. ROS-responsive MnO₂ mesoporous hydrogel to modulate liver-muscle crosstalk and mitigate NAFLD-associated sarcopenia via exosomal miR-582-5p delivery. Theranostics 2025; 15(10): 4579-92. [PMID: 40225561 DOI: 10.7150/thno.108280]

[146] Nicodemus GD, Shiplet KA, Kaltz SR, Bryant SJ. Dynamic compressive loading influences degradation behavior of PEG-PLA hydrogels. Biotechnol Bioeng 2009; 102(3): 948-59. [PMID: 18831003 DOI: 10.1002/bit.22105]

[147] Dong W, Yang H, Liu M, Mei L, Han J. Wound microenvironment-responsive peptide hydrogel with multifunctionalities for accelerating wound healing. J Pept Sci 2024; 30(7): e3595. [PMID: 38494339 DOI: 10.1002/psc.3595]

[148] Shur M, Akouissi O, Rizzo O, Colin DJ, Kolinski JM, et al. Revealing the complexity of ultra-soft hydrogel re-swelling inside the brain. Biomaterials 2023; 294: 122024. [PMID: 36716587 DOI: 10.1016/j.biomaterials.2023.122024]

[149] Bai M, Chen Y, Zhu L, Li Y, Ma T, et al. Bioinspired adaptive lipid-integrated bilayer coating for enhancing dynamic water retention in hydrogel-based flexible sensors. Nat Commun 2024; 15(1): 10569. [PMID: 39632850 DOI: 10.1038/s41467-024-54879-7]

[150] Boretti G, Baldursson HE, Buonarrivo L, Simonsson S, Brynjólfsson S, et al. Mechanical and biological characterization of ionic and photo-crosslinking effects on gelatin-based hydrogel for cartilage tissue engineering applications. Polymers (Basel) 2024; 16(19): 2741. [PMID: 39408454 DOI: 10.3390/polym16192741]

[151] Carrasco S, González L, Tapia M, Urbano BF, Aguayo C, et al. Enhancing alginate hydrogels as possible wound-healing patches: the synergistic impact of reduced graphene oxide and tannins on mechanical and adhesive properties. Polymers (Basel) 2024; 16(8): 1081. [PMID: 38675000 DOI: 10.3390/polym16081081]

[152] Tan Y, Ma L, Wu Y, Yi Z, Ma X, et al. Responsive hydrogel modulator with self-regulated polyphenol release for accelerating diabetic wound healing via precise immunoregulation. J Mater Chem B 2025; 13(11): 3700-15. [PMID: 39991790 DOI: 10.1039/d4tb02504k]

[153] Dong X, Sun Q, Xu J, Wang T. Development of a multifunctional composite hydrogel for enhanced wound healing: hemostasis, sterilization, and long-term moisturizing properties. ACS Appl Mater Interfaces 2024; 16(2): 2972-83. [PMID: 38170964 DOI: 10.1021/acsami.3c16149]

[154] Maity B, Alam S, Samanta S, Prakash RG, Govindaraju T. Antioxidant silk fibroin composite hydrogel for rapid healing of diabetic wound. Macromol Biosci 2022; 22(9): e2200097. [PMID: 35920099 DOI: 10.1002/mabi.202200097]

[155] Zhang S, Wang H, Liu F, Su Y, Han K, et al. Artificial intelligence-enabled hydrogels: innovations and applications. J Mater Chem B 2025; 13(46): 14967-14981. [PMID: 41165199 DOI: 10.1039/d5tb01944c]