{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:20:46Z","timestamp":1790032846771,"version":"4.0.1"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Osteoporosis, a prevalent systemic metabolic bone disease, is characterized by diminished bone mass, microarchitectural deterioration of bone tissue, and heightened bone fragility. In osteoporotic patients, chronic and progressive bone loss often leads to fractures and, in advanced cases, critical-sized bone defects. While traditional bone repair approaches are constrained by significant limitations, the advent of bioactive scaffolds has transformed the therapeutic paradigm for osteoporotic bone regeneration. Among these innovations, natural polymer-based hydrogel scaffolds have emerged as a particularly promising solution in bone tissue engineering, owing to their superior biocompatibility, tunable biodegradation properties, and exceptional ability to replicate the native extracellular matrix environment. This review systematically explores recent breakthroughs in modification techniques and therapeutic applications of natural hydrogel scaffolds for osteoporotic bone defect repair, while critically analyzing existing clinical challenges and proposing future research trajectories in this rapidly evolving field.<\/jats:p>","DOI":"10.3389\/fbioe.2025.1591896","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T01:33:50Z","timestamp":1745804030000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Innovative modification strategies and emerging applications of natural hydrogel scaffolds for osteoporotic bone defect regeneration"],"prefix":"10.3389","volume":"13","author":[{"given":"Yanan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.3390\/cells9071743","article-title":"Hyaluronic acid: redefining its role","volume":"9","author":"Abatangelo","year":"2020","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"28206","DOI":"10.1038\/s41598-024-78696-6","article-title":"Magnetic hydrogel scaffold based on hyaluronic acid\/chitosan and gelatin natural polymers","volume":"14","author":"Abou-Okeil","year":"2024","journal-title":"Sci. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"100914","DOI":"10.1016\/j.nantod.2020.100914","article-title":"Stimulus-responsive sequential release systems for drug and gene delivery","volume":"34","author":"Ahmadi","year":"2020","journal-title":"Nano Today"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7004","DOI":"10.1039\/d3tb00478c","article-title":"Nanocellulose-based hydrogels for drug delivery","volume":"11","author":"Ai","year":"2023","journal-title":"J. Mater Chem. B"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e84","DOI":"10.1590\/1807-3107bor-2018.vol32.0084","article-title":"Hyaluronic acid accelerates bone repair in human dental sockets: a randomized triple-blind clinical trial","volume":"32","author":"Alcantara","year":"2018","journal-title":"Braz Oral Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"786","DOI":"10.3390\/gels10120786","article-title":"Self-assembled hydrogel based on (Bio)polyelectrolyte complex of chitosan-gelatin: effect of composition on physicochemical properties","volume":"10","author":"Aleksandr","year":"2024","journal-title":"Gels"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1177\/0885328221998525","article-title":"In vivo evaluation of biocompatibility and immune modulation potential of poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone)-gelatin hydrogels enriched with nano-hydroxyapatite in the model of mouse","volume":"35","author":"Alipour","year":"2021","journal-title":"J. Biomater. Appl."},{"key":"B8","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1089\/ten.TEA.2013.0223","article-title":"In situ gelation for cell immobilization and culture in alginate foam scaffolds","volume":"20","author":"Andersen","year":"2014","journal-title":"Tissue Eng. Part A"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e2300065","DOI":"10.1002\/mabi.202300065","article-title":"Addition of bone-marrow mesenchymal stem cells to 3D-printed alginate\/gelatin hydrogel containing freeze-dried bone nanoparticles accelerates regeneration of critical size bone defects","volume":"24","author":"Bastami","year":"2024","journal-title":"Macromol. Biosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1056\/nejmcp1513724","article-title":"Postmenopausal osteoporosis","volume":"374","author":"Black","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1359\/jbmr.050917","article-title":"Vascular biology and the skeleton","volume":"21","author":"Brandi","year":"2006","journal-title":"J. Bone Min. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/s10616-015-9895-4","article-title":"Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects","volume":"68","author":"Bruzauskaite","year":"2016","journal-title":"Cytotechnology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"H41","DOI":"10.1002\/adma.201003963","article-title":"Hyaluronic acid hydrogels for biomedical applications","volume":"23","author":"Burdick","year":"2011","journal-title":"Adv. Mater"},{"key":"B14","doi-asserted-by":"publisher","first-page":"864","DOI":"10.3389\/fbioe.2020.00864","article-title":"High mineralization capacity of IDG-SW3 cells in 3D collagen hydrogel for bone healing in estrogen-deficient mice","volume":"8","author":"Chen","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"285","DOI":"10.3724\/zdxbyxb-2022-0702","article-title":"Preparation of silk fibroin\/hyaluronic acid composite hydrogel based on thiol-ene click chemistry","volume":"52","author":"Chen","year":"2023","journal-title":"Zhejiang Da Xue Xue Bao Yi Xue Ban."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202201067","article-title":"A multifunctional composite hydrogel that rescues the ROS microenvironment and guides the immune response for repair of osteoporotic bone defects","volume":"32","author":"Chen","year":"","journal-title":"Adv. Funct. Mater."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2106824","DOI":"10.1002\/smll.202106824","article-title":"Harnessing 4D printing bioscaffolds for advanced orthopedics","volume":"18","author":"Chen","year":"","journal-title":"Small"},{"key":"B18","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.actbio.2022.08.016","article-title":"Enzyme-manipulated hydrogelation of small molecules for biomedical applications","volume":"151","author":"Cheng","year":"2022","journal-title":"Acta Biomater."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e2001646","DOI":"10.1002\/adhm.202001646","article-title":"Biomimetic silk fibroin hydrogels strengthened by silica nanoparticles distributed nanofibers facilitate bone repair","volume":"10","author":"Cheng","year":"2021","journal-title":"Adv. Healthc. Mater"},{"key":"B20","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1002\/jcb.20449","article-title":"Cellular and molecular interactions regulating skeletogenesis","volume":"95","author":"Colnot","year":"2005","journal-title":"J. Cell Biochem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/s0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"283","DOI":"10.3390\/ijms23010283","article-title":"Enhanced BMP-2-mediated bone repair using an anisotropic silk fibroin scaffold coated with bone-like apatite","volume":"23","author":"Deininger","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"7039","DOI":"10.3390\/molecules28207039","article-title":"Hydrogel tissue bioengineered scaffolds in bone repair: a review","volume":"28","author":"Ding","year":"2023","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3109\/03008201003783011","article-title":"Reduced local blood supply to the tibial metaphysis is associated with ovariectomy-induced osteoporosis in mice","volume":"52","author":"Ding","year":"2011","journal-title":"Connect. Tissue Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"112539","DOI":"10.1016\/j.msec.2021.112539","article-title":"Bioinspired gelatin\/bioceramic composites loaded with bone morphogenetic protein-2 (BMP-2) promote osteoporotic bone repair","volume":"134","author":"Echave","year":"2022","journal-title":"Biomater. Adv."},{"key":"B26","doi-asserted-by":"publisher","first-page":"S120","DOI":"10.1007\/s00198-004-1817-9","article-title":"The potential of gene therapy for fracture healing in osteoporosis","volume":"16","author":"Egermann","year":"2005","journal-title":"Osteoporos. Int."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.actbio.2017.08.030","article-title":"Regenerating bone with bioactive glass scaffolds: a review of in vivo studies in bone defect models","volume":"62","author":"El-Rashidy","year":"2017","journal-title":"Acta Biomater."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1126\/science.aam7928","article-title":"Inflammation and metabolism in tissue repair and regeneration","volume":"356","author":"Eming","year":"2017","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","first-page":"140449","DOI":"10.1016\/j.ijbiomac.2025.140449","article-title":"Development of multifunctional PAA-alginate-carboxymethyl cellulose hydrogel-loaded fiber-reinforced biomimetic scaffolds for controlled release of curcumin","volume":"301","author":"Fatema","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"20220173","DOI":"10.1002\/exp.20220173","article-title":"Gel\/hydrogel-based in situ biomaterial platforms for cancer postoperative treatment and recovery","volume":"3","author":"Feng","year":"2023","journal-title":"Explor. (Beijing)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"8987","DOI":"10.1021\/jacs.2c00749","article-title":"Acid neutralization and immune regulation by calcium-aluminum-layered double hydroxide for osteoporosis reversion","volume":"144","author":"Fu","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"B32","doi-asserted-by":"publisher","first-page":"648","DOI":"10.3390\/pharmaceutics11120648","article-title":"PLGA-BMP-2 and PLA-17\u03b2-estradiol microspheres reinforcing a composite hydrogel for bone regeneration in osteoporosis","volume":"11","author":"Garcia-Garcia","year":"2019","journal-title":"Pharmaceutics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s10856-018-6064-2","article-title":"Chitosan\/gelatin scaffolds support bone regeneration","volume":"29","author":"Georgopoulou","year":"2018","journal-title":"J. Mater Sci. Mater Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.ijbiomac.2019.02.086","article-title":"Inductive co-crosslinking of cellulose nanocrystal\/chitosan hydrogels for the treatment of vertebral compression fractures","volume":"130","author":"Ghavimi","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"49762","DOI":"10.1021\/acsami.1c17472","article-title":"Addressing the osteoporosis problem-multifunctional injectable hybrid materials for controlling local bone tissue remodeling","volume":"13","author":"Gilarska","year":"2021","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B36","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.ijbiomac.2013.03.059","article-title":"Preparation of chitosan\/silk fibroin blending membrane fixed with alginate dialdehyde for wound dressing","volume":"58","author":"Gu","year":"2013","journal-title":"Int. J. Biol. Macromol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.jconrel.2021.08.055","article-title":"The role of natural polymers in bone tissue engineering","volume":"338","author":"Guo","year":"2021","journal-title":"J. Control Release"},{"key":"B38","doi-asserted-by":"publisher","first-page":"123453","DOI":"10.1016\/j.ijbiomac.2023.123453","article-title":"Chitosan-polyethylene oxide\/clay-alginate nanofiber hydrogel scaffold for bone tissue engineering: preparation, physical characterization, and biomimetic mineralization","volume":"233","author":"Hakimi","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4103\/regenmed.regenmed-d-24-00024","article-title":"Advances in orthopedic implants: the role of nanotechnology in enhancing performance and longevity","volume":"2","author":"Hamza","year":"2025","journal-title":"Regen. Med. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"110411","DOI":"10.1016\/j.msec.2019.110411","article-title":"Scaffold strategies for modulating immune microenvironment during bone regeneration","volume":"108","author":"He","year":"2020","journal-title":"Mater Sci. Eng. C Mater Biol. Appl."},{"key":"B41","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s11657-017-0334-3","article-title":"Screening for osteoporosis following non-vertebral fractures in patients aged 50 and older independently of gender or level of trauma energy-a Swiss trauma center approach","volume":"12","author":"Hemmeler","year":"2017","journal-title":"Arch. Osteoporos."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2902","DOI":"10.3390\/molecules27092902","article-title":"Hydrogels: properties and applications in biomedicine","volume":"27","author":"Ho","year":"2022","journal-title":"Molecules"},{"key":"B43","doi-asserted-by":"publisher","first-page":"100431","DOI":"10.1016\/j.mtbio.2022.100431","article-title":"PVA\/pectin composite hydrogels inducing osteogenesis for bone regeneration","volume":"16","author":"Hu","year":"2022","journal-title":"Mater Today Bio"},{"key":"B44","doi-asserted-by":"publisher","first-page":"7616","DOI":"10.1016\/j.biomaterials.2005.05.036","article-title":"In vitro characterization of chitosan-gelatin scaffolds for tissue engineering","volume":"26","author":"Huang","year":"2005","journal-title":"Biomaterials"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.2147\/ijn.s453199","article-title":"Self-Amplified pH\/ROS dual-responsive Co-delivery nano-system with chemo-photodynamic combination therapy in hepatic carcinoma treatment","volume":"19","author":"Huang","year":"2024","journal-title":"Int. J. Nanomedicine"},{"key":"B46","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.bioactmat.2022.04.034","article-title":"A non-invasive smart scaffold for bone repair and monitoring","volume":"19","author":"Huang","year":"2023","journal-title":"Bioact. Mater"},{"key":"B47","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.bioactmat.2020.01.012","article-title":"Chitosan based bioactive materials in tissue engineering applications-A review","volume":"5","author":"Islam","year":"2020","journal-title":"Bioact. Mater"},{"key":"B48","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.arr.2017.03.008","article-title":"Aging and cancer: the role of macrophages and neutrophils","volume":"36","author":"Jackaman","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"B49","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.carbpol.2007.04.002","article-title":"Mechanical properties and degradation behaviors of hyaluronic acid hydrogels cross-linked at various cross-linking densities","volume":"70","author":"Jeon","year":"2007","journal-title":"Carbohydr. Polym."},{"key":"B50","doi-asserted-by":"publisher","first-page":"101338","DOI":"10.1016\/j.mtbio.2024.101338","article-title":"Harnessing hydrogen sulfide in injectable hydrogels that guide the immune response and osteoclastogenesis balance for osteoporosis treatment","volume":"29","author":"Jiang","year":"2024","journal-title":"Mater Today Bio"},{"key":"B51","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.actbio.2014.11.012","article-title":"Photoinitiator-free synthesis of endothelial cell-adhesive and enzymatically degradable hydrogels","volume":"13","author":"Jones","year":"2015","journal-title":"Acta Biomater."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1002\/term.2110","article-title":"Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans","volume":"11","author":"Kawai","year":"2017","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"132675","DOI":"10.1016\/j.ijbiomac.2024.132675","article-title":"Photocrosslinked gelatin\/chondroitin sulfate\/chitosan-based composites with tunable multifunctionality for bone tissue regeneration","volume":"271","author":"Klara","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/s41578-020-0204-2","article-title":"Materials design for bone-tissue engineering","volume":"5","author":"Koons","year":"2020","journal-title":"Nat. Rev. Mater."},{"key":"B55","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/s0142-9612(00)00201-5","article-title":"Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: part 1. Structure, gelation rate and mechanical properties","volume":"22","author":"Kuo","year":"2001","journal-title":"Biomaterials"},{"key":"B56","doi-asserted-by":"publisher","first-page":"119451","DOI":"10.1016\/j.biomaterials.2019.119451","article-title":"Influence of hyaluronic acid modification on CD44 binding towards the design of hydrogel biomaterials","volume":"222","author":"Kwon","year":"2019","journal-title":"Biomaterials"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0378-5173(01)00691-3","article-title":"Biomedical applications of collagen","volume":"221","author":"Lee","year":"2001","journal-title":"Int. J. Pharm."},{"key":"B58","doi-asserted-by":"publisher","first-page":"122066","DOI":"10.1016\/j.biomaterials.2023.122066","article-title":"Advances in materials-based therapeutic strategies against osteoporosis","volume":"296","author":"Lei","year":"2023","journal-title":"Biomaterials"},{"key":"B59","doi-asserted-by":"publisher","first-page":"138323","DOI":"10.1016\/j.ijbiomac.2024.138323","article-title":"A review of self-healing hydrogels for bone repair and regeneration: materials, mechanisms, and applications","volume":"287","author":"Li","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"11","DOI":"10.53388\/bmec2024011","article-title":"Biomimetic fibril-like injectable hydrogels for wound management","volume":"3","author":"Li","year":"","journal-title":"Biomed. Eng. Commun."},{"key":"B61","doi-asserted-by":"publisher","first-page":"e2408044","DOI":"10.1002\/advs.202408044","article-title":"Concrete-inspired bionic bone glue repairs osteoporotic bone defects by gluing and remodeling aging macrophages","volume":"11","author":"Li","year":"","journal-title":"Adv. Sci. (Weinh)"},{"key":"B62","doi-asserted-by":"publisher","first-page":"23826","DOI":"10.1021\/acsami.2c01922","article-title":"Hofmeister effect mediated strong PHEMA-gelatin hydrogel actuator","volume":"14","author":"Li","year":"2022","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B63","doi-asserted-by":"publisher","first-page":"116922","DOI":"10.1016\/j.carbpol.2020.116922","article-title":"Self-healing hyaluronic acid hydrogels based on dynamic Schiff base linkages as biomaterials","volume":"250","author":"Li","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"B64","doi-asserted-by":"publisher","first-page":"106635","DOI":"10.1016\/j.phrs.2022.106635","article-title":"Cell death regulation: a new way for natural products to treat osteoporosis","volume":"187","author":"Li","year":"2023","journal-title":"Pharmacol. Res."},{"key":"B65","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1021\/acsami.2c16217","article-title":"In situ biomimetic mineralization of bone-like hydroxyapatite in hydrogel for the acceleration of bone regeneration","volume":"15","author":"Liang","year":"2023","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B66","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.bioactmat.2024.06.024","article-title":"Engineering biomimetic silk fibroin hydrogel scaffolds with \u201corganic-inorganic assembly\u201d strategy for rapid bone regeneration","volume":"40","author":"Liang","year":"2024","journal-title":"Bioact. Mater"},{"key":"B67","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1016\/j.bioactmat.2021.01.006","article-title":"Gold nanorods and nanohydroxyapatite hybrid hydrogel for preventing bone tumor recurrence via postoperative photothermal therapy and bone regeneration promotion","volume":"6","author":"Liao","year":"2021","journal-title":"Bioact. Mater"},{"key":"B68","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/s12033-020-00258-8","article-title":"Application of various delivery methods for CRISPR\/dCas9","volume":"62","author":"Liu","year":"2020","journal-title":"Mol. Biotechnol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"3949","DOI":"10.1021\/bm301180c","article-title":"Porous alginate hydrogel functionalized with virus as three-dimensional scaffolds for bone differentiation","volume":"13","author":"Luckanagul","year":"2012","journal-title":"Biomacromolecules"},{"key":"B70","doi-asserted-by":"publisher","first-page":"3612","DOI":"10.1021\/acsbiomaterials.4c00314","article-title":"Photoresponsive hydrogels for tissue engineering","volume":"10","author":"Luo","year":"2024","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B71","doi-asserted-by":"publisher","first-page":"133821","DOI":"10.1016\/j.ijbiomac.2024.133821","article-title":"The hyaluronic acid-gelatin hierarchical hydrogel for osteoporotic bone defect repairment","volume":"276","author":"Ma","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"153","DOI":"10.4103\/2321-3868.143616","article-title":"Polymeric hydrogels for burn wound care: advanced skin wound dressings and regenerative templates","volume":"2","author":"Madaghiele","year":"2014","journal-title":"Burns Trauma"},{"key":"B73","doi-asserted-by":"publisher","first-page":"10160","DOI":"10.1038\/s41598-022-14329-0","article-title":"Strontium doped bioglass incorporated hydrogel-based scaffold for amplified bone tissue regeneration","volume":"12","author":"Manoochehri","year":"2022","journal-title":"Sci. Rep."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.3390\/biom12121852","article-title":"Silk fibroin biomaterials and their beneficial role in skin wound healing","volume":"12","author":"Mazurek","year":"2022","journal-title":"Biomolecules"},{"key":"B75","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1159\/000381691","article-title":"Organic-inorganic composites toward biomaterial application","volume":"17","author":"Miyazaki","year":"2015","journal-title":"Front. Oral Biol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.jconrel.2015.07.031","article-title":"Silk as a potential candidate for bone tissue engineering","volume":"215","author":"Mottaghitalab","year":"2015","journal-title":"J. Control Release"},{"key":"B77","doi-asserted-by":"publisher","first-page":"6100","DOI":"10.1039\/d0tb00901f","article-title":"Engineered macroporous hydrogel scaffolds via pickering emulsions stabilized by MgO nanoparticles promote bone regeneration","volume":"8","author":"Pan","year":"2020","journal-title":"J. Mater Chem. B"},{"key":"B78","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.ijbiomac.2019.04.113","article-title":"Development of a nanocomposite scaffold of gelatin-alginate-graphene oxide for bone tissue engineering","volume":"133","author":"Purohit","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1016\/j.biomaterials.2008.12.050","article-title":"The challenge of establishing preclinical models for segmental bone defect research","volume":"30","author":"Reichert","year":"2009","journal-title":"Biomaterials"},{"key":"B80","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1126\/science.2821619","article-title":"New perspectives in cell adhesion: RGD and integrins","volume":"238","author":"Ruoslahti","year":"1987","journal-title":"Science"},{"key":"B81","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.ijpharm.2018.03.034","article-title":"Bone regeneration in osteoporosis by delivery BMP-2 and PRGF from tetronic-alginate composite thermogel","volume":"543","author":"Segredo-Morales","year":"2018","journal-title":"Int. J. Pharm."},{"key":"B82","doi-asserted-by":"publisher","first-page":"111083","DOI":"10.1016\/j.colsurfb.2020.111083","article-title":"Interfacial reinforcement in bioceramic\/biopolymer composite bone scaffold: the role of coupling agent","volume":"193","author":"Shuai","year":"2020","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"B83","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/s8756-3282(97)00100-2","article-title":"Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure","volume":"21","author":"Silva","year":"1997","journal-title":"Bone"},{"key":"B84","doi-asserted-by":"publisher","first-page":"117011","DOI":"10.1016\/j.bone.2023.117011","article-title":"Restoring implant fixation strength in osteoporotic bone with a hydrogel locally delivering zoledronic acid and bone morphogenetic protein 2. A longitudinal in vivo microCT study in rats","volume":"180","author":"Siverino","year":"2024","journal-title":"Bone"},{"key":"B85","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.0105-2896.2005.00260.x","article-title":"Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes","volume":"205","author":"Stout","year":"2005","journal-title":"Immunol. Rev."},{"key":"B86","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nature11409","article-title":"Highly stretchable and tough hydrogels","volume":"489","author":"Sun","year":"2012","journal-title":"Nature"},{"key":"B87","doi-asserted-by":"publisher","first-page":"275","DOI":"10.3390\/gels8050275","article-title":"Mesenchymal stem cells-hydrogel microspheres system for bone regeneration in calvarial defects","volume":"8","author":"Teng","year":"2022","journal-title":"Gels"},{"key":"B88","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.ijbiomac.2018.10.049","article-title":"Modified hyaluronic acid based materials for biomedical applications","volume":"121","author":"Tiwari","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1021\/acsbiomaterials.0c01047","article-title":"Gap junction liposomes for efficient delivery of chemotherapeutics to solid tumors","volume":"6","author":"Trementozzi","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B90","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.bioactmat.2017.10.001","article-title":"3D bioactive composite scaffolds for bone tissue engineering","volume":"3","author":"Turnbull","year":"2018","journal-title":"Bioact. Mater"},{"key":"B91","doi-asserted-by":"publisher","first-page":"e2100088","DOI":"10.1002\/mabi.202100088","article-title":"Regenerating critical size rat segmental bone defects with a self-healing hybrid nanocomposite hydrogel: effect of bone condition and BMP-2 incorporation","volume":"21","author":"van Houdt","year":"2021","journal-title":"Macromol. Biosci."},{"key":"B92","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.ijbiomac.2014.07.008","article-title":"Alginate composites for bone tissue engineering: a review","volume":"72","author":"Venkatesan","year":"2015","journal-title":"Int. J. Biol. Macromol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1084005","DOI":"10.3389\/fpubh.2023.1084005","article-title":"The prevalence of osteoporosis in China, a community based cohort study of osteoporosis","volume":"11","author":"Wang","year":"","journal-title":"Front. Public Health"},{"key":"B94","doi-asserted-by":"publisher","first-page":"5814","DOI":"10.3390\/ijms24065814","article-title":"Hormone-related and drug-induced osteoporosis: a cellular and molecular overview","volume":"24","author":"Wang","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"B95","doi-asserted-by":"publisher","first-page":"101369","DOI":"10.1016\/j.mtbio.2024.101369","article-title":"Microenvironment-responsive injectable hydrogel for neuro-vascularized bone regeneration","volume":"29","author":"Wang","year":"","journal-title":"Mater Today Bio"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1039\/d3tb02031b","article-title":"Photo-crosslinked integrated triphasic scaffolds with gradient composition and strength for osteochondral regeneration","volume":"12","author":"Wang","year":"","journal-title":"J. Mater Chem. B"},{"key":"B97","doi-asserted-by":"publisher","first-page":"5815","DOI":"10.2147\/ijn.s416098","article-title":"Fused deposition modeling printed PLA\/nano beta-TCP composite bone tissue engineering scaffolds for promoting osteogenic induction function","volume":"18","author":"Wang","year":"","journal-title":"Int. J. Nanomedicine"},{"key":"B98","doi-asserted-by":"publisher","first-page":"149444","DOI":"10.1016\/j.cej.2024.149444","article-title":"3D printing of personalized magnesium composite bone tissue engineering scaffold for bone and angiogenesis regeneration","volume":"484","author":"Wang","year":"","journal-title":"Chem. Eng. J."},{"key":"B99","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.compositesb.2023.110641","article-title":"3D printing of lithium osteogenic bioactive composite scaffold for enhanced bone regeneration","author":"Wang","year":"","journal-title":"Compos. Part B Eng."},{"key":"B100","doi-asserted-by":"publisher","first-page":"109192","DOI":"10.1016\/j.compositesb.2021.109192","article-title":"3D printing of PLA\/n-HA composite scaffolds with customized mechanical properties and biological functions for bone tissue engineering","volume":"224","author":"Wang","year":"","journal-title":"Compos. Part B Eng."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1515\/ntrev-2021-0083","article-title":"Fabrication and properties of PLA\/nano-HA composite scaffolds with balanced mechanical properties and biological functions for bone tissue engineering application","volume":"10","author":"Wang","year":"","journal-title":"Nanotechnol. Rev."},{"key":"B102","doi-asserted-by":"publisher","first-page":"302","DOI":"10.3390\/gels9040302","article-title":"Tough, injectable calcium phosphate cement based composite hydrogels to promote osteogenesis","volume":"9","author":"Wang","year":"","journal-title":"Gels"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1002\/inmd.20220005","article-title":"Dynamic responsiveness of self\u2010assembling peptide\u2010based nano\u2010drug systems","volume":"1","author":"Wang","year":"","journal-title":"Interdiscip. Med."},{"key":"B104","doi-asserted-by":"publisher","first-page":"eadq6700","DOI":"10.1126\/sciadv.adq6700","article-title":"Stem cell-homing biomimetic hydrogel promotes the repair of osteoporotic bone defects through osteogenic and angiogenic coupling","volume":"10","author":"Wei","year":"2024","journal-title":"Sci. Adv."},{"key":"B105","doi-asserted-by":"publisher","first-page":"e2409683","DOI":"10.1002\/advs.202409683","article-title":"Programmed transformation of osteogenesis microenvironment by a multifunctional hydrogel to enhance repair of infectious bone defects","volume":"12","author":"Xie","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"B106","doi-asserted-by":"publisher","first-page":"100641","DOI":"10.1016\/j.mser.2021.100641","article-title":"Collagen- and hyaluronic acid-based hydrogels and their biomedical applications","volume":"146","author":"Xu","year":"2021","journal-title":"Mater Sci. Eng. R. Rep."},{"key":"B107","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.bioactmat.2021.10.029","article-title":"Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering","volume":"12","author":"Xue","year":"2022","journal-title":"Bioact. Mater"},{"key":"B108","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1039\/c3tb21103g","article-title":"Injectable and redox-responsive hydrogel with adaptive degradation rate for bone regeneration","volume":"2","author":"Yang","year":"2014","journal-title":"J. Mater Chem. B"},{"key":"B109","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1080\/15583724.2022.2137525","article-title":"Constructions and properties of physically cross-linked hydrogels based on natural polymers","volume":"63","author":"Yang","year":"2022","journal-title":"Polym. Rev."},{"key":"B110","doi-asserted-by":"publisher","first-page":"3565","DOI":"10.1038\/s41467-024-48023-8","article-title":"A mechanical-assisted post-bioprinting strategy for challenging bone defects repair","volume":"15","author":"Yang","year":"","journal-title":"Nat. Commun."},{"key":"B111","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.1021\/acsbiomaterials.3c01468","article-title":"Biomimetic bone-like composite hydrogel scaffolds composed of collagen fibrils and natural hydroxyapatite for promoting bone repair","volume":"10","author":"Yang","year":"","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B112","doi-asserted-by":"publisher","first-page":"18235","DOI":"10.1021\/acsami.0c00275","article-title":"Intrafibrillar mineralized collagen-hydroxyapatite-based scaffolds for bone regeneration","volume":"12","author":"Yu","year":"2020","journal-title":"ACS Appl. Mater Interfaces"},{"key":"B113","doi-asserted-by":"publisher","first-page":"8174","DOI":"10.3390\/ijms25158174","article-title":"Promotion of bone formation in a rat osteoporotic vertebral body defect model via suppression of osteoclastogenesis by ectopic embryonic calvaria derived mesenchymal stem cells","volume":"25","author":"Yu","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B114","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3877\/cma.j.issn.2096-112X.2020.01.009","article-title":"Hyaluronic acid-based hydrogels with tobacco mosaic virus containing cell adhesive peptide induce bone repair in normal and osteoporotic rats","volume":"1","author":"Yuan","year":"2020","journal-title":"Biomater. Transl."},{"key":"B115","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1002\/jbm.a.36997","article-title":"Sustained delivery of alendronate by engineered collagen scaffold for the repair of osteoporotic bone defects and resistance to bone loss","volume":"108","author":"Zeng","year":"2020","journal-title":"J. Biomed. Mater Res. A"},{"key":"B116","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.biomaterials.2015.06.023","article-title":"Growth of lanthanide-doped LiGdF4 nanoparticles induced by LiLuF4 core as tri-modal imaging bioprobes","volume":"65","author":"Zhai","year":"2015","journal-title":"Biomaterials"},{"key":"B117","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.actbio.2020.07.024","article-title":"Bio-surface coated titanium scaffolds with cancellous bone-like biomimetic structure for enhanced bone tissue regeneration","volume":"114","author":"Zhang","year":"2020","journal-title":"Acta Biomater."},{"key":"B118","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3390\/md19050264","article-title":"Preparation of alginate-based biomaterials and their applications in biomedicine","volume":"19","author":"Zhang","year":"","journal-title":"Mar. Drugs"},{"key":"B119","doi-asserted-by":"publisher","first-page":"1800875","DOI":"10.1002\/advs.201800875","article-title":"Adaptable hydrogels mediate cofactor-assisted activation of biomarker-responsive drug delivery via positive feedback for enhanced tissue regeneration","volume":"5","author":"Zhang","year":"2018","journal-title":"Adv. Sci. (Weinh)"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1063\/5.0035504","article-title":"Hydrogel: a potential therapeutic material for bone tissue engineering","volume":"11","author":"Zhang","year":"","journal-title":"AIP Adv."},{"key":"B121","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/654597","article-title":"The application of polysaccharide biocomposites to repair cartilage defects","volume":"2014","author":"Zhao","year":"2014","journal-title":"Int. J. Polym. Sci."},{"key":"B122","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.pmatsci.2016.04.001","article-title":"Rise of silicene: a competitive 2D material","volume":"83","author":"Zhao","year":"2016","journal-title":"Prog. Mater. Sci."},{"key":"B123","doi-asserted-by":"publisher","first-page":"13041","DOI":"10.1021\/acsnano.1c02147","article-title":"Capturing magnesium ions via microfluidic hydrogel microspheres for promoting cancellous bone regeneration","volume":"15","author":"Zhao","year":"2021","journal-title":"ACS Nano"},{"key":"B124","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.actbio.2023.10.029","article-title":"Scaffold-based non-viral CRISPR delivery platform for efficient and prolonged gene activation to accelerate tissue regeneration","volume":"173","author":"Zhong","year":"2024","journal-title":"Acta Biomater."},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1002\/viw.20200189","article-title":"Algae: a natural active material for biomedical applications","volume":"2","author":"Zhong","year":"2021","journal-title":"View"},{"key":"B126","doi-asserted-by":"publisher","first-page":"3739","DOI":"10.7150\/thno.97412","article-title":"An injectable magnesium-loaded hydrogel releases hydrogen to promote osteoporotic bone repair via ROS scavenging and immunomodulation","volume":"14","author":"Zhou","year":"2024","journal-title":"Theranostics"},{"key":"B127","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1039\/c9tb02716e","article-title":"Functional DNA-based hydrogel intelligent materials for biomedical applications","volume":"8","author":"Zhou","year":"2020","journal-title":"J. Mater Chem. B"},{"key":"B128","doi-asserted-by":"publisher","first-page":"6861","DOI":"10.1021\/acsomega.0c06057","article-title":"Modified alginate-based hydrogel as a carrier of the CB2 agonist JWH133 for bone engineering","volume":"6","author":"Zhou","year":"2021","journal-title":"ACS Omega"},{"key":"B129","doi-asserted-by":"publisher","first-page":"5103","DOI":"10.7150\/thno.74548","article-title":"Silk fibroin-based biomaterials for cartilage\/osteochondral repair","volume":"12","author":"Zhou","year":"2022","journal-title":"Theranostics"}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1591896\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T01:33:52Z","timestamp":1745804032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1591896\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":129,"alternative-id":["10.3389\/fbioe.2025.1591896"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2025.1591896","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"article-number":"1591896"}}