{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:51:29Z","timestamp":1787028689426,"version":"build-2736575974"},"reference-count":93,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>Large bone defects resulting from trauma, tumor resection, infection, or degenerative diseases pose a major clinical challenge in orthopedic surgery and regenerative medicine. Despite advances in biomaterials and surgical techniques, successful outcomes are often compromised by poor vascularization, limited osteoinduction, and donor-site morbidity associated with autografts or allografts. However, conventional delivery systems suffer from burst release, rapid clearance, off-target effects, and supraphysiologic dosing, which can lead to undesirable complications such as ectopic ossification and inflammation, with some reports raising concerns about the long-term tumorigenic risk. Heparin, a naturally highly sulfated glycosaminoglycan structurally related to heparan sulfate, has emerged as a particularly attractive candidate for affinity-based biomaterial systems. It naturally binds over 300 growth factors, including bone morphogenetic proteins. By protecting these proteins from enzymatic degradation, enhancing their bioavailability, and mediating receptor clustering, heparin provides both biochemical stability and biofunctional modulation. This review provides a comprehensive overview of heparin-based delivery strategies in bone tissue engineering. We begin by describing the biological functions of heparin in modulating growth factor activity. We then discuss in detail the different heparin-based biomaterials designed to sustain the release of growth factors for bone tissue engineering, including the heparin\u2013polycation coacervate system; heparin-based supramolecules; and heparin-based hydrogels, nanoparticles, and microspheres for sustained release of bone morphogenic proteins and other growth factors for bone tissue engineering. Finally, we assess the clinical and translational relevance of heparin-based systems, identify key challenges, and outline future perspectives, highlighting the potential of these biomaterials for providing safer and more effective therapies for bone regeneration.<\/jats:p>","DOI":"10.3390\/jfb17030156","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T08:47:42Z","timestamp":1774255662000},"page":"156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Heparin-Based Biomaterials for Sustained Release of Growth Factors for Bone Tissue Engineering and Regeneration"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1370-4974","authenticated-orcid":false,"given":"Keisuke","family":"Nakayama","sequence":"first","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-1548","authenticated-orcid":false,"given":"Xueqin","family":"Gao","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britney S.","family":"Force","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-3331","authenticated-orcid":false,"given":"Marc J.","family":"Philippon","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"},{"name":"The Steadman Clinic, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Huard","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1302\/0301-620X.60B2.350882","article-title":"The biology of fracture healing in long bones","volume":"60-B","author":"McKibbin","year":"1978","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jcb.10435","article-title":"Fracture healing as a post-natal developmental process: Molecular, spatial, and temporal aspects of its regulation","volume":"88","author":"Gerstenfeld","year":"2003","journal-title":"J. Cell Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.injury.2011.03.031","article-title":"The biology of fracture healing","volume":"42","author":"Marsell","year":"2011","journal-title":"Injury"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/00003086-200002000-00003","article-title":"Bone graft materials. An overview of the basic science","volume":"371","author":"Bauer","year":"2000","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.2106\/00004623-200212000-00001","article-title":"Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: A prospective, controlled, randomized study of four hundred and fifty patients","volume":"84","author":"Govender","year":"2002","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.spinee.2011.04.023","article-title":"A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: Emerging safety concerns and lessons learned","volume":"11","author":"Carragee","year":"2011","journal-title":"Spine J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"877","DOI":"10.7326\/0003-4819-158-12-201306180-00005","article-title":"Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: A meta-analysis of individual-participant data","volume":"158","author":"Simmonds","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, J.F., Jan, J.S., and Hu, J.J. (2025). Heparin-Based Growth Factor Delivery Platforms: A Review. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17091145"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gatica Portillo, D.R., Li, Y., Goyal, N., Rowan, B.G., Al-Horani, R.A., and Anbalagan, M. (2025). Heparin, Heparin-like Molecules, and Heparin Mimetics in Breast Cancer: A Concise Review. Biomolecules, 15.","DOI":"10.3390\/biom15071034"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1039\/C6MB00857G","article-title":"The nature of the conserved basic amino acid sequences found among 437 heparin binding proteins determined by network analysis","volume":"13","author":"Rudd","year":"2017","journal-title":"Mol. Biosyst."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.3390\/molecules20046342","article-title":"Heparin\/Heparan sulfate proteoglycans glycomic interactome in angiogenesis: Biological implications and therapeutical use","volume":"20","author":"Chiodelli","year":"2015","journal-title":"Molecules"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/1521-3773(20020201)41:3<390::AID-ANIE390>3.0.CO;2-B","article-title":"Heparin-protein interactions","volume":"41","author":"Capila","year":"2002","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev-biochem-060713-035314","article-title":"Demystifying heparan sulfate-protein interactions","volume":"83","author":"Xu","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19892","DOI":"10.1074\/jbc.M111.228114","article-title":"A systems biology approach for the investigation of the heparin\/heparan sulfate interactome","volume":"286","author":"Ori","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.actbio.2013.09.012","article-title":"Lysine-based polycation:heparin coacervate for controlled protein delivery","volume":"10","author":"Johnson","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Carlsson, P., and Kjellen, L. (2012). Heparin Biosynthesis, Springer Nature. Handbook of Experimental Pharmacology.","DOI":"10.1007\/978-3-642-23056-1_2"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17R","DOI":"10.1093\/glycob\/cwh051","article-title":"Interactions of heparin\/heparan sulfate with proteins: Appraisal of structural factors and experimental approaches","volume":"14","author":"Powell","year":"2004","journal-title":"Glycobiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"0589","DOI":"10.1098\/rsif.2015.0589","article-title":"Heparan sulfate and heparin interactions with proteins","volume":"12","author":"Meneghetti","year":"2015","journal-title":"J. R. Soc. Interface"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"a004952","DOI":"10.1101\/cshperspect.a004952","article-title":"Heparan sulfate proteoglycans","volume":"3","author":"Sarrazin","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1432-1033.1996.0295n.x","article-title":"Human bone morphogenetic protein 2 contains a heparin-binding site which modifies its biological activity","volume":"237","author":"Ruppert","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The Fibroblast Growth Factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100ra189","DOI":"10.1126\/scitranslmed.3002614","article-title":"Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing","volume":"3","author":"Martino","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.actbio.2013.08.045","article-title":"Incorporation of heparin into biomaterials","volume":"10","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/j.biomaterials.2012.11.019","article-title":"The effect of a heparin-based coacervate of fibroblast growth factor-2 on scarring in the infarcted myocardium","volume":"34","author":"Chu","year":"2013","journal-title":"Biomaterials"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121708","DOI":"10.1016\/j.biomaterials.2022.121708","article-title":"The use of heparin\/polycation coacervate sustain release system to compare the bone regenerative potentials of 5 BMPs using a critical sized calvarial bone defect model","volume":"288","author":"Gao","year":"2022","journal-title":"Biomaterials"},{"key":"ref_26","first-page":"588","article-title":"Comparison of 5 BMPs for their chondrogenic potentials and microfracture-mediated cartilage repair using heparin\/PEAD coacervate sustained release polymer","volume":"52","author":"Gao","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/S0167-5273(16)12004-2","article-title":"Old and new applications of non-anticoagulant heparin","volume":"212","author":"Cassinelli","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C97","DOI":"10.1152\/ajpcell.00009.2010","article-title":"Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands","volume":"299","author":"Rao","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13444","DOI":"10.1073\/pnas.1110121108","article-title":"Injectable fibroblast growth factor-2 coacervate for persistent angiogenesis","volume":"108","author":"Chu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/btpr.728","article-title":"Design, synthesis, and biocompatibility of an arginine-based polyester","volume":"28","author":"Chu","year":"2012","journal-title":"Biotechnol. Prog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jconrel.2011.03.021","article-title":"Hyaluronic acid: Evaluation as a potential delivery vehicle for vitronectin:growth factor complexes in wound healing applications","volume":"153","author":"Xie","year":"2011","journal-title":"J. Control Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jconrel.2010.11.025","article-title":"A [polycation:heparin] complex releases growth factors with enhanced bioactivity","volume":"150","author":"Chu","year":"2011","journal-title":"J. Control Release"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"667","DOI":"10.5966\/sctm.2013-0027","article-title":"Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells","volume":"2","author":"Li","year":"2013","journal-title":"Stem Cells Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1021\/acs.biomac.8b01013","article-title":"Enhanced Skull Bone Regeneration by Sustained Release of BMP-2 in Interpenetrating Composite Hydrogels","volume":"19","author":"Kim","year":"2018","journal-title":"Biomacromolecules"},{"key":"ref_35","first-page":"241","article-title":"Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo","volume":"29","author":"Siverino","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.bone.2008.06.019","article-title":"Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model","volume":"43","author":"Patel","year":"2008","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1186\/s13287-019-1434-3","article-title":"A comparison of BMP2 delivery by coacervate and gene therapy for promoting human muscle-derived stem cell-mediated articular cartilage repair","volume":"10","author":"Gao","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.biomaterials.2017.01.036","article-title":"Dual delivery of growth factors with coacervate-coated poly(lactic-co-glycolic acid) nanofiber improves neovascularization in a mouse skin flap model","volume":"124","author":"Lee","year":"2017","journal-title":"Biomaterials"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.actbio.2019.03.052","article-title":"Coacervate-mediated exogenous growth factor delivery for scarless skin regeneration","volume":"90","author":"Park","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.biomaterials.2015.08.050","article-title":"Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair","volume":"72","author":"Chen","year":"2015","journal-title":"Biomaterials"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jconrel.2020.08.002","article-title":"Dual delivery of stem cells and insulin-like growth factor-1 in coacervate-embedded composite hydrogels for enhanced cartilage regeneration in osteochondral defects","volume":"327","author":"Cho","year":"2020","journal-title":"J. Control Release"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.biomaterials.2012.10.005","article-title":"Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds","volume":"34","author":"Lee","year":"2013","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nnano.2017.109","article-title":"Sulfated glycopeptide nanostructures for multipotent protein activation","volume":"12","author":"Lee","year":"2017","journal-title":"Nat. Nanotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"122357","DOI":"10.1016\/j.biomaterials.2023.122357","article-title":"A supramolecular polymer-collagen microparticle slurry for bone regeneration with minimal growth factor","volume":"302","author":"McClendon","year":"2023","journal-title":"Biomaterials"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1021\/acs.nanolett.6b00054","article-title":"Supramolecular Nanofibers Enhance Growth Factor Signaling by Increasing Lipid Raft Mobility","volume":"16","author":"Newcomb","year":"2016","journal-title":"Nano Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7985","DOI":"10.1016\/j.biomaterials.2010.07.021","article-title":"FGF-2 and VEGF functionalization of starPEG-heparin hydrogels to modulate biomolecular and physical cues of angiogenesis","volume":"31","author":"Zieris","year":"2010","journal-title":"Biomaterials"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3858\/emm.2012.44.5.039","article-title":"Comparison between heparin-conjugated fibrin and collagen sponge as bone morphogenetic protein-2 carriers for bone regeneration","volume":"44","author":"Yang","year":"2012","journal-title":"Exp. Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6113","DOI":"10.1016\/j.biomaterials.2012.05.030","article-title":"Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2","volume":"33","author":"Bhakta","year":"2012","journal-title":"Biomaterials"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"137120","DOI":"10.1016\/j.ijbiomac.2024.137120","article-title":"An injectable carboxymethyl chitosan-based hydrogel with controlled release of BMP-2 for efficient treatment of bone defects","volume":"282","author":"Zhou","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41536-023-00322-2","article-title":"Local BMP2 hydrogel therapy for robust bone regeneration in a porcine model of Legg-Calve-Perthes disease","volume":"8","author":"Ma","year":"2023","journal-title":"NPJ Regen. Med."},{"key":"ref_51","first-page":"111","article-title":"Multiscale design of stiffening and ROS scavenging hydrogels for the augmentation of mandibular bone regeneration","volume":"20","author":"Wu","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eaay1240","DOI":"10.1126\/sciadv.aay1240","article-title":"Heparin-mediated delivery of bone morphogenetic protein-2 improves spatial localization of bone regeneration","volume":"6","author":"Hettiaratchi","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1007\/s10439-024-03530-z","article-title":"Development and Characterization of Heparin-Containing Hydrogel\/3D-Printed Scaffold Composites for Craniofacial Reconstruction","volume":"52","author":"Brown","year":"2024","journal-title":"Ann. Biomed. Eng."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"103919","DOI":"10.1016\/j.identj.2025.103919","article-title":"An Electrospun Heparin Modified Nanofiber Membrane Carrying Multiple Growth Factors for Dental Pulp Regeneration","volume":"75","author":"Li","year":"2025","journal-title":"Int. Dent. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1038\/s41467-018-04525-w","article-title":"Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing","volume":"9","author":"Ishihara","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"015016","DOI":"10.1088\/1748-605X\/ae30bd","article-title":"Enhancing the efficiency of bone tissue regeneration by using a 3D printed scaffold optimized with heparan sulfate proteoglycan 2","volume":"21","author":"Ku","year":"2026","journal-title":"Biomed. Mater."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s40204-022-00213-7","article-title":"Delivery of bone morphogenetic protein-2 by crosslinking heparin to nile tilapia skin collagen for promotion of rat calvaria bone defect repair","volume":"12","author":"Ma","year":"2023","journal-title":"Prog. Biomater."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"119059","DOI":"10.1016\/j.carbpol.2021.119059","article-title":"Effect of sulfated chitosan hydrogel on vascularization and osteogenesis","volume":"281","author":"Jiang","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"213030","DOI":"10.1016\/j.bioadv.2022.213030","article-title":"Dopamine\/DOPAC-assisted immobilization of bone morphogenetic protein-2 loaded Heparin\/PEI nanogels onto three-dimentional printed calcium phosphate ceramics for enhanced osteoinductivity and osteogenicity","volume":"140","author":"Tang","year":"2022","journal-title":"Biomater. Adv."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Chen, X., Gao, C.Y., Chu, X.Y., Zheng, C.Y., Luan, Y.Y., He, X., Yang, K., and Zhang, D.L. (2022). VEGF-Loaded Heparinised Gelatine-Hydroxyapatite-Tricalcium Phosphate Scaffold Accelerates Bone Regeneration via Enhancing Osteogenesis-Angiogenesis Coupling. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.915181"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.actbio.2022.11.064","article-title":"Combined application of BMP-2 and naturally occurring bioactive factor mixtures for the optimized therapy of segmental bone defects","volume":"157","author":"Vater","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1021\/acsabm.8b00523","article-title":"Scaffold with Orientated Microtubule Structure Containing Polylysine-Heparin Sodium Nanoparticles for the Controlled Release of TGF-beta1 in Cartilage Tissue Engineering","volume":"1","author":"Sun","year":"2018","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sarsenova, M., Raimagambetov, Y., Issabekova, A., Karzhauov, M., Kudaibergen, G., Akhmetkarimova, Z., Batpen, A., Ramankulov, Y., and Ogay, V. (2022). Regeneration of Osteochondral Defects by Combined Delivery of Synovium-Derived Mesenchymal Stem Cells, TGF-beta1 and BMP-4 in Heparin-Conjugated Fibrin Hydrogel. Polymers, 14.","DOI":"10.3390\/polym14245343"},{"key":"ref_64","first-page":"242","article-title":"Synergizing adaptive immunity and regenerative signals to enhance osteochondral defects repair","volume":"46","author":"Lin","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.biomaterials.2005.08.030","article-title":"Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel","volume":"27","author":"Jeon","year":"2006","journal-title":"Biomaterials"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1007\/s11095-006-9039-9","article-title":"Heparin immobilized porous PLGA microspheres for angiogenic growth factor delivery","volume":"23","author":"Chung","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s11373-008-9277-4","article-title":"Enhancement of ectopic bone formation by bone morphogenetic protein-2 delivery using heparin-conjugated PLGA nanoparticles with transplantation of bone marrow-derived mesenchymal stem cells","volume":"15","author":"Kim","year":"2008","journal-title":"J. Biomed. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"929","DOI":"10.2147\/IJN.S18753","article-title":"Controlled release of chitosan\/heparin nanoparticle-delivered VEGF enhances regeneration of decellularized tissue-engineered scaffolds","volume":"6","author":"Tan","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1016\/j.actbio.2011.04.018","article-title":"Heparin-decorated, hyaluronic acid-based hydrogel particles for the controlled release of bone morphogenetic protein 2","volume":"7","author":"Xu","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.actbio.2020.07.026","article-title":"Effects of controlled dual growth factor delivery on bone regeneration following composite bone-muscle injury","volume":"114","author":"Subbiah","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6520","DOI":"10.1021\/acsabm.4c00679","article-title":"Microsphere-Composite Hydrogel for Recruiting Stem Cells and Promoting Osteogenic Differentiation","volume":"7","author":"Zhou","year":"2024","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Kudaibergen, G., Mukhlis, S., Mukhambetova, A., Issabekova, A., Sekenova, A., Sarsenova, M., Temirzhan, A., Baidarbekov, M., Umbayev, B., and Ogay, V. (2024). Repair of Rat Calvarial Critical-Sized Defects Using Heparin-Conjugated Fibrin Hydrogel Containing BMP-2 and Adipose-Derived Pericytes. Bioengineering, 11.","DOI":"10.3390\/bioengineering11050437"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1097\/00007632-200211010-00015","article-title":"Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2","volume":"27","author":"Burkus","year":"2002","journal-title":"Spine"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.spinee.2006.04.010","article-title":"Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: A case study","volume":"7","author":"Perri","year":"2007","journal-title":"Spine J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.spinee.2016.06.007","article-title":"RhBMP-2-induced radiculitis in patients undergoing transforaminal lumbar interbody fusion: Relationship to dose","volume":"16","author":"Villavicencio","year":"2016","journal-title":"Spine J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1517\/17425247.2014.941355","article-title":"Coacervate delivery systems for proteins and small molecule drugs","volume":"11","author":"Johnson","year":"2014","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1182\/bloodadvances.2017013672","article-title":"2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia","volume":"2","author":"Tkaczynski","year":"2018","journal-title":"Blood Adv."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1160\/TH08-01-0032","article-title":"Heparin and low-molecular-weight heparin","volume":"99","author":"Gray","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.1002\/anie.200300640","article-title":"A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next?","volume":"43","author":"Petitou","year":"2004","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/bs.ircmb.2016.02.009","article-title":"Heparan Sulfate: Biosynthesis, Structure, and Function","volume":"325","author":"Li","year":"2016","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.addr.2007.08.041","article-title":"Biomimetic materials for tissue engineering","volume":"60","author":"Ma","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.addr.2019.08.005","article-title":"Hydrogel vehicles for sequential delivery of protein drugs to promote vascular regeneration","volume":"149\u2013150","author":"Wei","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"17813","DOI":"10.1021\/acsnano.5c03297","article-title":"Affinity Modifications of Porous Microscaffolds Impact Bone Regeneration by Modulating the Delivery Kinetics of Small Extracellular Vesicles","volume":"19","author":"Gao","year":"2025","journal-title":"ACS Nano"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.biomaterials.2006.08.033","article-title":"The effect of heparin-functionalized PEG hydrogels on three-dimensional human mesenchymal stem cell osteogenic differentiation","volume":"28","author":"Benoit","year":"2007","journal-title":"Biomaterials"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1016\/j.biomaterials.2014.02.038","article-title":"Differentiation of endothelial progenitor cells into endothelial cells by heparin-modified supramolecular pluronic nanogels encapsulating bFGF and complexed with VEGF165 genes","volume":"35","author":"Yang","year":"2014","journal-title":"Biomaterials"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1021\/acs.biomac.2c00585","article-title":"Heparinized Gelatin-Based Hydrogels for Differentiation of Induced Pluripotent Stem Cells","volume":"23","author":"Arkenberg","year":"2022","journal-title":"Biomacromolecules"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1016\/j.addr.2012.01.016","article-title":"Strategies for controlled delivery of growth factors and cells for bone regeneration","volume":"64","author":"Vo","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.22203\/eCM.v013a01","article-title":"Animal models for implant biomaterial research in bone: A review","volume":"13","author":"Pearce","year":"2007","journal-title":"Eur. Cell Mater."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1021\/acsbiomaterials.6b00509","article-title":"Fibroblast Growth Factor-1 Released from a Heparin Coacervate Improves Cardiac Function in a Mouse Myocardial Infarction Model","volume":"3","author":"Wang","year":"2017","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1021\/acsbiomaterials.5b00077","article-title":"Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction","volume":"1","author":"Johnson","year":"2015","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jconrel.2015.03.034","article-title":"Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction","volume":"207","author":"Awada","year":"2015","journal-title":"J. Control Release"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jare.2024.10.032","article-title":"Bioinspired injectable hydrogels for bone regeneration","volume":"75","author":"Tang","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Takematsu, E., Murphy, M., Hou, S., Steininger, H., Alam, A., Ambrosi, T.H., and Chan, C.K.F. (2023). Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration. 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