Biomaterial-mediated blood clot formation: a key to unlocking osteogenic synergy for bone regeneration

Dong Zhang , Laiqiang Tong , Lijie Mao , Dong Han , Fangping Chen , Changsheng Liu

Bone Research ›› 2026, Vol. 14 ›› Issue (1) : 102

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Bone Research ›› 2026, Vol. 14 ›› Issue (1) :102 DOI: 10.1038/s41413-026-00559-9
Review Article
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Biomaterial-mediated blood clot formation: a key to unlocking osteogenic synergy for bone regeneration
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Abstract

Bone hemorrhage presents serious clinical challenges due to its high morbidity and mortality. Autologous coagulation forms blood clots that both halt bleeding and provide a natural scaffold for bone repair. The dynamic formation and dissolution of blood clots maintain a delicate balance between hemostasis and regeneration. Clot architecture and cytokine composition play pivotal roles in directing bone repair. These insights inspire biomimetic strategies using engineered biomaterials to regulate clot behavior, a central theme in designing bone-replacement systems that integrate hemostasis with osteogenesis. This review highlights the processes of clot formation following bone trauma and the contribution of cytokine-mediated signaling to bone repair. Particular emphasis is placed on how biomaterial implants modulate clot function via their physicochemical properties, such as chemical composition, structural characteristics, hydrophilicity, and surface charge. Additionally, the review examines the role of the clots during the early stages of bone injury and discusses the rational design principles for materials aimed at optimizing coagulation control and osteogenesis. Overall, this review reframes the clot not as a passive by-product of trauma but as an interface through which biomaterials seamlessly merge hemostasis and osteogenesis, offering a roadmap for multifunctional bone-replacement systems that halt bleeding while programming robust bone repair.

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Dong Zhang, Laiqiang Tong, Lijie Mao, Dong Han, Fangping Chen, Changsheng Liu. Biomaterial-mediated blood clot formation: a key to unlocking osteogenic synergy for bone regeneration. Bone Research, 2026, 14 (1) : 102 DOI:10.1038/s41413-026-00559-9

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References

[1]

Spahn DR, et al.The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit. Care, 2019, 2398

[2]

Naghavi M, et al.Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet, 2017, 390: 1151-1210.

[3]

Yang Y, Xiao YBiomaterials regulating bone hematoma for osteogenesis. Adv. Health. Mater., 2020, 9: 2000726.

[4]

Chen S, et al.Biomaterials with structural hierarchy and controlled 3D nanotopography guide endogenous bone regeneration. Sci. Adv., 2021, 7eabg3089

[5]

Chen M, et al.Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis. Bone Res., 2021, 921.

[6]

Zhu G, et al.Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds. Bioact. Mater., 2021, 64110-4140

[7]

Shiu HT, Leung PC, Ko CHThe roles of cellular and molecular components of a hematoma at early stage of bone healing. J. Tissue Eng. Regener. Med., 2018, 12: E1911-E1925.

[8]

Bastian OW, Koenderman L, Alblas J, Leenen LP, Blokhuis TJNeutrophils contribute to fracture healing by synthesizing fibronectin+ extracellular matrix rapidly after injury. Clin. Immunol., 2016, 164: 78-84.

[9]

Stegen S, van Gastel N, Carmeliet GBringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration. Bone, 2015, 70: 19-27.

[10]

Adekambi T, et al.Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J. Clin. Investig., 2015, 125: 1827-1838.

[11]

Kolar P, Gaber T, Perka C, Duda GN, Buttgereit FHuman early fracture hematoma is characterized by inflammation and hypoxia. Clin. Orthop. Relat. Res., 2011, 469: 3118-3126.

[12]

Wang X, Zhang Y, Ji W, Ao JCategorising bone defect hematomas—enhance early bone healing. Med. Hypotheses, 2018, 113: 77-80.

[13]

Wu L, Liu J, Qiu T, Dai HThe natural reticular hematoma scaffold modulating inflammatory microenvironment and promoting bone regeneration. Compos. Part B Eng., 2025, 295: 112199.

[14]

Walters G, Pountos I, Giannoudis PVThe cytokines and micro-environment of fracture haematoma: current evidence. J. Tissue Eng. Regener. Med., 2018, 12e1662-e1677.

[15]

Huangfu Y, et al.An off-the-shelf artificial blood clot hydrogel neutralizing multiple proinflammatory mediators for pro-regenerative periodontitis treatment. Adv. Sci., 2025, 12e04106

[16]

Harwood PJ, Newman JB, Michael ALJOTrauma(ii) An update on fracture healing and non-union. Orthop. Trauma, 2010, 28: 228-242

[17]

Woloszyk A, et al.Fracture hematoma micro-architecture influences transcriptional profile and plays a crucial role in determining bone healing outcomes. Biomater. Adv., 2022, 139: 213027.

[18]

Echeverri LF, Herrero MA, Lopez JM, Oleaga GEarly stages of bone fracture healing: formation of a fibrin-collagen scaffold in the fracture hematoma. Bull. Math. Biol., 2015, 77156-183.

[19]

Shiu HT, Goss B, Lutton C, Crawford R, Xiao YFormation of Blood Clot on Biomaterial Implants Influences Bone Healing. Tissue Eng. Part B-Rev., 2014, 20: 697-712.

[20]

Sung YK, Lee DR, Chung DJAdvances in the development of hemostatic biomaterials for medical application. Biomater. Res, 2021, 2537

[21]

Diethorn ML, Weld LMPhysiologic mechanisms of hemostasis and fibrinolysis. J. Cardiovasc. Nurs., 1989, 4: 1-10.

[22]

Khonsary SGuyton and Hall: textbook of medical physiology. Surg. Neurol. Int., 2017, 8: 275.

[23]

Rand ML, et al.Phosphatidylserine exposure and other apoptotic-like events in Bernard-Soulier syndrome platelets. Am. J. Hematol., 2010, 85584-592.

[24]

Nurden ATPlatelets, inflammation and tissue regeneration. Thromb. Haemost., 2011, 105: S13-S33.

[25]

Wang S, et al.Current applications of platelet gels in wound healing—a review. Wound Repair Regen., 2021, 29: 370-379.

[26]

Heemskerk JW, Bevers EM, Lindhout TPlatelet activation and blood coagulation. Thromb. Haemost., 2002, 88: 186-193.

[27]

Versteeg HH, Heemskerk JW, Levi M, Reitsma PHNew fundamentals in hemostasis. Physiol. Rev., 2013, 93: 327-358.

[28]

Harper D, Young A, McNaught C-EThe physiology of wound healing. Surg. - Oxf. Int. Ed., 2014, 32: 445-450

[29]

Kilian O, et al.New blood vessel formation and expression of VEGF receptors after implantation of platelet growth factor-enriched biodegradable nanocrystalline hydroxyapatite. Growth Factors, 2005, 23: 125-133.

[30]

Lord STFibrinogen and fibrin: scaffold proteins in hemostasis. Curr. Opin. Hematol., 2007, 14: 236-241.

[31]

Behrens AM, Sikorski MJ, Kofinas PHemostatic strategies for traumatic and surgical bleeding. J. Biomed. Mater. Res A, 2014, 102: 4182-4194.

[32]

Wang, X. et al. Alteration of clot architecture using bone substitute biomaterials (beta-tricalcium phosphate) significantly delays the early bone healing process. J. Mater. Chem. B. 6 (2018).

[33]

Girard N, Cauvin ERJ, Gauthier O, Gault SBiphasic calcium phosphate microparticles mixed with autologous blood: application for the reconstruction of a large mandibular bone defect in a dog. J. Vet. Dent., 2020, 37: 201-209.

[34]

Yuasa M, et al.Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J. Clin. Investig., 2015, 125: 3117-3131.

[35]

Karp JM, Sarraf F, Shoichet MS, Davies JEFibrin-filled scaffolds for bone-tissue engineering: an in vivo study. J. Biomed. Mater. Res A, 2004, 71: 162-171.

[36]

Michael C, et al.Combined computational modeling and experimental study of the biomechanical mechanisms of platelet-driven contraction of fibrin clots. Commun. Biol., 2023, 6: 869.

[37]

Wolberg AS, Campbell RAThrombin generation, fibrin clot formation and hemostasis. Transfus. Apher. Sci., 2008, 3815-23.

[38]

Wolberg ASThrombin generation and fibrin clot structure. Blood Rev., 2007, 21: 131-142.

[39]

Bennett JS, Berger BW, Billings PCThe structure and function of platelet integrins. J. Thromb. Haemost., 2009, 7: 200-205.

[40]

Raghavendran HRB, et al.Synergistic interaction of platelet-derived growth factor (PDGF) with the surface of PLLA/Col/HA and PLLA/HA scaffolds produces rapid osteogenic differentiation. Colloids Surf. B-Biointerfaces, 2016, 139: 68-78.

[41]

Fan W, Crawford R, Xiao YThe ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization. Differentiation, 2011, 81: 181-191.

[42]

Kells AF, Coats SR, Schwartz HS, Hoover RLTGF-β and PDGF act synergistically in affecting the growth of human osteoblast-enriched cultures. Connect. Tissue Res., 1995, 31: 117-124.

[43]

Solovieva, A. et al. Immobilization of platelet-rich plasma onto COOH plasma-coated PCL nanofibers boost viability and proliferation of human mesenchymal stem cells. Polymers. 9 (2017).

[44]

Kolar P, et al.The early fracture hematoma and its potential role in fracture healing. Tissue Eng. Part B Rev., 2010, 16: 427-434.

[45]

Bab I, et al.Kinetics and differentiation of marrow stromal cells in diffusion chambers in vivo. J. Cell Sci., 1986, 84: 139-151.

[46]

Cho T-J, Gerstenfeld LC, Einhorn TADifferential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J. Bone Miner. Res., 2002, 17: 513-520.

[47]

Kon T, et al.Expression of osteoprotegerin, receptor activator of NF-κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J. Bone Miner. Res., 2001, 16: 1004-1014.

[48]

Li L, et al.Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis. Bioact. Mater., 2023, 19: 24-37

[49]

Pieters M, Wolberg ASFibrinogen and fibrin: an illustrated review. Res. Pract. Thromb. Haemost., 2019, 3: 161-172.

[50]

Klatt C, et al.Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J. Clin. Investig., 2018, 128: 3906-3925.

[51]

Weisel JW, Litvinov RIRed blood cells: the forgotten player in hemostasis and thrombosis. J. Thromb. Haemost., 2019, 17: 271-282.

[52]

Diaz-Rodriguez P, Gonzalez P, Serra J, Landin MKey parameters in blood-surface interactions of 3D bioinspired ceramic materials. Mater. Sci. Eng. C-Mater. Biol. Appl., 2014, 41: 232-239.

[53]

Sperling C, Fischer M, Maitz MF, Werner CBlood coagulation on biomaterials requires the combination of distinct activation processes. Biomaterials, 2009, 30: 4447-4456.

[54]

Ma WJ, et al.DLC coatings: effects of physical and chemical properties on biological response. Biomaterials, 2007, 28: 1620-1628.

[55]

Huang H-H, et al.Blood responses to titanium surface with TiO2 nano-mesh structure. Clin. Oral. Implants Res., 2012, 23: 379-383.

[56]

Quan K, et al.Black hemostatic sponge based on facile prepared cross-linked graphene. Colloids Surf. B Biointerfaces, 2015, 132: 27-33.

[57]

Zhang W, et al.Paraffin-coated hydrophobic hemostatic zeolite gauze for rapid coagulation with minimal adhesion. ACS Appl. Mater. Interfaces, 2021, 13: 52174-52180.

[58]

Park J-Y, Kyung K-H, Tsukada K, Kim S-H, Shiratori SBiodegradable polycaprolactone nanofibres with β-chitosan and calcium carbonate produce a hemostatic effect. Polymer, 2017, 123: 194-202.

[59]

Zhu T, et al.Superhydrophobic/superhydrophilic Janus fabrics reducing blood loss. Adv. Health. Mater., 2018, 7e1701086

[60]

He M, et al.Bioinspired interfacial engineering of multiscale micro/nano-structured surfaces with robust superhydrophobic and tunable adhesion. Chem. Eng. J., 2024, 501: 157482.

[61]

Li Z, et al.Superhydrophobic hemostatic nanofiber composites for fast clotting and minimal adhesion. Nat. Commun., 2019, 1011

[62]

Ekdahl KN, et al.Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv. Drug Deliv. Rev., 2011, 631042-1050.

[63]

Qi J, Zhang H, Wang Y, Mani MP, Jaganathan SKDevelopment and blood compatibility assessment of electrospun polyvinyl alcohol blended with metallocene polyethylene and plectranthus amboinicus (PVA/mPE/PA) for bone tissue engineering. Int. J. Nanomed., 2018, 13: 2777-2788.

[64]

Huang N, et al.Hemocompatibility of titanium oxide films. Biomaterials, 2003, 24: 2177-2187.

[65]

Ricklin D, Lambris JDProgress and trends in complement therapeutics. Adv. Exp. Med. Biol., 2013, 735: 1-22.

[66]

Anderson JM, Rodriguez A, Chang DTForeign body reaction to biomaterials. Semin Immunol., 2008, 20: 86-100.

[67]

Yu L, et al.Highly efficient artificial blood coagulation shortcut confined on Ca-zeolite surface. Nano Res., 2021, 14: 3309-3318.

[68]

Sperling C, Schweiss RB, Streller U, Werner CIn vitro hemocompatibility of self-assembled monolayers displaying various functional groups. Biomaterials, 2005, 26: 6547-6557.

[69]

Tan JS, Butterfield DE, Voycheck CL, Caldwell KD, Li JTSurface modification of nanoparticles by PEO/PPO block copolymers to minimize interactions with blood components and prolong blood circulation in rats. Biomaterials, 1993, 14: 823-833.

[70]

Kim D, El-Shall H, Dennis D, Morey TInteraction of PLGA nanoparticles with human blood constituents. Colloids Surf. B-Biointerfaces, 2005, 40: 83-91.

[71]

Cho J, Mosher DFEnhancement of thrombogenesis by plasma fibronectin cross-linked to fibrin and assembled in platelet thrombi. Blood, 2006, 107: 3555-3563.

[72]

Mosher DFCross-linking of cold-insoluble globulin by fibrin-stabilizing factor. J. Biol. Chem., 1975, 250: 6614-6621.

[73]

Gossart A, et al.Coating of cobalt chrome substrates with thin films of polar/hydrophobic/ionic polyurethanes: characterization and interaction with human immunoglobulin G and fibronectin. Colloids Surf. B-Biointerfaces, 2019, 179: 114-120.

[74]

Shang X, et al.Unusual zymogen activation patterns in the protein corona of Ca-zeolites. Nat. Catal., 2021, 4: 607.

[75]

Walsh TG, Metharom P, Berndt MCThe functional role of platelets in the regulation of angiogenesis. Platelets, 2015, 26199-211.

[76]

Huang J, et al.Platelet integrin alphaIIbbeta3: signal transduction, regulation, and its therapeutic targeting. J. Hematol. Oncol., 2019, 12: 26.

[77]

Sekhon UDS, Sen Gupta APlatelets and platelet-inspired biomaterials technologies in wound healing applications. Acs Biomater. Sci. Eng., 2018, 41176-1192.

[78]

Ruggeri ZM, Mendolicchio GLAdhesion mechanisms in platelet function. Circ. Res, 2007, 100: 1673-1685.

[79]

Hickman DA, Pawlowski CL, Sekhon UDS, Marks J, Gupta ASBiomaterials and advanced technologies for hemostatic management of bleeding. Adv. Mater., 2018, 30: 201700859.

[80]

Zhai Z, et al.Co-assembled supramolecular hydrogels of cell adhesive peptide and alginate for rapid hemostasis and efficacious wound healing. Soft Matter, 2019, 158603-8610.

[81]

Lee KY, Mooney DJAlginate: properties and biomedical applications. Prog. Polym. Sci., 2012, 37: 106-126.

[82]

Rhee, P. et al. QuikClot use in trauma for hemorrhage control: case series of 103 documented uses. J. Trauma Acute Care Surg. 64 (2008).

[83]

Davies JEUnderstanding peri-implant endosseous healing. J. Dent. Educ., 2003, 67: 932-949.

[84]

Kikuchi L, Park JY, Victor C, Davies JEPlatelet interactions with calcium-phosphate-coated surfaces. Biomaterials, 2005, 26: 5285-5295.

[85]

Lam WA, et al.Mechanics and contraction dynamics of single platelets and implications for clot stiffening. Nat. Mater., 2011, 10: 61-66.

[86]

Bandyopadhyay D, Baruah H, Gupta B, Sharma SSilver nano particles prevent platelet adhesion on immobilized fibrinogen. Indian J. Clin. Biochem., 2012, 27: 164-170.

[87]

Shrivastava S, et al.Characterization of antiplatelet properties of silver nanoparticles. ACS Nano, 2009, 3: 1357-1364.

[88]

Tsuji K, et al.BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet., 2006, 38: 1424-1429.

[89]

Wang X, Friis T, Glatt V, Crawford R, Xiao YStructural properties of fracture haematoma: current status and future clinical implications. J. Tissue Eng. Regener. Med., 2017, 11: 2864-2875.

[90]

Pomini KT, et al.Fibrin sealant derived from human plasma as a scaffold for bone grafts associated with photobiomodulation therapy. Int. J. Mol. Sci., 2019, 20: 1761.

[91]

Groothuis A, et al.Mechanical stimulation of the pro-angiogenic capacity of human fracture haematoma: involvement of VEGF mechano-regulation. Bone, 2010, 47438-444.

[92]

Schindeler A, McDonald MM, Bokko P, Little DGBone remodeling during fracture repair: the cellular picture. Semin Cell Dev. Biol., 2008, 19: 459-466.

[93]

Yu X, Tang X, Gohil SV, Laurencin CTBiomaterials for bone regenerative engineering. Adv. Health. Mater., 2015, 4: 1268-1285.

[94]

Shats EA, Nair CH, Dhall DPInteraction of endothelial cells and fibroblasts with modified fibrin networks: role in atherosclerosis. Atherosclerosis, 1997, 129: 9-15.

[95]

Chen Y, Li W, Zhang C, Wu Z, Liu JRecent developments of biomaterials for additive manufacturing of bone scaffolds. Adv. Health. Mater., 2020, 23e2000724

[96]

Leghissa GC, Zaffe D, Assenza B, Botticelli ARGuided bone regeneration using titanium grids: report of 10 cases. Clin. Oral. Implants Res., 1999, 10: 62-68.

[97]

Di Iorio D, et al.Quantitative evaluation of the fibrin clot extension on different implant surfaces: an in vitro study. J. Biomed. Mater. Res. Part B-Appl. Biomater., 2005, 74B: 636-642.

[98]

Boix M, et al.ATR-FTIR measurements of albumin and fibrinogen adsorption: Inert versus calcium phosphate ceramics. J. Biomed. Mater. Res. Part A, 2015, 103: 3493-3502.

[99]

Shakir M, Jolly R, Khan MS, Rauf A, Kazmi SNano-hydroxyapatite/beta-CD/chitosan nanocomposite for potential applications in bone tissue engineering. Int. J. Biol. Macromol., 2016, 93: 276-289.

[100]

Fernandez-Montes Moraleda B, San Roman J, Rodriguez-Lorenzo LMInfluence of surface features of hydroxyapatite on the adsorption of proteins relevant to bone regeneration. J. Biomed. Mater. Res. Part A, 2013, 101: 2332-2339.

[101]

Rosengren Å, et al.Plasma protein adsorption pattern on characterized ceramic biomaterials. Biomaterials, 2002, 23: 1237-1247.

[102]

Young BR, Lambrecht LK, Cooper SL, Mosher DFBiomaterials: interfacial phenomena and applications. Adv. Chem., 1982, 22: 317-350. American chemical society

[103]

Takabatake K, et al.Effect of geometry and microstructure of honeycomb TCP scaffolds on bone regeneration. J. Biomed. Mater. Res A, 2014, 102: 2952-2960.

[104]

Marx REPlatelet-rich plasma (PRP): what is PRP and what is not PRP?. Implant Dent., 2001, 10: 225-228.

[105]

Padilla-Lopategui S, et al.Biocooperative regenerative materials by harnessing blood-clotting and peptide self-assembly. Adv. Mater., 2024, 36e2407156

[106]

Preininger B, et al.An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark—a pilot study. Eur. Cell Mater., 2012, 23: 262-271. discussion 271-262

[107]

Milillo, L., Cinone, F., Lo Presti, F., Lauritano, D. & Petruzzi, M. The role of blood clot in guided bone regeneration: biological considerations and clinical applications with titanium foil. Materials14 (2021).

[108]

Kopf BS, Ruch S, Berner S, Spencer ND, Maniura-Weber KThe role of nanostructures and hydrophilicity in osseointegration: in-vitro protein-adsorption and blood-interaction studies. J. Biomed. Mater. Res. Part A, 2015, 103: 2661-2672.

[109]

Alexandre Gehrke S, et al.Effect of different morphology of titanium surface on the bone healing in defects filled only with blood clot: a new animal study design. Biomed. Res. Int., 2018, 20184265474

[110]

Yang J, Zhou Y, Wei F, Xiao YBlood clot formed on rough titanium surface induces early cell recruitment. Clin. Oral. Implants Res., 2016, 27: 1031-1038.

[111]

Weiner S, Simon J, Ehrenberg DS, Zweig B, Ricci JLThe effects of laser microtextured collars upon crestal bone levels of dental implants. Implant Dent., 2008, 17: 217-228.

[112]

MacDonald DE, Deo N, Markovic B, Stranick M, Somasundaran PAdsorption and dissolution behavior of human plasma fibronectin on thermally and chemically modified titanium dioxide particles. Biomaterials, 2002, 23: 1269-1279.

[113]

Trento GDS, et al.Bone tissue formation around two titanium implant surfaces placed in bone defects filled with bone substitute material or blood clot: a pilot study. Clin. Implant Dent. Relat. Res, 2019, 21: 1175-1180.

[114]

Bai L, et al.Targeting early healing phase with titania nanotube arrays on tunable diameters to accelerate bone regeneration and osseointegration. Small, 2021, 17e2006287

[115]

Bai, L., Chen, P., Tang, B., Hang, R. & Xiao, Y. Correlation between LncRNA profiles in the blood clot formed on nano-scaled implant surfaces and osseointegration. Nanomaterials. 11 (2021).

[116]

Bai L, et al.A micro/nano-biomimetic coating on titanium orchestrates osteo/angio-genesis and osteoimmunomodulation for advanced osseointegration. Biomaterials, 2021, 278121162

[117]

Wei F, et al.Blood prefabricated hydroxyapatite/tricalcium phosphate induces ectopic vascularized bone formation via modulating the osteoimmune environment. Biomater. Sci., 2018, 6: 2156-2171.

[118]

Decco O, Cura A, Beltran V, Lezcano M, Engelke WBone augmentation in rabbit tibia using microfixed cobalt-chromium membranes with whole blood, tricalcium phosphate and bone marrow cells. Int. J. Clin. Exp. Med., 2015, 8: 135-144

[119]

Balaguer T, et al.Combination of blood and biphasic calcium phosphate microparticles for the reconstruction of large bone defects in dog: a pilot study. J. Biomed. Mater. Res. Part A, 2018, 106: 1842-1850.

[120]

Balaguer T, et al.Biphasic calcium phosphate microparticles for bone formation: benefits of combination with blood clot. Tissue Eng. Part A, 2010, 16: 3495-3505.

[121]

Kim, B.-S. & Lee, J. Enhanced bone healing by improved fibrin-clot formation via fibrinogen adsorption on biphasic calcium phosphate granules. Clin. Oral Implants Res. 26 (2015).

[122]

Liu R, et al.Blood prefabrication subcutaneous small animal model for the evaluation of bone substitute materials. ACS Biomater. Sci. Eng., 2018, 4: 2516-2527.

[123]

Jing L, et al.Proteomic analysis identified LBP and CD14 as key proteins in blood/biphasic calcium phosphate microparticle interactions. Acta Biomater., 2021, 127: 298-312.

[124]

Ko CL, et al.Properties of osteoconductive biomaterials: calcium phosphate cement with different ratios of platelet-rich plasma as identifiers. Mater. Sci. Eng. C. Mater. Biol. Appl, 2013, 33: 3537-3544.

[125]

Mellier C, et al.A straightforward approach to enhance the textural, mechanical and biological properties of injectable calcium phosphate apatitic cements (CPCs): CPC/blood composites, a comprehensive study. Acta Biomater., 2017, 62: 328-339.

[126]

Lu HH, Pollack SR, Ducheyne P45S5 Bioactive glass surface charge variations and the formation of a surface calcium phosphate layer in a solution containing fibronectin. J. Biomed. Mater. Res., 2001, 54: 454-461.

[127]

Putra NE, Mirzaali MJ, Apachitei I, Zhou J, Zadpoor AAMulti-material additive manufacturing technologies for Ti-, Mg-, and Fe-based biomaterials for bone substitution. Acta Biomater., 2020, 109: 1-20.

[128]

GonzÁLez-Carrasco JLMetals as bone repair materials. Bone Repair Biomater., 2009, 109: 154-193.

[129]

Gruenewald TA, et al.Reaction of bone nanostructure to a biodegrading magnesium WZ21 implant—a scanning small-angle X-ray scattering time study. Acta Biomater., 2016, 31: 448-457.

[130]

Jaiswal S, Dubey A, Haldar S, Roy P, Lahiri DDifferential in vitro degradation and protein adhesion behaviour of spark plasma sintering fabricated magnesium-based temporary orthopaedic implant in serum and simulated body fluid. Biomed. Mater., 2020, 15: 015006.

[131]

Tang Y, et al.How surface electronegativity and calcium release in enamel mediate the adsorption and lubrication of salivary proteins: the role of interfacial water. Friction, 2025, 139440912.

[132]

Wang, H. et al. Effects of alloy elements on adsorption of fibrinogen on biodegradable magnesium alloys surfaces: the MD simulations and experimental studies. Appl. Surface Sci. 512, 145725 (2020).

[133]

Visalakshan, R. M. et al. Nanotopography-induced unfolding of fibrinogen modulates leukocyte binding and activation. Adv. Funct. Mater.29 (2019).

[134]

Lin S, Van den Bergh W, Baker S, Jones JRProtein interactions with nanoporous sol-gel derived bioactive glasses. Acta Biomater., 2011, 73606-3615.

[135]

Wang XY, Xie WM, Zhang D, He QWave and vegetation effects on flow and suspended sediment characteristics: a flume study. Estuar., Coast. Shelf Sci., 2016, 182: 1-11.

[136]

Baker CJ, Smith SA, Morrissey JHPolyphosphate in thrombosis, hemostasis, and inflammation. Res Pract. Thromb. Haemost., 2019, 3: 18-25.

[137]

Gu J-T, et al.Polyphosphate-crosslinked collagen scaffolds for hemostasis and alveolar bone regeneration after tooth extraction. Bioact. Mater., 2022, 15: 68-81

[138]

Rother S, et al.Sulfated hyaluronan alters endothelial cell activation in vitro by controlling the biological activity of the angiogenic factors vascular endothelial growth factor-A and tissue inhibitor of metalloproteinase-3. ACS Appl. Mater. Interfaces, 2017, 9: 9539-9550.

[139]

Al-Maawi S, et al.Covalent linkage of sulfated hyaluronan to the collagen scaffold Mucograft (R) enhances scaffold stability and reduces proinflammatory macrophage activation in vivo. Bioact. Mater., 2022, 8: 420-434

[140]

Hoemann CD, et al.Chitosan-glycerol phosphate/blood implants elicit hyaline cartilage repair integrated with porous subchondral bone in microdrilled rabbit defects. Osteoarthr. Cartil., 2007, 15: 78-89.

[141]

Marchand C, Rivard GE, Sun J, Hoemann CDSolidification mechanisms of chitosan-glycerol phosphate/blood implant for articular cartilage repair. Osteoarthr. Cartil., 2009, 17: 953-960.

[142]

Shen EC, et al.Releasing growth factors from activated human platelets after chitosan stimulation: a possible bio-material for platelet-rich plasma preparation. Clin. Oral. Implants Res., 2006, 17: 572-578.

[143]

Deprés-Tremblay G, Chevrier A, Tran-Khanh N, Nelea M, Buschmann MDChitosan inhibits platelet-mediated clot retraction, increases platelet-derived growth factor release, and increases residence time and bioactivity of platelet-rich plasma in vivo. Biomed. Mater., 2017, 13: 015005.

[144]

Dwivedi G, Chevrier A, Hoemann CD, Buschmann MDInjectable freeze-dried chitosan-platelet-rich-plasma implants improve marrow-stimulated cartilage repair in a chronic-defect rabbit model. J. Tissue Eng. Regener. Med., 2019, 13599-611.

[145]

Lafantaisie-Favreau C-H, et al.Subchondral pre-solidified chitosan/blood implants elicit reproducible early osteochondral wound-repair responses including neutrophil and stromal cell chemotaxis, bone resorption and repair, enhanced repair tissue integration and delayed matrix deposition. BMC Musculoskelet. Disord., 2013, 1427

[146]

Kulkarni M, et al.Wettability studies of topologically distinct titanium surfaces. Colloids Surf. B-Biointerfaces, 2015, 129: 47-53.

[147]

Alfarsi MA, Hamlet SM, Ivanovski SThe effect of platelet proteins released in response to titanium implant surfaces on macrophage pro-inflammatory cytokine gene expression. Clin. Implant Dent. Relat. Res., 2015, 17: 1036-1047.

[148]

Wu S, Liu X, Gao CRole of adsorbed proteins on hydroxyapatite-coated titanium in osteoblast adhesion and osteogenic differentiation. Sci. Bull., 2015, 60: 691-700.

[149]

Tunali M, Ozdemir H, Kucukodaci Z, Akman S, Firatli EIn vivo evaluation of titanium-prepared platelet-rich fibrin (T-PRF): a new platelet concentrate. Br. J. Oral. Maxillofac. Surg., 2013, 51: 438-443.

[150]

Cho S-A, Lee B-K, Park S-H, Ahn J-JThe bone integration effects of platelet-rich fibrin by removal torque of titanium screw in rabbit tibia. Platelets, 2014, 25: 562-566.

[151]

Romero-Gavilan F, et al.Protein adsorption/desorption dynamics on Ca-enriched titanium surfaces: biological implications. J. Biol. Inorg. Chem., 2021, 26: 715-726.

[152]

Sabino RM, Kauk K, Movafaghi S, Kota A, Popat KCInteraction of blood plasma proteins with superhemophobic titania nanotube surfaces. Nanomed.-Nanotechnol. Biol. Med., 2019, 21: 102046.

[153]

Xu R, et al.Zwitterionic PMCP-functionalized titanium surface resists protein adsorption, promotes cell adhesion, and enhances osteogenic activity. Colloids Surf. B: Biointerfaces, 2021, 206111928.

[154]

Rosales AM, Anseth KSThe design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater., 2016, 115012.

[155]

Tong Z, et al.Adaptable hydrogel with reversible linkages for regenerative medicine: dynamic mechanical microenvironment for cells. Bioact. Mater., 2021, 61375-1387

[156]

Yu Z, et al.Application of fibrin-based hydrogels for nerve protection and regeneration after spinal cord injury. J. Biol. Eng., 2020, 1422

[157]

Lee HH, et al.Release of bioactive adeno-associated virus from fibrin scaffolds: effects of fibrin glue concentrations. Tissue Eng. Part A, 2011, 17: 1969-1978.

[158]

Rocha CA, et al.Maxillary sinus lift response to platelet-rich plasma associated with autogenous bone, ceramic biphasic HA/beta-TCP (70:30), or deproteinized bovine bone. Int. J. Implant Dent., 2020, 679

[159]

Son S-R, et al.Platelet-rich plasma encapsulation in hyaluronic acid/gelatin-BCP hydrogel for growth factor delivery in BCP sponge scaffold for bone regeneration. J. Biomater. Appl., 2015, 29: 988-1002.

[160]

Zhou H, Xu HHKThe fast release of stem cells from alginate-fibrin microbeads in injectable scaffolds for bone tissue engineering. Biomaterials, 2011, 32: 7503-7513.

[161]

Vorwald CE, Gonzalez-Fernandez T, Joshee S, Sikorski P, Leach JKTunable fibrin-alginate interpenetrating network hydrogels to support cell spreading and network formation. Acta Biomater., 2020, 108: 142-152.

[162]

Ho W, Tawil B, Dunn JC, Wu BMThe behavior of human mesenchymal stem cells in 3D fibrin clots: dependence on fibrinogen concentration and clot structure. Tissue Eng., 2006, 12: 1587-1595.

[163]

Richter A, et al.Triple modification of alginate hydrogels by fibrin blending, iron nanoparticle embedding, and serum protein-coating synergistically promotes strong endothelialization. Adv. Mater. Interfaces, 2021, 8: 2002015.

[164]

Balgude AP, Yu X, Szymanski A, Bellamkonda RVAgarose gel stiffness determines rate of DRG neurite extension in 3D cultures. Biomaterials, 2001, 221077-1084.

[165]

Yao S, et al.Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale, 2016, 8: 10252-10265.

[166]

Du J, et al.Prompt peripheral nerve regeneration induced by a hierarchically aligned fibrin nanofiber hydrogel. Acta Biomater., 2017, 55: 296-309.

[167]

Urist MRBone: formation by autoinduction. Science, 1965, 150: 893-899.

[168]

van den Dolder J, de Ruijter AJE, Spauwen PHM, Jansen JAObservations on the effect of BMP-2 on rat bone marrow cells cultured on titanium substrates of different roughness. Biomaterials, 2003, 24: 1853-1860.

[169]

Ao Q, et al.Fibrin glue/fibronectin/heparin-based delivery system of Bmp2 induces osteogenesis in MC3T3-E1 cells and bone formation in rat calvarial critical-sized defects. ACS Appl. Mater. Interfaces, 2020, 12: 13400-13410.

[170]

Fan Q, et al.Implantable blood clot loaded with BMP-2 for regulation of osteoimmunology and enhancement of bone repair. Bioact. Mater., 2021, 6: 4014-4026

[171]

Berkmann JC, et al.In vivo validation of spray-dried mesoporous bioactive glass microspheres acting as prolonged local release systems for BMP-2 to support bone regeneration. Pharmaceutics, 2020, 12: 823.

[172]

Ren WH, Yang LJ, Dong SZInduction of reparative dentin formation in dogs with combined recombinant human bone morphogenetic protein 2 and fibrin sealant. Chin. J. Dent. Res, 1999, 221-24

[173]

Liu Y, et al.Segmental bone regeneration using an rhBMP-2-loaded gelatin/nanohydroxyapatite/fibrin scaffold in a rabbit model. Biomaterials, 2009, 30: 6276-6285.

[174]

Ben-David D, et al.Low dose BMP-2 treatment for bone repair using a PEGylated fibrinogen hydrogel matrix. Biomaterials, 2013, 34: 2902-2910.

[175]

Huang CYC, Deitzer MA, Cheung HSEffects of fibrinolytic inhibitors on chondrogenesis of bone-marrow derived mesenchymal stem cells in fibrin gels. Biomech. Model. Mechanobiol., 2007, 6: 5-11.

[176]

Marcinczyk M, et al.Laminin-111 enriched fibrin hydrogels for skeletal muscle regeneration. Biomaterials, 2017, 141: 233-2423.

[177]

Park K-H, Kim H, Moon S, Na KBone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering. J. Biosci. Bioeng., 2009, 108: 530-537.

[178]

Dong Nyoung H, Hospodiuk M, Ozbolat ITSynergistic interplay between human MSCs and HUVECs in 3D spheroids laden in collagen/fibrin hydrogels for bone tissue engineering. Acta Biomater., 2019, 95: 348-356.

[179]

Carr MEJrShen LL, Hermans JMass–length ratio of fibrin fibers from gel permeation and light scattering. Biopolymers, 1977, 16: 1-15.

[180]

Davis HE, Miller SL, Case EM, Leach JKSupplementation of fibrin gels with sodium chloride enhances physical properties and ensuing osteogenic response. Acta Biomater., 2011, 7: 691-699.

[181]

Hu L, et al.Extracellular vesicles from bone marrow-derived macrophages enriched in ARG1 enhance microglial phagocytosis and haematoma clearance following intracerebral haemorrhage. J. Extracell. Vesicles, 2025, 14e70041

[182]

Zhang G, Drinnan CT, Geuss LR, Suggs LJVascular differentiation of bone marrow stem cells is directed by a tunable three-dimensional matrix. Acta Biomater., 2010, 6: 3395-3403.

[183]

Mendez JJ, et al.Mesenchymal stromal cells form vascular tubes when placed in fibrin sealant and accelerate wound healing in vivo. Biomaterials, 2015, 40: 61-67.

[184]

Zhou W, et al.Peptide-based inflammation-responsive implant coating sequentially regulates bone regeneration to enhance interfacial osseointegration. Nat. Commun., 2025, 163283

[185]

Julier Z, Park AJ, Briquez PS, Martino MMPromoting tissue regeneration by modulating the immune system. Acta Biomater., 2017, 53: 13-28.

[186]

Tanaka R, Saito Y, Fujiwara Y, Jo J-i, Tabata YPreparation of fibrin hydrogels to promote the recruitment of anti-inflammatory macrophages. Acta Biomater., 2019, 89: 152-165.

[187]

Ohba S, et al.Efficacy of platelet-rich plasma gel and hyaluronan hydrogel as carriers of electrically polarized hydroxyapatite microgranules for accelerating bone formation. J. Biomed. Mater. Res. Part A, 2012, 100A: 3167-3176.

[188]

Zhao YH, et al.The combined use of cell sheet fragments of periodontal ligament stem cells and platelet-rich fibrin granules for avulsed tooth reimplantation. Biomaterials, 2013, 34: 5506-5520.

[189]

Dohan Ehrenfest DM, Rasmusson L, Albrektsson TClassification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol., 2009, 27: 158-167.

[190]

Wu CL, et al.Platelet-rich fibrin increases cell attachment, proliferation and collagen-related protein expression of human osteoblasts. Aust. Dent. J., 2012, 57: 207-212.

[191]

Song Y, et al.Nano-biphasic calcium phosphate/polyvinyl alcohol composites with enhanced bioactivity for bone repair via low-temperature three-dimensional printing and loading with platelet-rich fibrin. Int. J. Nanomed., 2018, 13: 505-523.

[192]

Chen FM, Zhang M, Wu ZFToward delivery of multiple growth factors in tissue engineering. Biomaterials, 2010, 31: 6279-6308.

[193]

Anitua E, Sanchez M, Orive GPotential of endogenous regenerative technology for in situ regenerative medicine. Adv. Drug Deliv. Rev., 2010, 62: 741-752.

[194]

Jooybar E, et al.Developing hyaluronic acid microgels for sustained delivery of platelet lysate for tissue engineering applications. Int. J. Biol. Macromol., 2020, 144: 837-846.

[195]

Santo VE, Gomes ME, Mano JF, Reis RLChitosan-chondroitin sulphate nanoparticles for controlled delivery of platelet lysates in bone regenerative medicine. J. Tissue Eng. Regen. Med., 2012, 6: s47-s59.

[196]

Sadeghinia A, Davaran S, Salehi R, Jamalpoor ZNano-hydroxy apatite/chitosan/gelatin scaffolds enriched by a combination of platelet-rich plasma and fibrin glue enhance proliferation and differentiation of seeded human dental pulp stem cells. Biomed. Pharmacother., 2019, 109: 1924-1931.

[197]

Siddiqui JA, Partridge NCPhysiological bone remodeling: systemic regulation and growth factor involvement. Physiology, 2016, 31: 233-245.

[198]

Kiernan, C.H., Wolvius, E.B., Brama, P.A.J., Farrell, E. The immune response to allogeneic differentiated mesenchymal stem cells in the context of bone tissue engineering. Tissue Eng. Part B Rev.24, 75–83 (2018).

[199]

Wu M, Chen G, Li YPTGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res., 2016, 416009.

Funding

National Natural Science Foundation of China (No. 32171342;32471407), National Key Research and Development Program of China (2023YFC2413600; 2022YFB3804303), Shanghai Pujiang Program (16PJD015) and Joint Fund for equipment pre-research of the ministry of education (6141A02022618).

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