Bioaugmented osteosynthesis: precise monitoring and intervention of the bone healing microenvironment

Gaoxiang Xu , Junyang Chen , Zhikang Xiao , Jianzhong Xu , Licheng Zhang , Peifu Tang

Bone Research ›› 2025, Vol. 13 ›› Issue (1) : 95

PDF
Bone Research ›› 2025, Vol. 13 ›› Issue (1) :95 DOI: 10.1038/s41413-025-00466-5
Review Article
letter

Bioaugmented osteosynthesis: precise monitoring and intervention of the bone healing microenvironment

Author information +
History +
PDF

Abstract

Bone healing is integral to orthopedic research, focusing on the restoration of bone function through a complex interplay of inflammatory responses, soft callus formation, hard callus development, and the final remodeling phase. While the natural progression of bone healing is a finely tuned process, it can be disrupted by inflammatory dysregulation, ranging from chronic inflammation to acute inflammatory anomalies, and by the depletion of essential repair substances under both chronic and acute conditions. Current strategies to enhance bone healing employ a multifaceted approach, including biochemical modulation of the local microenvironment through essential nutrient supplementation (e.g., calcium and vitamin D), biomechanical optimization via improved internal fixation stability, and advanced regenerative techniques incorporating bioactive factors, stem cell therapies, and functional biomaterials. Despite these efforts, challenges persist in the precise characterization of the local microenvironment and the precise control of in vivo bioactive molecule delivery. This review comprehensively summarizes the current research progress in bone healing, providing significant reference for understanding the mechanisms of bone healing and for guiding further research. It is expected to lay the theoretical foundation for the development of more effective therapeutic strategies for bone healing.

Cite this article

Download citation ▾
Gaoxiang Xu, Junyang Chen, Zhikang Xiao, Jianzhong Xu, Licheng Zhang, Peifu Tang. Bioaugmented osteosynthesis: precise monitoring and intervention of the bone healing microenvironment. Bone Research, 2025, 13(1): 95 DOI:10.1038/s41413-025-00466-5

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Ho-Shui-Ling A, et al. . Bone regeneration strategies: engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives. Biomaterials, 2018, 180: 143-162.

[2]

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

[3]

Schell H, et al. . The haematoma and its role in bone healing. J. Exp. Orthop., 2017, 45

[4]

Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: which are the important molecules?. Injury, 2007, 38: S11-S25.

[5]

Little DG, Ramachandran M, Schindeler A. The anabolic and catabolic responses in bone repair. J. Bone Jt. Surg. Br., 2007, 89: 425-433.

[6]

Ikebuchi Y, et al. . Coupling of bone resorption and formation by RANKL reverse signalling. Nature, 2018, 561: 195-200.

[7]

Gao Y, et al. . Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration. Mol. Ther., 2024, 32: 1479-1496.

[8]

Andrzejowski P, Giannoudis PV. The ‘diamond concept’ for long bone non-union management. J. Orthop. Traumatol., 2019, 20: 21

[9]

Chen B, et al. . Synergistic enhancement of tendon-to-bone healing via anti-inflammator y and pro-differentiation effects caused by sustained release of Mg2+/curcumin from injectable self-healing hydrogels. Theranostics, 2021, 11: 5911-5925.

[10]

Chen M, et al. . Histone deacetylase inhibition enhances extracellular vesicles from muscle to promote osteogenesis via miR-873-3p. Sig. Transduct. Target Ther., 2024, 9: 256

[11]

Yin P, et al. . Deciphering immune landscape remodeling unravels the underlying mechanism for synchronized muscle and bone aging. Adv. Sci., 2024, 11: e2304084.

[12]

Yin P, et al. . Cell-based therapies for degenerative musculoskeletal diseases. Adv. Sci., 2023, 10: e2207050.

[13]

Zhang D, Wu X, Chen J, Lin K. The development of collagen based composite scaffolds for bone regeneration. Bioact. Mater., 2018, 3: 129-138. DOI:

[14]

Boskey AL. Erratum: bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep., 2015, 4: 710

[15]

Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed. Res. Int., 2015, 2015: 421746

[16]

Dimitriou R, Jones E, McGonagle D, Giannoudis PV. Bone regeneration: current concepts and future directions. BMC Med., 2011, 966

[17]

Street, J. et al. Is human fracture hematoma inherently angiogenic? Clin. Orthop. Relat. Res. 378, 224–237 (2000).

[18]

Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J. Cell Biochem., 2003, 88: 873-884.

[19]

Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol., 2012, 8: 133-143.

[20]

Ma S, et al. . Microsphere-gel composite system with mesenchymal stem cell recruitment, antibacterial, and immunomodulatory properties promote bone regeneration via sequential release of LL37 and W9 peptides. ACS Appl. Mater. Interfaces, 2022, 14: 38525-38540.

[21]

Schlundt C, et al. . Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone, 2018, 106: 78-89.

[22]

Marsell R, Einhorn TA. The biology of fracture healing. Injury, 2011, 42: 551-555.

[23]

Gerstenfeld LC, et al. . Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J. Bone Miner. Res., 2003, 18: 1584-1592.

[24]

Vallés G, et al. . Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells. Stem Cell Res. Ther., 2020, 11: 57

[25]

Osta B, Lavocat F, Eljaafari A, Miossec P. Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells. Front. Immunol., 2014, 5: 425

[26]

Bahney CS, et al. . Cellular biology of fracture healing. J. Orthop. Res., 2019, 37: 35-50.

[27]

Toya M, et al. . CCL2 promotes osteogenesis by facilitating macrophage migration during acute inflammation. Front. Cell Dev. Biol., 2023, 11: 1213641

[28]

Loi F, et al. . Inflammation, fracture and bone repair. Bone, 2016, 86: 119-130.

[29]

Pajarinen J, et al. . Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019, 196: 80-89.

[30]

Ferron M, et al. . Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell, 2010, 142: 296-308.

[31]

Lu C, et al. . Effect of age on vascularization during fracture repair. J. Orthop. Res., 2008, 26: 1384-1389.

[32]

Yu B, Pacureanu A, Olivier C, Cloetens P, Peyrin F. Assessment of the human bone lacuno-canalicular network at the nanoscale and impact of spatial resolution. Sci. Rep., 2020, 104567

[33]

Zura R, et al. . Epidemiology of fracture nonunion in 18 human bones. JAMA Surg., 2016, 151: e162775

[34]

Osta B, Benedetti G, Miossec P. Classical and paradoxical effects of TNF-α on bone homeostasis. Front. Immunol., 2014, 5: 48

[35]

Lin T-H, et al. . Decreased osteogenesis in mesenchymal stem cells derived from the aged mouse is associated with enhanced NF-κB activity. J. Orthop. Res., 2017, 35: 281-288.

[36]

Clark D, Nakamura M, Miclau T, Marcucio R. Effects of aging on fracture healing. Curr. Osteoporos. Rep., 2017, 15: 601-608.

[37]

Meyer RAJr., et al. . Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J. Orthop. Res., 2001, 19: 428-435.

[38]

Quarto R, Thomas D, Liang CT. Bone progenitor cell deficits and the age-associated decline in bone repair capacity. Calcif. Tissue Int., 1995, 56: 123-129.

[39]

Ferretti C, et al. . Human periosteal derived stem cell potential: the impact of age. Stem Cell Rev. Rep., 2015, 11: 487-500.

[40]

Cheung WH, et al. . Enhancement of osteoporotic fracture healing by vibration treatment: the role of osteocytes. Injury, 2021, 52: S97-S100.

[41]

Hemmatian H, Bakker AD, Klein-Nulend J, van Lenthe GH. Aging, osteocytes, and mechanotransduction. Curr. Osteoporos. Rep., 2017, 15: 401-411.

[42]

Kayal RA, et al. . TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J. Bone Miner. Res., 2010, 25: 1604-1615.

[43]

Göktürk E, et al. . Oxygen-free radicals impair fracture healing in rats. Acta Orthop. Scand., 1995, 66: 473-475.

[44]

Xu D, et al. . The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization. Front. Immunol., 2023, 14: 1148107

[45]

Ding P, et al. . Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation. Bone Res., 2022, 10: 42

[46]

Magruder ML, Parsa S, Gordon AM, Ng M, Wong CHJ. Inflammatory bowel disease patients undergoing total hip arthroplasty have higher odds of implant-related complications. Hip. Int., 2024, 34: 498-502.

[47]

Batoon L, Millard SM, Raggatt LJ, Pettit AR. Osteomacs and bone regeneration. Curr. Osteoporos. Rep., 2017, 15: 385-395.

[48]

Cenci S, et al. . Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc. Natl. Acad. Sci. USA, 2003, 100: 10405-10410.

[49]

Histing T, et al. . Delayed fracture healing in aged senescence-accelerated P6 mice. J. Invest. Surg., 2013, 26: 30-35.

[50]

Recknagel S, et al. . Experimental blunt chest trauma impairs fracture healing in rats. J. Orthop. Res., 2011, 29: 734-739.

[51]

Granata V, et al. . The osteoblast secretome in Staphylococcus aureus osteomyelitis. Front. Immunol., 2022, 13: 1048505

[52]

Kudo O, et al. . Proinflammatory cytokine (TNFalpha/IL-1alpha) induction of human osteoclast formation. J. Pathol., 2002, 198: 220-227.

[53]

Lamret F, et al. . Human osteoblast-conditioned media can influence Staphylococcus aureus biofilm formation. Int. J. Mol. Sci., 2022, 23: 14393

[54]

Metsemakers WJ, et al. . Individual risk factors for deep infection and compromised fracture he aling after intramedullary nailing of tibial shaft fractures: a single centre experience of 480 patients. Injury, 2015, 46: 740-745.

[55]

Tay W-H, de Steiger R, Richardson M, Gruen R, Balogh ZJ. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury, 2014, 45: 1653-1658.

[56]

Menges T, et al. . Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications. Crit. Care Med., 1999, 27: 733-740.

[57]

Hurtgen BJ, et al. . Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing. J. Musculoskelet. Neuronal Interact., 2016, 16: 122-134. DOI:

[58]

Zhang E, et al. . The effects of mechanical instability on PDGF mediated inflammatory response at early stage of fracture healing under diabetic condition. Comput Methods Prog. Biomed., 2023, 229: 107319.

[59]

Stich S, et al. . Human periosteum-derived progenitor cells express distinct chemokine receptors and migrate upon stimulation with CCL2, CCL25, CXCL8, CXCL12, and CXCL13. Eur. J. Cell Biol., 2008, 87: 365-376.

[60]

Schmidt-Bleek K, et al. . Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res., 2012, 347: 567-573.

[61]

Uutela M, et al. . PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood, 2004, 104: 3198-3204.

[62]

Pape HC, Moore EE, McKinley T, Sauaia A. Pathophysiology in patients with polytrauma. Injury, 2022, 53: 2400-2412.

[63]

Rapp AE, et al. . Fracture healing is delayed in immunodeficient NOD/scidIL2Rγcnull mice. PLoS One, 2016, 11: e0147465

[64]

Karnes JM, Daffner SD, Watkins CM. Multiple roles of tumor necrosis factor-alpha in fracture healing. Bone, 2015, 78: 87-93.

[65]

Wallace A, Cooney TE, Englund R, Lubahn JD. Effects of interleukin-6 ablation on fracture healing in mice. J. Orthop. Res., 2011, 29: 1437-1442.

[66]

Ishikawa M, et al. . MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing. PLoS One, 2014, 9: e104954

[67]

Lisowska B, Kosson D, Domaracka K. Lights and shadows of NSAIDs in bone healing: the role of prostaglandins in bone metabolism. Drug. Des. Devel. Ther., 2018, 12: 1753-1758.

[68]

Marquez-Lara A, Hutchinson ID, Nuñez FJr., Smith TL, Miller AN. Nonsteroidal anti-inflammatory drugs and bone-healing: a systematic review of research quality. JBJS Rev., 2016, 4e4

[69]

Saint-Pastou Terrier C, Gasque P. Bone responses in health and infectious diseases: a focus on osteoblasts. J. Infect., 2017, 75: 281-292.

[70]

Ono T, et al. . IL-17-producing γδ T cells enhance bone regeneration. Nat. Commun., 2016, 710928

[71]

Gorter EA, Hamdy NA, Appelman-Dijkstra NM, Schipper IB. The role of vitamin D in human fracture healing: a systematic review of the literature. Bone, 2014, 64: 288-297.

[72]

McCann RM, et al. . Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model. J. Orthop. Res., 2008, 26: 384-393.

[73]

van Driel M, et al. . Evidence that both 1alpha,25-dihydroxyvitamin D3 and 24-hydroxylated D3 enhance human osteoblast differentiation and mineralization. J. Cell Biochem., 2006, 99: 922-935.

[74]

van Leeuwen JP, van Driel M, van den Bemd GJ, Pols HA. Vitamin D control of osteoblast function and bone extracellular matrix mineralization. Crit. Rev. Eukaryot. Gene Expr., 2001, 11: 199-226.

[75]

Saito M, et al. . Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Bone, 2010, 46: 1170-1179.

[76]

Doetsch AM, et al. . The effect of calcium and vitamin D3 supplementation on the healing of the proximal humerus fracture: a randomized placebo-controlled study. Calcif. Tissue Int., 2004, 75: 183-188.

[77]

Russell RG. Bisphosphonates: the first 40 years. Bone, 2011, 49: 2-19.

[78]

Matos MA, Tannuri U, Guarniero R. The effect of zoledronate during bone healing. J. Orthop. Traumatol., 2010, 11: 7-12.

[79]

Lewiecki EM. Treatment of osteoporosis with denosumab. Maturitas, 2010, 66: 182-186.

[80]

Gerstenfeld LC, et al. . Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J. Bone Miner. Res., 2009, 24: 196-208.

[81]

Adami S, et al. . Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J. Bone Jt. Surg. Am., 2012, 94: 2113-2119.

[82]

Silva BC, Costa AG, Cusano NE, Kousteni S, Bilezikian JP. Catabolic and anabolic actions of parathyroid hormone on the skeleton. J. Endocrinol. Invest., 2011, 34: 801-810. DOI:

[83]

Alkhiary YM, et al. . Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J. Bone Jt. Surg. Am., 2005, 87: 731-741

[84]

Kakar S, et al. . Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J. Bone Miner. Res., 2007, 22: 1903-1912.

[85]

Jørgensen NR, Schwarz P. Effects of anti-osteoporosis medications on fracture healing. Curr. Osteoporos. Rep., 2011, 9: 149-155.

[86]

Aspenberg P, et al. . Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J. Bone Miner. Res., 2010, 25: 404-414.

[87]

Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop., 2010, 81: 234-236.

[88]

Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE. Recombinant human platelet-derived growth factor: biology and clinical applications. J. Bone Jt. Surg. Am., 2008, 90: 48-54.

[89]

Caplan AI, Correa D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J. Orthop. Res., 2011, 29: 1795-1803.

[90]

Sun H, et al. . Recombinant human platelet-derived growth factor-BB versus autologous bone graft in foot and ankle fusion: A systematic review and meta-analysis. Foot Ankle Surg., 2017, 23: 32-39.

[91]

Sadat-Ali M, et al. . Genetic Influence of Fracture Nonunion (FNU): a systematic review. Pharmgenom. Pers. Med., 2023, 16: 569-575

[92]

Chiba T, et al. . Transforming growth factor-β1 suppresses bone morphogenetic protein-2-induced mesenchymal-epithelial transition in HSC-4 human oral squamous cell carcinoma cells via Smad1/5/9 pathway suppression. Oncol. Rep., 2017, 37: 713-720.

[93]

Hoeben A, et al. . Vascular endothelial growth factor and angiogenesis. Pharm. Rev., 2004, 56: 549-580.

[94]

Behr B, Tang C, Germann G, Longaker MT, Quarto N. Locally applied vascular endothelial growth factor A increases the osteogenic healing capacity of human adipose-derived stem cells by promoting osteogenic and endothelial differentiation. Stem Cells, 2011, 29: 286-296.

[95]

Kaigler D, Wang Z, Horger K, Mooney DJ, Krebsbach PH. VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J. Bone Miner. Res., 2006, 21: 735-744.

[96]

Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J. R. Soc. Interface, 2011, 8: 153-170.

[97]

Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, Ten Dijke P, Sanchez-Duffhues G. Bone morphogenetic protein receptor signal transduction in human disease. J. Pathol., 2019, 247: 9-20.

[98]

Cecchi S, Bennet SJ, Arora M. Bone morphogenetic protein-7: review of signalling and efficacy in fracture healing. J. Orthop. Transl., 2016, 4: 28-34

[99]

Hissnauer TN, et al. . Bone morphogenetic protein-2 for the treatment of congenital pseudarthrosis of the tibia or persistent tibial nonunion in children and adolescents: a retrospective study with a minimum 2-year follow-up. J. Mater. Sci. Mater. Med., 2017, 28: 60

[100]

Singh R, Bleibleh S, Kanakaris NK, Giannoudis PV. Upper limb non-unions treated with BMP-7: efficacy and clinical results. Injury, 2016, 47: S33-s39.

[101]

Zara JN, et al. . High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng. Part A, 2011, 17: 1389-1399.

[102]

Baksh D, Boland GM, Tuan RS. Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation. J. Cell Biochem., 2007, 101: 1109-1124.

[103]

Jones EA, Giannoudis PV, Kouroupis D. Bone repair with skeletal stem cells: rationale, progress to date and clinical application. Ther. Adv. Musculoskelet. Dis., 2016, 8: 57-71.

[104]

Kim SJ, et al. . A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osteoblast(Ossron) injection to treat fractures. BMC Musculoskelet. Disord., 2009, 1020

[105]

Marcacci M, et al. . Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. Tissue Eng., 2007, 13: 947-955.

[106]

Peterson B, et al. . Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng., 2005, 11: 120-129.

[107]

Di Bella C, Farlie P, Penington AJ. Bone regeneration in a rabbit critical-sized skull defect using autologous adipose-derived cells. Tissue Eng. Part A, 2008, 14: 483-490.

[108]

Fan J, et al. . Enhanced osteogenesis of adipose-derived stem cells by regulating bone morphogenetic protein signaling antagonists and agonists. Stem Cells Transl. Med., 2016, 5: 539-551.

[109]

Mesimäki K, et al. . Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int. J. Oral. Maxillofac. Surg., 2009, 38: 201-209.

[110]

Qin Y, Wang L, Gao Z, Chen G, Zhang C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci. Rep., 2016, 621961

[111]

Li W, et al. . Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. Acs. Appl. Mater. Interfaces, 2018, 10: 5240-5254.

[112]

Sun Y, et al. . Mir-21 overexpressing mesenchymal stem cells accelerate fracture healing in a rat closed femur fracture model. Biomed. Res. Int., 2015, 2015: 412327

[113]

Xie H, et al. . Extracellular vesicle-functionalized decalcified bone matrix scaffolds with enhanced pro-angiogenic and pro-bone regeneration activities. Sci. Rep., 2017, 745622

[114]

Wang R, Xu B. TGFβ1-modified MSC-derived exosome attenuates osteoarthritis by inhibiting PDGF-BB secretion and H-type vessel activity in the subchondral bone. Acta Histochem., 2022, 124: 151933

[115]

Li C, et al. . Sustained release of exosomes loaded into polydopamine-modified chitin conduits promotes peripheral nerve regeneration in rats. Neural Regen. Res., 2022, 17: 2050-2057.

[116]

Jin Q-H, et al. . Bone marrow aspirate concentration provided better results in cartilage regeneration to microfracture in knee of osteoarthritic patients. Knee Surg. Sports Traumatol. Arthrosc., 2021, 29: 1090-1097.

[117]

Hernigou P, Housset V, Dubory A, Rouard H, Auregan JC. Early injection of autologous bone marrow concentrates decreases infection risk and improves healing of acute severe open tibial fractures. Injury, 2022, 53: S26-S33.

[118]

Yang J, et al. . Efficacy of adjuvant treatment for fracture nonunion/delayed union: a network meta-analysis of randomized controlled trials. BMC Musculoskelet. Disord., 2022, 23481

[119]

Fang J, et al. . Platelet-rich plasma therapy in the treatment of diseases associated with orthopedic injuries. Tissue Eng. Part B Rev., 2020, 26: 571-585.

[120]

LaPrade RF, et al. . Biologic treatments for sports injuries II think tank-current concepts, future research, and barriers to advancement, part 1: biologics overview, ligament injury, tendinopathy. Am. J. Sports Med., 2016, 44: 3270-3283.

[121]

Van Lieshout EMM, Den Hartog D. Effect of platelet-rich plasma on fracture healing. Injury, 2021, 52: S58-S66.

[122]

Ranjan R, et al. . Autologous platelet-rich plasma in the delayed union of long bone fractures - a quasi experimental study. J. Orthop., 2022, 36: 76-81.

[123]

Cho A-R, et al. . The incorporation of platelet-rich plasma into calcium phosphate cement enhances bone regeneration in osteoporosis. Pain. Phys., 2014, 17: E737-E745

[124]

Sakata M, et al. . Bone regeneration of osteoporotic vertebral body defects using platelet-rich plasma and gelatin β-tricalcium phosphate sponges. Tissue Eng. Part A, 2018, 24: 1001-1010.

[125]

Simman R, Hoffmann A, Bohinc RJ, Peterson WC, Russ AJ. Role of platelet-rich plasma in acceleration of bone fracture healing. Ann. Plast. Surg., 2008, 61: 337-344.

[126]

Badran Z, Abdallah M-N, Torres J, Tamimi F. Platelet concentrates for bone regeneration: Current evidence and future challenges. Platelets, 2018, 29: 105-112.

[127]

Langer R, Vacanti JP. Tissue engineering. Science, 1993, 260: 920-926.

[128]

Gallo, N., Natali, M. L., Sannino, A. & Salvatore, L. An overview of the use of equine collagen as emerging material for biomedical applications. J. Funct. Biomater.11, 79 (2020).

[129]

Liu X, Zheng C, Luo X, Wang X, Jiang H. Recent advances of collagen-based biomaterials: multi-hierarchical structure, modification and biomedical applications. Mater. Sci. Eng. C. Mater. Biol. Appl., 2019, 99: 1509-1522.

[130]

Elgali I, Omar O, Dahlin C, Thomsen P. Guided bone regeneration: materials and biological mechanisms revisited. Eur. J. Oral. Sci., 2017, 125: 315-337.

[131]

Borrego-González S, Rico-Llanos G, Becerra J, Díaz-Cuenca A, Visser R. Sponge-like processed D-periodic self-assembled atelocollagen supports bone formation in vivo. Mater. Sci. Eng. C. Mater. Biol. Appl., 2021, 120: 111679

[132]

Briquez, P. S., Tsai, H. M., Watkins, E. A. & Hubbell, J. A. Engineered bridge protein with dual affinity for bone morphogenetic protein-2 and collagen enhances bone regeneration for spinal fusion. Sci. Adv. 7, eabh4302 (2021).

[133]

Tan H, Chu CR, Payne KA, Marra KG. Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials, 2009, 30: 2499-2506.

[134]

Aguilar, A. et al. Application of chitosan in bone and dental engineering. Molecules24, 3009 (2019).

[135]

Ressler, A. Chitosan-based biomaterials for bone tissue engineering applications: a short review. Polymers14, 3430 (2022).

[136]

Rowley JA, Madlambayan G, Mooney DJ. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 1999, 20: 45-53.

[137]

Yan H, et al. . Hybrid use of combined and sequential delivery of growth factors and ultrasound stimulation in porous multilayer composite scaffolds to promote both vascularization and bone formation in bone tissue engineering. J. Biomed. Mater. Res. A, 2016, 104: 195-208.

[138]

Wong, S. K., Yee, M. M. F., Chin, K. Y. & Ima-Nirwana, S. A review of the application of natural and synthetic scaffolds in bone regeneration. J. Funct. Biomater.14, 286 (2023).

[139]

Farah S, Anderson DG, Langer R. Physical and mechanical properties of PLA, and their functions in widespread applications - a comprehensive review. Adv. Drug Deliv. Rev., 2016, 107: 367-392.

[140]

Donate R, et al. . Comparison between calcium carbonate and β-tricalcium phosphate as additives of 3D printed scaffolds with polylactic acid matrix. J. Tissue Eng. Regen. Med., 2020, 14: 272-283.

[141]

Zhang HY, et al. . Bioresorbable magnesium-reinforced PLA membrane for guided bone/tissue regeneration. J. Mech. Behav. Biomed. Mater., 2020, 112: 104061

[142]

Wu L, Ding J. In vitro degradation of three-dimensional porous poly(D,L-lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials, 2004, 25: 5821-5830.

[143]

Gentile P, Chiono V, Carmagnola I, Hatton PV. An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. Int. J. Mol. Sci., 2014, 15: 3640-3659.

[144]

Zhao D, et al. . Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioact. Mater., 2021, 6: 346-360. DOI:

[145]

Wang DX, et al. . Enhancing the bioactivity of Poly(lactic-co-glycolic acid) scaffold with a nano-hydroxyapatite coating for the treatment of segmental bone defect in a rabbit model. Int. J. Nanomed., 2013, 8: 1855-1865.

[146]

Park J, et al. . Surface modification of a three-dimensional polycaprolactone scaffold by polydopamine, biomineralization, and BMP-2 immobilization for potential bone tissue applications. Colloids Surf. B Biointerfaces, 2021, 199: 111528

[147]

Zhou H, Lee J. Nanoscale hydroxyapatite particles for bone tissue engineering. Acta Biomater., 2011, 7: 2769-2781.

[148]

Taraballi F, Bauza G, McCulloch P, Harris J, Tasciotti E. Concise review: biomimetic functionalization of biomaterials to stimulate the endogenous healing process of cartilage and bone tissue. Stem Cells Transl. Med., 2017, 6: 2186-2196.

[149]

Ielo, I., Calabrese, G., De Luca, G. & Conoci, S. Recent advances in hydroxyapatite-based biocomposites for bone tissue regeneration in orthopedics. Int. J. Mol. Sci.23, 9721 (2022).

[150]

Ebrahimi M, Botelho MG, Dorozhkin SV. Biphasic calcium phosphates bioceramics (HA/TCP): concept, physicochemical properties and the impact of standardization of study protocols in biomaterials research. Mater. Sci. Eng. C. Mater. Biol. Appl., 2017, 71: 1293-1312.

[151]

Wang Y, et al. . Enhancing bone regeneration through 3D printed biphasic calcium phosphate scaffolds featuring graded pore sizes. Bioact. Mater., 2025, 46: 21-36. DOI:

[152]

Wang Y, et al. . Targeted sub-attomole cancer biomarker detection based on phase singularity 2D nanomaterial-enhanced plasmonic biosensor. Nanomicro Lett., 2021, 13: 96

[153]

Ryu J-J, Jang C-HA. liquid crystal-based biosensor for sensitive detection of tumor necrosis factor-alpha. Mikrochim Acta, 2023, 191: 55

[154]

Cennamo N, et al. . Towards a point-of-care test to cover atto-femto and pico-nano molar concentration ranges in interleukin 6 detection exploiting PMMA-based plasmonic biosensor chips. Talanta, 2023, 256: 124284

[155]

Giorgi-Coll S, Marín MJ, Sule O, Hutchinson PJ, Carpenter KLH. Aptamer-modified gold nanoparticles for rapid aggregation-based detection of inflammation: an optical assay for interleukin-6. Microchim. Acta, 2019, 187: 13.

[156]

Wang W, et al. . A label-free fiber optic SPR biosensor for specific detection of C-reactive protein. Sci. Rep., 2017, 716904

[157]

Baek SH, et al. . Gold nanoparticle-enhanced and roll-to-roll nanoimprinted LSPR platform for detecting interleukin-10. Front. Chem., 2020, 8: 285

[158]

Chen J, et al. . Accurately tunable AuNC-ZIF content architecture based on coordination-dissociation mechanism enables highly brightness dual-site fluorescent biosensor. Adv. Sci., 2025, 12: e2408400.

[159]

Xu G, et al. . Self-assembled Gold@silver-ZIF structure-induced dual-enhancement luminescence synergized with interpretable machine learning empower precise monitoring of inflammatory homeostasis. Nano Today, 2025, 64: 102776

[160]

Herrera B, Inman GJ. A rapid and sensitive bioassay for the simultaneous measurement of multiple bone morphogenetic proteins. Identification and quantification of BMP4, BMP6 and BMP9 in bovine and human serum. BMC Cell Biol., 2009, 1020

[161]

Lian H, Wang H, Han Q, Wang C. Quantification of rhBMP2 in bioactive bone materials. Regen. Biomater., 2020, 7: 71-75.

[162]

Wojciechowski JP, et al. . A facile method to quantify synthetic peptide concentrations on biomaterials. ACS. Appl. Mater. Interfaces, 2024, 16: 49880-49888.

[163]

Li J, et al. . A fluorescence biosensor for VEGF detection based on DNA assembly structure switching and isothermal amplification. Biosens. Bioelectron., 2017, 89: 964-969.

[164]

Han, J. et al. Chaperone copolymer assisted G-quadruplex-based signal amplification assay for highly sensitive detection of VEGF. Biosensors12, 262 (2022).

[165]

Deb A, Nalkar GR, Chowdhury D. Biogenic carbon dot-based fluorescence-mediated immunosensor for the detection of disease biomarker. Anal. Chim. Acta, 2023, 1242: 340808

[166]

Zou M, Li D, Yuan R, Xiang Y. A target-responsive autonomous aptamer machine biosensor for enzyme-free and sensitive detection of protein biomarkers. J. Mater. Chem. B, 2018, 6: 4146-4150.

[167]

Kan A, Ding S, Ouyang A, Zhang N, Jiang W. Magnetic separation-assisted cluster-amplified versatile fluorescent aptasensors for the sensitive detection of target biomolecules. Analyst, 2023, 148: 5972-5979.

[168]

Xiluan Y, et al. . Chemiluminescent detection of platelet derived growth factor-BB based on sandwich label-free aptasensor and biotin–streptavidin strategy. J. Immunol. Methods, 2022, 506: 113289

[169]

Higgins E, Suh GA, Tande AJ. Enhancing diagnostics in orthopedic infections. J. Clin. Microbiol., 2022, 60: e0219621

[170]

Zhou C, et al. . One stone, three birds: one AIEgen with three colors for fast differentiation of three pathogens. Chem. Sci., 2020, 11: 4730-4740.

[171]

He S, et al. . Rapid and sensitive quantification of bacterial viability using ratiometric fluorescence sensing. Anal. Chem., 2024, 96: 11018-11025.

[172]

Zhao M, et al. . Rapid, direct, visualized and antibody-free bacterial detection with extra species identification and susceptibility evaluation capabilities. Biosens. Bioelectron., 2023, 221: 114902

[173]

Kim TH, et al. . Blood culture-free ultra-rapid antimicrobial susceptibility testing. Nature, 2024, 632: 893-902.

[174]

Trivanovic D, et al. . Immune and stem cell compartments of acetabular and femoral bone marrow in hip osteoarthritis patients. Osteoarthr. Cartil., 2022, 30: 1116-1129.

[175]

Ki M-R, Nguyen TKM, Park T-I, Park H-M, Pack SP. Biomimetic silica particles with self-loading BMP-2 knuckle epitope peptide and its delivery for bone regeneration. Pharmaceutics, 2023, 15: 1061

[176]

Chen G, et al. . Effects of surface functionalization of PLGA membranes for guided bone regeneration on proliferation and behavior of osteoblasts. J. Biomed. Mater. Res. A, 2013, 101: 44-53.

[177]

Emad M, et al. . Impact of hydroxyapatite nanoparticles on the cellular processes of stem cells derived from dental tissue sources. Cell Tissue Res., 2025, 400: 319-330.

[178]

Grgurević L, et al. . Systemic lipid metabolism dysregulation as a possible driving force of fracture non-unions?. Bioengineering, 2024, 11: 1135

[179]

Wang C, et al. . Extracellular vesicles derived from osteogenic-differentiated human bone marrow-derived mesenchymal cells rescue osteogenic ability of bone marrow-derived mesenchymal cells impaired by hypoxia. Biomedicines, 2023, 11: 2804

[180]

Pelham H, et al. . Implantable strain sensor to monitor fracture healing with standard radiography. Sci. Rep., 2017, 71489

[181]

Klosterhoff BS, et al. . Wireless sensor enables longitudinal monitoring of regenerative niche mechanics during rehabilitation that enhance bone repair. Bone, 2020, 135: 115311

[182]

Hu X, et al. . Laser direct-write sensors on carbon-fiber-reinforced poly-ether-ether-ketone for smart orthopedic implants. Adv. Sci., 2022, 9: e2105499.

[183]

Wu S, et al. . Mesopore controls the responses of blood clot-immune complex via modulating fibrin network. Adv. Sci., 2022, 9: e2103608.

[184]

Langer R. New methods of drug delivery. Science, 1990, 249: 1527-1533.

[185]

Lutolf MP, et al. . Repair of bone defects using synthetic mimetics of collagenous extracellular matrices. Nat. Biotechnol., 2003, 21: 513-518.

[186]

Gan Q, et al. . A dual-delivery system of pH-responsive chitosan-functionalized mesoporous silica nanoparticles bearing BMP-2 and dexamethasone for enhanced bone regeneration. J. Mater. Chem. B, 2015, 3: 2056-2066.

[187]

Wang X, et al. . Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration. Biomaterials, 2018, 179: 164-174.

[188]

Crasto GJ, et al. . Controlled bone formation using ultrasound-triggered release of BMP-2 from liposomes. J. Control Rel., 2016, 243: 99-108.

[189]

Kim J, et al. . In vivo evaluation of MMP sensitive high-molecular weight HA-based hydrogels for bone tissue engineering. J. Biomed. Mater. Res. A, 2010, 95: 673-681.

[190]

Hsu CW, Olabisi RM, Olmsted-Davis EA, Davis AR, West JL. Cathepsin K-sensitive poly(ethylene glycol) hydrogels for degradation in response to bone resorption. J. Biomed. Mater. Res. A, 2011, 98: 53-62.

[191]

López-Noriega A, et al. . Thermally triggered release of a pro-osteogenic peptide from a functionalized collagen-based scaffold using thermosensitive liposomes. J. Control Rel., 2014, 187: 158-166.

[192]

Reis, B., Vehlow, D., Rust, T., Kuckling, D. & Müller, M. Thermoresponsive catechol based-polyelectrolyte complex coatings for controlled release of bortezomib. Int. J. Mol. Sci.20, 6081 (2019).

[193]

Aw MS, Addai-Mensah J, Losic D. A multi-drug delivery system with sequential release using titania nanotube arrays. Chem. Commun., 2012, 48: 3348-3350.

[194]

Matsuo T, et al. . Injectable magnetic liposomes as a novel carrier of recombinant human BMP-2 for bone formation in a rat bone-defect model. J. Biomed. Mater. Res. A, 2003, 66: 747-754.

Funding

the National Key Research and Development Program of China (2022YFC2504300)

the Joint Co-construction Project of Medical Science and Technology Tackling Program in Henan Province (LHGJ20240248),and the 2024 Postdoctoral Research Initiation Grant for the First Affiliated Hospital of Zhengzhou University (72402).

the Key R&D and Promotion Projects in Henan Province of China (242102311139)

RIGHTS & PERMISSIONS

The Author(s)

PDF

38

Accesses

0

Citation

Detail

Sections
Recommended

/