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Bone Healing and Remodelling

Overview

Bone regeneration is a complex, well-orchestrated physiological process of bone formation that occurs during normal fracture healing and continues as remodelling throughout adult life [1]. In the specific context of segmental bone defects, the resulting repair tissue is predominantly trabecular bone [3]. This repair tissue possesses normal bone mineral content [3] and has gained mechanical strength [3].

Current evidence regarding growth factors accelerating fracture healing is promising [2]. However, results should be interpreted with caution until phase III, level I studies become available [2]. Developing additional measures to assess biological healing will improve reliability and permit assessment of stages of fracture healing [4]. Proper recognition of the etiology of osteoporosis is an essential step in improving bone health and preventing further bone loss [43]. The expert consensus on bone repair strategy for osteoporotic fractures in China aims to standardize clinical practice by concentrating on epidemiology, characteristics, and management strategies of common osteoporotic fractures with bone defect [6].

M2 macrophages were clearly prevalent during the ossification phase of bone fracture healing [44]. There is still no hard proof whether traumatic brain injury results in accelerated fracture healing [45]. The pathophysiological background of whether traumatic brain injury results in accelerated fracture healing remains unclarified [45]. Identification and targeted interventions for inflammatory induced bone resorption remain limited [9]. Further research is required to advance early detection and treatments for inflammatory induced bone resorption [9].

Animal data and limited scientifically robust clinical evidence in humans indicate that physicians should consider only short-term administration of COX-2 inhibitors or other drugs for pain management in patients in the phase of fracture or other bone defect healing [7]. There is no clinical evidence to support the use of PRP in the treatment of long-bone defects and nonunions [19]. The use of PRF/BMSC during the standard procedure is effective in shortening nonunion healing time [42].

How It Works

Bone repair follows specific regenerative patterns and involves changes in the expression of several thousand genes [25]. Understanding cellular and molecular pathways is critical for advancing fracture treatment and understanding skeletal growth, repair, and aging [24]. Knowledge of key pathways in bone biology can improve surgeon understanding, clinical recognition, and treatment of bone homeostasis–related diseases [10].

Mechanobiological and Computational Assessment: Computational modeling quantifies the effects of the initial healing phase on healing outcome to better understand biological and mechanobiological mechanisms for treatment strategy optimization [8]. Developing additional measures to assess biological healing will improve reliability and permit assessment of stages of fracture healing [4].

Inflammatory and Immunomodulatory Targets: Understanding the effects of standard orthopaedic interventions on local and systemic inflammatory responses and early fracture healing is important for optimizing fracture union [12]. Immunomodulation is emerging as a potential therapeutic target to improve bone fracture healing [5]. A better understanding of bone biology and osteoimmunology can help to improve evolving cell therapy-based strategies for regenerative treatments [22]. Identification and targeted interventions for inflammatory induced bone resorption remain limited, and further research is required to advance early detection and treatments [9].

Signaling Pathways and Growth Factors: The balance between signalling molecules involved in bone formation with their inhibitors, particularly between BMPs and their antagonists, is a critical determinant of osteogenesis, skeletal development, fracture repair, and bone remodelling [21]. New insights into TGFβ/BMP signaling on bone will open new prospects for generating novel therapies against clinical disorders [23]. Current evidence of growth factors accelerating fracture healing is promising, but results should be interpreted with caution until phase III, level I studies become available [2]. The combined action of low-dose FGF-2 and BMP-2 increases the speed and extent of bone healing and may be a solution to current problems with high-dose BMP-2 [13].

Clinical Modalities and Defect Repair: Prospective, randomised, double-blind, placebo-controlled trials demonstrate the clinical efficacy of ultrasound in accelerating fracture healing [11]. In segmental bone defect repair, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength [3]. Drilled hole defects in mouse femur models enable experimental genetics studies to investigate cellular and molecular mechanisms of spontaneous cortical and cancellous bone repair [20].

Stress Fracture Pathophysiology: Stress fractures arise when bone stresses exceed the capacity of bone to withstand and heal from those stresses, resulting from either excessive bone strain with microdamage accumulation or depressed bony remodeling in response to normal strain [26].

What the Evidence Shows

Bone remodeling is regulated by mechanisms that are currently understood and outlined in existing reviews [14]. Hypoxia can modify bone remodeling, although clinical studies have shown contradictory results [37].

Growth Factors and Proteins: Current evidence suggests growth factors may accelerate fracture healing, but results require cautious interpretation until phase III, level I studies are available [2]. Recombinant human bone morphogenetic protein-2 (rhBMP-2) accelerates healing in a rabbit ulnar osteotomy model, with treated sites healing approximately 33% faster than untreated or buffer-treated sites and exhibiting mechanical properties up to twofold greater at three and four weeks [35]. The combined action of low-dose fibroblast growth factor-2 (FGF-2) and BMP-2 increases the speed and extent of bone healing, potentially addressing problems associated with high-dose BMP-2 [13].

Cellular and Tissue Engineering Therapies: Bone grafting enhances bone regeneration and fracture healing through osteoconductive, osteoinductive, and osteogenic capacities [34]. Tissue engineering is a developing option intended to reduce the limitations of bone grafts and improve the healing processes of bone fractures and defects [15]. Cell therapy holds promise as an alternative to autologous bone grafting for promoting bone repair, aiming to avoid drawbacks such as donor-site morbidity and loss of bone stock [16]. Evidence for bone healing shows promising results for mesenchymal stem cells (MSCs) and BMP in the treatment of non-unions [38]. There is no clinical evidence to support the use of platelet-rich plasma (PRP) in the treatment of long-bone defects and nonunions [19].

Gene Therapy: Local and regional gene therapy has improved healing in preclinical trials of articular and other musculoskeletal conditions [36]. Direct percutaneous gene delivery to enhance healing of segmental bone defects results in repair tissue that is predominantly trabecular bone with normal bone mineral content and gained mechanical strength [3].

Adjunctive Modalities: The combinatory use of PRP and hyperbaric oxygen (HBO) resulted in increased bone regeneration and neovascularization compared to other groups in preclinical settings [41]. Prospective, randomised, double-blind, placebo-controlled trials demonstrate the clinical efficacy of ultrasound in accelerating fracture healing [11]. In the surgical treatment of stable knee osteochondritis dissecans (OCD) lesions, bone stimulator use did not appear to improve radiographic or clinical healing [39].

Immunomodulation and Pharmacology: Immunomodulation is emerging as a potential therapeutic target to improve bone fracture healing due to the role of immune cells [5]. Understanding the effects of standard orthopaedic interventions on local and systemic inflammatory responses and early fracture healing is important for optimizing fracture union [12]. Short-term administration of COX-2 inhibitors or other NSAIDs is indicated for pain management in patients in the phase of fracture or other bone defect healing, based on animal data and limited clinical evidence [7]. The balance of evidence suggests that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control without a significantly increased risk of sequelae related to disrupted healing [17].

Assessment, Modeling, and Comorbidities: Computational modeling has quantified the effects of the initial healing phase on healing outcome to better understand biological and mechanobiological mechanisms for treatment optimization [8]. Developing additional measures to assess biological healing will improve reliability and permit assessment of stages of fracture healing [4]. Latest techniques for evaluating bone healing during distraction osteogenesis provide novel information for future evaluation [47]. Type 2 diabetes mellitus (T2DM) influences factors that impair bone fracture healing [46].

Clinical Contexts: Standardizing clinical practice in bone repair of osteoporotic fractures involves concentrating on epidemiology, characteristics, and management strategies of common osteoporotic fractures with bone defect [6]. Molecular mechanisms, clinical evidence, and potential adverse effects of drugs used or under development for osteoporosis treatment aid clinicians in selecting the best treatment option [18]. Improvement of graft healing to bone is crucial for facilitating early and aggressive rehabilitation and ensuring rapid return to pre-injury levels of activity in anterior cruciate ligament reconstruction [40].

Practical Considerations

Knowledge of key pathways in bone biology can improve surgeon understanding, clinical recognition, and treatment of bone homeostasis–related diseases [10]. Tissue engineering is a new and developing option introduced to reduce limitations of bone grafts and improve the healing processes of bone fractures and defects [15]. Cell therapy holds promise as an alternative to autologous bone grafting for promoting bone repair, avoiding drawbacks such as donor-site morbidity and loss of bone stock [16]. Direct percutaneous gene delivery for segmental bone defects results in repair tissue that is predominantly trabecular bone with normal bone mineral content and gained mechanical strength [3].

Biologic Reconstructions: Viable bone autograft can provide more durable long-term reconstructions and growing reconstructions in the pediatric population at the expense of high short-term complication rates and donor-site morbidity [28]. Immunomodulation: Emerging as a potential therapeutic target to improve bone fracture healing [5]. Assessment: Developing additional measures to assess biological healing is needed to improve reliability and permit assessment of fracture healing stages [4].

Pharmacologic Management: Physicians should consider only short-term administration of COX-2 inhibitors or other NSAIDs for pain management in patients in the phase of fracture or other bone defect healing, due to limited scientifically robust clinical evidence in humans [7]. The balance of evidence suggests that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing [17]. Osteoporosis Management: Reviews provide overviews of molecular mechanisms, clinical evidence, and potential adverse effects of drugs currently used or under development for the treatment of osteoporosis to aid clinicians in selecting the best treatment option [18]. Increasing physician awareness of medication-induced osteoporosis side effects will allow for monitoring of bone health and therapeutic interventions to prevent or treat drug-induced osteoporosis [32]. Expert consensus aims to standardize clinical practice in bone repair of osteoporotic fractures by concentrating on epidemiology, characteristics, and management strategies of common osteoporotic fractures with bone defect [6].

Growth Factors and BMPs: Current evidence regarding growth factors accelerating fracture healing is promising, but results require cautious interpretation until phase III, level I studies become available [2]. The major constraints for routine use of BMP are inadequate clinical trials in humans and the need to comprehensively assess the cost-effectiveness and budget impact of BMP [30]. Distraction Osteogenesis: Well-designed clinical studies are needed to establish safe and effective guidelines for various modalities to enhance new bone formation during distraction osteogenesis in children [31]. Alternative Surfaces: Clinical results for alternative bearing surfaces are currently only short- to mid-term, and factors such as brittle fracture and high cost must be considered [27].

Osteolysis Management: Management of osteolysis progression after total knee arthroplasty requires a global assessment of the character and progression of the osteolysis weighed against patient-specific risk factors to determine if surgery or continued radiographic surveillance is indicated [29]. There is a clinical need for continued advances in bone engineering to address deficits in treating bone loss from trauma, tumors, and arthritis [33].

Key Evidence

  • [L4] Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. (10.1186/1741-7015-9-66)
  • [L5] Current evidence of growth factors accelerating fracture healing is promising, but results should be interpreted with caution until phase III, level I studies become available. (10.1016/j.injury.2007.02.013)
  • [L5] At this time, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength. (10.2106/jbjs.e.00464)
  • [L5] In the future, developing additional measures to assess biological healing will improve the reliability and permit us to assess stages of fracture healing. (10.1016/j.injury.2014.04.003)
  • [L5] Owing to these efforts, immunomodulation is emerging as a potential therapeutic target to improve bone fracture healing. (10.1007/s11914-018-0423-2)
  • [L5] The consensus aims to standardize clinical practice in bone repair of osteoporotic fractures by concentrating on epidemiology, characteristics, and management strategies of common osteoporotic fractures with bone defect. (10.3389/fendo.2022.989648)
  • [L4] These animal data, together with the view of limited scientifically robust clinical evidence in humans, indicate that physicians consider only short-term administration of COX-2 inhibitors or other drugs in the pain management of patients who are in the phase of fracture or other bone defect healing. (10.1097/bor.0b013e32836200b8)
  • [L5] Findings quantified the effects of the initial healing phase on healing outcome to better understand the biological and mechanobiological mechanisms and their utilization in the design and optimization of treatment strategies. (10.1186/s12891-019-2854-z)
  • [L5] Identification and targeted interventions for inflammatory induced bone resorption remain limited, and further research is required to advance early detection and treatments. (10.3389/fphys.2020.511799)
  • [L5] Knowledge of key pathways in bone biology can improve surgeon understanding, clinical recognition, and treatment of bone homeostasis–related diseases. (10.5435/jaaos-d-23-00164)
  • [L1] Prospective, randomised, double-blind, placebo-controlled trials demonstrate its clinical efficacy in accelerating fracture healing. (10.1016/j.injury.2008.01.015)
  • [L5] Understanding the effects of standard orthopaedic interventions on the local and systemic inflammatory responses and early fracture healing is important for optimizing fracture union. (10.5435/jaaos-d-16-00646)
  • [L5] The combined action of low-dose FGF-2 and BMP-2 increases the speed and extent of bone healing and may be a solution to the current problems with high-dose BMP-2. (10.5435/jaaos-22-10-677)
  • [Paper] This review outlines the current understanding of bone remodeling and its regulation. (10.1196/annals.1365.035)
  • [L4] Tissue engineering is a new and developing option introduced to reduce limitations of bone grafts and improve the healing processes of bone fractures and defects. (10.1186/1749-799X-9-18)
  • [L4] Cell therapy holds promise as an alternative to autologous bone grafting for promoting bone repair, avoiding drawbacks such as donor-site morbidity and loss of bone stock. (10.1016/j.otsr.2013.11.010)
  • [L4] The balance of evidence suggests that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing. (10.2106/jbjs.j.01743)
  • [L4] This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs currently used or under development for the treatment of osteoporosis to aid clinicians in selecting the best treatment option. (10.3390/ijms20102557)
  • [L3] There is no clinical evidence to support the use of PRP in the treatment of long-bone defects and nonunions. (10.1016/j.injury.2007.02.009)
  • [L5] These models enable experimental genetics studies to investigate the cellular and molecular mechanisms of spontaneous cortical and cancellous bone repair and may be useful for pharmacological studies. (10.1007/s00223-009-9314-y)
  • [Paper] The balance between signalling molecules involved in bone formation with their inhibitors, particularly between BMPs and their antagonists, is a critical determinant of osteogenesis, skeletal development, fracture repair, and bone remodelling. (10.1016/j.injury.2006.02.039)
  • [Paper] A better understanding of bone biology and osteoimmunology can help to improve evolving cell therapy-based strategies for regenerative treatments. (10.1016/j.injury.2016.10.008)
  • [L5] These new insights into TGFβ/BMP signaling on bone will open new prospects for generating novel therapies against clinical disorders. (10.7150/ijbs.2929)
  • [Paper] Understanding these cellular and molecular pathways is critical for advancing fracture treatment and understanding skeletal growth, repair, and aging. (10.1016/j.injury.2005.07.019)
  • [L5] The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. (10.1016/j.injury.2011.03.031)
  • [Paper] Stress fractures arise when bone stresses exceed the capacity of bone to withstand and heal from those stresses, resulting from either excessive bone strain with microdamage accumulation or depressed bony remodeling in response to normal strain. (10.1016/j.csm.2005.08.010)
  • [L4] However, clinical results are currently only short- to mid-term, and factors such as brittle fracture and high cost must be considered. (10.5435/00124635-199807000-00001)
  • [L5] Biologic reconstructions with viable bone autograft can provide more durable long-term reconstructions and growing reconstructions in the pediatric population at the expense of high short-term complication rates and donor-site morbidity. (10.5435/jaaos-d-25-00228)
  • [L5] Management requires a global assessment of the character and progression of the osteolysis weighed against patient-specific risk factors to determine if surgery or continued radiographic surveillance is indicated. (10.5435/jaaos-d-13-00189)
  • [L5] The major constraints for routine use of BMP are inadequate clinical trials in humans and the need to comprehensively assess the cost-effectiveness and budget impact of BMP. (10.1016/j.injury.2006.12.012)
  • [L5] Well-designed clinical studies are needed to establish safe and effective guidelines for various modalities to enhance new bone formation during distraction osteogenesis in children. (10.5435/00124635-201102000-00005)
  • [L5] Increasing physician awareness of these side effects will allow for monitoring of bone health and therapeutic interventions to prevent or treat drug-induced osteoporosis. (10.1177/1759720x14546350)
  • [L5] The paper emphasizes the clinical need for continued advances in bone engineering to address deficits in treating bone loss from trauma, tumors, and arthritis. (10.1243/09544119jeim770)
  • [L5] Bone grafting enhances bone regeneration and fracture healing through osteoconductive, osteoinductive, and osteogenic capacities. (10.1530/eor-24-0032)
  • [L5] Osteotomy sites treated with rhBMP-2 healed approximately 33% faster than did osteotomy sites either treated with buffer or left untreated, with mechanical properties as much as twofold greater at three and four weeks. (10.2106/00004623-200108000-00012)
  • [L5] Local and regional gene therapy has improved healing in preclinical trials of articular and other musculoskeletal conditions. (10.1196/annals.1402.065)
  • [L4] Clinical studies, although with contradictory results, have shown that hypoxia can modify bone remodeling. (10.3390/ijms23063233)
  • [L4] The evidence for bone healing shows promising results, particularly for MSCs and BMP in the treatment of non-unions. (10.1177/17531934251327034)
  • [L3] In the surgical treatment of stable knee OCD lesions, bone stimulator use did not appear to improve radiographic or clinical healing. (10.1177/2325967120s00178)
  • [L4] Improvement of graft healing to bone is crucial for facilitating an early and aggressive rehabilitation and ensuring rapid return to pre-injury levels activity. (10.1186/1758-2555-1-21)
  • [L5] Combinatory use of PRP and HBO resulted in increased bone regeneration and neovascularization compared to all other groups. (10.1016/j.injury.2016.09.039)
  • [L3] This study supports the concept that the use of PRF/BMSC, during the standard procedure, is effective in shortening nonunion healing time. (10.1016/j.injury.2016.09.021)
  • [L4] Proper recognition of the etiology of osteoporosis is an essential step in improving bone health and preventing further bone loss. (10.3390/jcm11092382)
  • [L5] M2 macrophages were clearly prevalent during the ossification phase. (10.1016/j.bone.2015.10.019)
  • [L4] Despite numerous studies over the last 3 decades, there is still no hard proof whether traumatic brain injury results in accelerated fracture healing, and the pathophysiological background remains unclarified. (10.1155/2015/204842)
  • [L4] This review synthesizes current knowledge on the factors influencing the impairment of bone fracture healing under Type 2 Diabetes Mellitus (T2DM) conditions. (10.3389/fendo.2018.00006)
  • [L4] This review comprehensively summarizes the latest techniques for evaluating bone healing during distraction osteogenesis, providing novel and significant information for evaluating bone healing in the future. (10.1186/s12891-022-05458-8)

References

[1] Bone regeneration: current concepts and future directions. BMC Medicine. 2011. DOI: 10.1186/1741-7015-9-66

[2] Can we accelerate fracture healing?. Injury. 2007. DOI: 10.1016/j.injury.2007.02.013

[3] Direct Percutaneous Gene Delivery to Enhance Healing of Segmental Bone Defects. The Journal of Bone & Joint Surgery. 2006. DOI: 10.2106/jbjs.e.00464

[4] Biological perspectives of delayed fracture healing. Injury. 2014. DOI: 10.1016/j.injury.2014.04.003

[5] The Role of the Immune Cells in Fracture Healing. Current Osteoporosis Reports. 2018. DOI: 10.1007/s11914-018-0423-2

[6] Expert consensus on the bone repair strategy for osteoporotic fractures in China. Frontiers in Endocrinology. 2022. DOI: 10.3389/fendo.2022.989648

[7] NSAIDs and fracture healing. Current Opinion in Rheumatology. 2013. DOI: 10.1097/bor.0b013e32836200b8

[8] Computational modeling of human bone fracture healing affected by different conditions of initial healing stage. BMC Musculoskeletal Disorders. 2019. DOI: 10.1186/s12891-019-2854-z

[9] The Effect of Inflammation on Bone. Frontiers in Physiology. 2021. DOI: 10.3389/fphys.2020.511799

[10] Bone Homeostasis and Physiology in Normal and Orthopaedic Disease Conditions. Journal of the American Academy of Orthopaedic Surgeons. 2023. DOI: 10.5435/jaaos-d-23-00164

[11] External adjuncts to enhance fracture healing: What is the role of ultrasound?. Injury. 2008. DOI: 10.1016/j.injury.2008.01.015

[12] Osteoimmunology: Effects of Standard Orthopaedic Interventions on Inflammatory Response and Early Fracture Healing. Journal of the American Academy of Orthopaedic Surgeons. 2018. DOI: 10.5435/jaaos-d-16-00646

[13] Optimizing BMP-2-induced bone repair with FGF-2. Journal of the American Academy of Orthopaedic Surgeons. 2014. DOI: 10.5435/jaaos-22-10-677

[14] Bone Remodeling. Annals of the New York Academy of Sciences. 2006. DOI: 10.1196/annals.1365.035

[15] Bone regenerative medicine: classic options, novel strategies, and future directions. Journal of Orthopaedic Surgery and Research. 2014. DOI: 10.1186/1749-799X-9-18

[16] Cell therapy for bone repair. Orthopaedics & Traumatology: Surgery & Research. 2014. DOI: 10.1016/j.otsr.2013.11.010

[17] The Effect of Nonsteroidal Anti-Inflammatory Drug Administration on Acute Phase Fracture-Healing: A Review. Journal of Bone and Joint Surgery. 2012. DOI: 10.2106/jbjs.j.01743

[18] Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review. International Journal of Molecular Sciences. 2019. DOI: 10.3390/ijms20102557

[19] Growth factors — BMPs, DBMs, and buffy coat products: are there any proven differences amongst them?. Injury. 2007. DOI: 10.1016/j.injury.2007.02.009

[20] Drilled Hole Defects in Mouse Femur as Models of Intramembranous Cortical and Cancellous Bone Regeneration. Calcified Tissue International. 2009. DOI: 10.1007/s00223-009-9314-y

[21] The role of inhibitory molecules in fracture healing. Injury. 2006. DOI: 10.1016/j.injury.2006.02.039

[22] The roles of immune cells in bone healing; what we know, do not know and future perspectives. Injury. 2016. DOI: 10.1016/j.injury.2016.10.008

[23] TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation. International Journal of Biological Sciences. 2012. DOI: 10.7150/ijbs.2929

[24] Current concepts of molecular aspects of bone healing. Injury. 2005. DOI: 10.1016/j.injury.2005.07.019

[25] The biology of fracture healing. Injury. 2011. DOI: 10.1016/j.injury.2011.03.031

[26] The Pathophysiology of Stress Fractures. Clinics in Sports Medicine. 2006. DOI: 10.1016/j.csm.2005.08.010

[27] Alternative Bearing Surfaces for Total Joint Arthroplasty. Journal of the American Academy of Orthopaedic Surgeons. 1998. DOI: 10.5435/00124635-199807000-00001

[28] Autograft and Biologic Living Bone Reconstructions in Orthopaedic Oncology. Journal of the American Academy of Orthopaedic Surgeons. 2025. DOI: 10.5435/jaaos-d-25-00228

[29] Evaluating the Progression of Osteolysis After Total Knee Arthroplasty. Journal of the American Academy of Orthopaedic Surgeons. 2015. DOI: 10.5435/jaaos-d-13-00189

[30] Bone morphogenic protein and its application in trauma cases: A current concept update. Injury. 2007. DOI: 10.1016/j.injury.2006.12.012

[31] Enhancement of Bone Formation During Distraction Osteogenesis: Pediatric Applications. Journal of the American Academy of Orthopaedic Surgeons. 2011. DOI: 10.5435/00124635-201102000-00005

[32] Medication-induced osteoporosis: screening and treatment strategies. Therapeutic Advances in Musculoskeletal Disease. 2014. DOI: 10.1177/1759720x14546350

[33] Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine. 2010. DOI: 10.1243/09544119jeim770

[34] Long bone uninfected non-union: grafting techniques. EFORT Open Reviews. 2024. DOI: 10.1530/eor-24-0032

[35] Recombinant Human Bone Morphogenetic Protein-2 Accelerates Healing in a Rabbit Ulnar Osteotomy Model. The Journal of Bone and Joint Surgery-American Volume. 2001. DOI: 10.2106/00004623-200108000-00012

[36] Gene Therapy in Musculoskeletal Repair. Annals of the New York Academy of Sciences. 2007. DOI: 10.1196/annals.1402.065

[37] Molecular Mechanisms Involved in Hypoxia-Induced Alterations in Bone Remodeling. International Journal of Molecular Sciences. 2022. DOI: 10.3390/ijms23063233

[38] The role of orthobiologics in bone healing and joint and tendon degeneration in the upper limb. Journal of Hand Surgery (European Volume). 2025. DOI: 10.1177/17531934251327034

[39] ADJUVANT TREATMENT OF OCD LESIONS OF THE KNEE WITH BONE STIMULATORS. Orthopaedic Journal of Sports Medicine. 2020. DOI: 10.1177/2325967120s00178

[40] Graft healing in anterior cruciate ligament reconstruction. BMC Sports Science, Medicine and Rehabilitation. 2009. DOI: 10.1186/1758-2555-1-21

[41] Synergistic effects of HBO and PRP improve bone regeneration with autologous bone grafting. Injury. 2016. DOI: 10.1016/j.injury.2016.09.039

[42] Radiological assessment of the PRF/BMSC efficacy in the treatment of aseptic nonunions: A retrospective study on 90 subjects. Injury. 2016. DOI: 10.1016/j.injury.2016.09.021

[43] Secondary Osteoporosis and Metabolic Bone Diseases. Journal of Clinical Medicine. 2022. DOI: 10.3390/jcm11092382

[44] Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone. 2018. DOI: 10.1016/j.bone.2015.10.019

[45] Improved Fracture Healing in Patients with Concomitant Traumatic Brain Injury: Proven or Not?. Mediators of Inflammation. 2015. DOI: 10.1155/2015/204842

[46] The Impact of Type 2 Diabetes on Bone Fracture Healing. Frontiers in Endocrinology. 2018. DOI: 10.3389/fendo.2018.00006

[47] The progress in quantitative evaluation of callus during distraction osteogenesis. BMC Musculoskeletal Disorders. 2022. DOI: 10.1186/s12891-022-05458-8

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i. NonCommercial means not primarily intended for or directed towards commercial advantage or monetary compensation. For purposes of this Public License, the exchange of the Licensed Material for other material subject to Copyright and Similar Rights by digital file-sharing or similar means is NonCommercial provided there is no payment of monetary compensation in connection with the exchange.

j. Share means to provide material to the public by any means or process that requires permission under the Licensed Rights, such as reproduction, public display, public performance, distribution, dissemination, communication, or importation, and to make material available to the public including in ways that members of the public may access the material from a place and at a time individually chosen by them.

k. Sui Generis Database Rights means rights other than copyright resulting from Directive 96/9/EC of the European Parliament and of the Council of 11 March 1996 on the legal protection of databases, as amended and/or succeeded, as well as other essentially equivalent rights anywhere in the world.

l. You means the individual or entity exercising the Licensed Rights under this Public License. Your has a corresponding meaning.

Section 2 -- Scope.

a. License grant.

1. Subject to the terms and conditions of this Public License, the Licensor hereby grants You a worldwide, royalty-free, non-sublicensable, non-exclusive, irrevocable license to exercise the Licensed Rights in the Licensed Material to:

a. reproduce and Share the Licensed Material, in whole or in part, for NonCommercial purposes only; and

b. produce, reproduce, and Share Adapted Material for NonCommercial purposes only.

2. Exceptions and Limitations. For the avoidance of doubt, where Exceptions and Limitations apply to Your use, this Public License does not apply, and You do not need to comply with its terms and conditions.

3. Term. The term of this Public License is specified in Section 6(a).

4. Media and formats; technical modifications allowed. The Licensor authorizes You to exercise the Licensed Rights in all media and formats whether now known or hereafter created, and to make technical modifications necessary to do so. The Licensor waives and/or agrees not to assert any right or authority to forbid You from making technical modifications necessary to exercise the Licensed Rights, including technical modifications necessary to circumvent Effective Technological Measures. For purposes of this Public License, simply making modifications authorized by this Section 2(a) (4) never produces Adapted Material.

5. Downstream recipients.

a. Offer from the Licensor -- Licensed Material. Every recipient of the Licensed Material automatically receives an offer from the Licensor to exercise the Licensed Rights under the terms and conditions of this Public License.

b. No downstream restrictions. You may not offer or impose any additional or different terms or conditions on, or apply any Effective Technological Measures to, the Licensed Material if doing so restricts exercise of the Licensed Rights by any recipient of the Licensed Material.

6. No endorsement. Nothing in this Public License constitutes or may be construed as permission to assert or imply that You are, or that Your use of the Licensed Material is, connected with, or sponsored, endorsed, or granted official status by, the Licensor or others designated to receive attribution as provided in Section 3(a)(1)(A)(i).

b. Other rights.

1. Moral rights, such as the right of integrity, are not licensed under this Public License, nor are publicity, privacy, and/or other similar personality rights; however, to the extent possible, the Licensor waives and/or agrees not to assert any such rights held by the Licensor to the limited extent necessary to allow You to exercise the Licensed Rights, but not otherwise.

2. Patent and trademark rights are not licensed under this Public License.

3. To the extent possible, the Licensor waives any right to collect royalties from You for the exercise of the Licensed Rights, whether directly or through a collecting society under any voluntary or waivable statutory or compulsory licensing scheme. In all other cases the Licensor expressly reserves any right to collect such royalties, including when the Licensed Material is used other than for NonCommercial purposes.

Section 3 -- License Conditions.

Your exercise of the Licensed Rights is expressly made subject to the following conditions.

a. Attribution.

1. If You Share the Licensed Material (including in modified form), You must:

a. retain the following if it is supplied by the Licensor with the Licensed Material:

i. identification of the creator(s) of the Licensed Material and any others designated to receive attribution, in any reasonable manner requested by the Licensor (including by pseudonym if designated);

ii. a copyright notice;

iii. a notice that refers to this Public License;

iv. a notice that refers to the disclaimer of warranties;

v. a URI or hyperlink to the Licensed Material to the extent reasonably practicable;

b. indicate if You modified the Licensed Material and retain an indication of any previous modifications; and

c. indicate the Licensed Material is licensed under this Public License, and include the text of, or the URI or hyperlink to, this Public License.

2. You may satisfy the conditions in Section 3(a)(1) in any reasonable manner based on the medium, means, and context in which You Share the Licensed Material. For example, it may be reasonable to satisfy the conditions by providing a URI or hyperlink to a resource that includes the required information.

3. If requested by the Licensor, You must remove any of the information required by Section 3(a)(1)(A) to the extent reasonably practicable.

4. If You Share Adapted Material You produce, the Adapter's License You apply must not prevent recipients of the Adapted Material from complying with this Public License.

Section 4 -- Sui Generis Database Rights.

Where the Licensed Rights include Sui Generis Database Rights that apply to Your use of the Licensed Material:

a. for the avoidance of doubt, Section 2(a)(1) grants You the right to extract, reuse, reproduce, and Share all or a substantial portion of the contents of the database for NonCommercial purposes only;

b. if You include all or a substantial portion of the database contents in a database in which You have Sui Generis Database Rights, then the database in which You have Sui Generis Database Rights (but not its individual contents) is Adapted Material; and

c. You must comply with the conditions in Section 3(a) if You Share all or a substantial portion of the contents of the database.

For the avoidance of doubt, this Section 4 supplements and does not replace Your obligations under this Public License where the Licensed Rights include other Copyright and Similar Rights.

Section 5 -- Disclaimer of Warranties and Limitation of Liability.

a. UNLESS OTHERWISE SEPARATELY UNDERTAKEN BY THE LICENSOR, TO THE EXTENT POSSIBLE, THE LICENSOR OFFERS THE LICENSED MATERIAL AS-IS AND AS-AVAILABLE, AND MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND CONCERNING THE LICENSED MATERIAL, WHETHER EXPRESS, IMPLIED, STATUTORY, OR OTHER. THIS INCLUDES, WITHOUT LIMITATION, WARRANTIES OF TITLE, MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT, ABSENCE OF LATENT OR OTHER DEFECTS, ACCURACY, OR THE PRESENCE OR ABSENCE OF ERRORS, WHETHER OR NOT KNOWN OR DISCOVERABLE. WHERE DISCLAIMERS OF WARRANTIES ARE NOT ALLOWED IN FULL OR IN PART, THIS DISCLAIMER MAY NOT APPLY TO YOU.

b. TO THE EXTENT POSSIBLE, IN NO EVENT WILL THE LICENSOR BE LIABLE TO YOU ON ANY LEGAL THEORY (INCLUDING, WITHOUT LIMITATION, NEGLIGENCE) OR OTHERWISE FOR ANY DIRECT, SPECIAL, INDIRECT, INCIDENTAL, CONSEQUENTIAL, PUNITIVE, EXEMPLARY, OR OTHER LOSSES, COSTS, EXPENSES, OR DAMAGES ARISING OUT OF THIS PUBLIC LICENSE OR USE OF THE LICENSED MATERIAL, EVEN IF THE LICENSOR HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH LOSSES, COSTS, EXPENSES, OR DAMAGES. WHERE A LIMITATION OF LIABILITY IS NOT ALLOWED IN FULL OR IN PART, THIS LIMITATION MAY NOT APPLY TO YOU.

c. The disclaimer of warranties and limitation of liability provided above shall be interpreted in a manner that, to the extent possible, most closely approximates an absolute disclaimer and waiver of all liability.

Section 6 -- Term and Termination.

a. This Public License applies for the term of the Copyright and Similar Rights licensed here. However, if You fail to comply with this Public License, then Your rights under this Public License terminate automatically.

b. Where Your right to use the Licensed Material has terminated under Section 6(a), it reinstates:

1. automatically as of the date the violation is cured, provided it is cured within 30 days of Your discovery of the violation; or

2. upon express reinstatement by the Licensor.

For the avoidance of doubt, this Section 6(b) does not affect any right the Licensor may have to seek remedies for Your violations of this Public License.

c. For the avoidance of doubt, the Licensor may also offer the Licensed Material under separate terms or conditions or stop distributing the Licensed Material at any time; however, doing so will not terminate this Public License.

d. Sections 1, 5, 6, 7, and 8 survive termination of this Public License.

Section 7 -- Other Terms and Conditions.

a. The Licensor shall not be bound by any additional or different terms or conditions communicated by You unless expressly agreed.

b. Any arrangements, understandings, or agreements regarding the Licensed Material not stated herein are separate from and independent of the terms and conditions of this Public License.

Section 8 -- Interpretation.

a. For the avoidance of doubt, this Public License does not, and shall not be interpreted to, reduce, limit, restrict, or impose conditions on any use of the Licensed Material that could lawfully be made without permission under this Public License.

b. To the extent possible, if any provision of this Public License is deemed unenforceable, it shall be automatically reformed to the minimum extent necessary to make it enforceable. If the provision cannot be reformed, it shall be severed from this Public License without affecting the enforceability of the remaining terms and conditions.

c. No term or condition of this Public License will be waived and no failure to comply consented to unless expressly agreed to by the Licensor.

d. Nothing in this Public License constitutes or may be interpreted as a limitation upon, or waiver of, any privileges and immunities that apply to the Licensor or You, including from the legal processes of any jurisdiction or authority.

Creative Commons is not a party to its public licenses. Notwithstanding, Creative Commons may elect to apply one of its public licenses to material it publishes and in those instances will be considered the “Licensor.” The text of the Creative Commons public licenses is dedicated to the public domain under the CC0 Public Domain Dedication. Except for the limited purpose of indicating that material is shared under a Creative Commons public license or as otherwise permitted by the Creative Commons policies published at creativecommons.org/policies, Creative Commons does not authorize the use of the trademark "Creative Commons" or any other trademark or logo of Creative Commons without its prior written consent including, without limitation, in connection with any unauthorized modifications to any of its public licenses or any other arrangements, understandings, or agreements concerning use of licensed material. For the avoidance of doubt, this paragraph does not form part of the public licenses.

Creative Commons may be contacted at creativecommons.org.