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Wound Healing and Scar Biology

45 citationsUpdated Sep 2026
Illustration: Wound Healing and Scar Biology

Overview

No single mechanism fully accounts for the development of hypertrophic scars or their eventual spontaneous resolution [1]. A pivotal difference between normal and hypertrophic scars may be a lack or late induction of myofibroblast apoptotic cell death [5]. Specific TGFβ isoforms and downstream mediators determine the balance between scar formation and tissue regeneration, where inhibition of the canonical signalling pathway blocks regeneration [2]. While insights from the past 5 to 10 years hold out hope that rational, drug-based treatments may one day replace invasive surgery and other physical treatments [1], research supporting some techniques within scar management programmes remains limited, with anecdotal evidence and clinical experience continuing to prevail in the choice of treatment [12].

Optimal wound healing requires adequate nutrition, as deficiencies impede the normal processes that allow progression through stages of repair [8]. Depletion of macrophages restricted to the early stage of the repair response significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimized scar formation [6]. An altered immune response following burn and thoracic trauma is associated with a reduced capacity for wound healing [3]. Molecular cascades of cytokines and erstwhile factors are responsible for delayed wound healing in diabetic wounds [16]. FGF gene expression is associated with improved patient-reported outcome after Achilles tendon repair and may be used as a predictor for healing [11].

Wound management is a significant healthcare and financial burden requiring a multidisciplinary approach, necessitating that orthopaedic surgeons be familiar with fundamental principles and evidenced-based concepts for managing acute and chronic wounds to optimize outcomes [27]. Closed incision negative-pressure wound therapy (ciNPWT) has been shown to be clinically effective for incisions at high risk for perioperative complications, though specific indications continue to be defined [30]. Negative pressure wound therapy (NPWT) provides effective temporary wound coverage but does not allow a delay in definitive free-flap reconstruction [45]. A clear wound healing goal must be determined for negative pressure wound therapy, and discontinuation should be considered if no improvement is observed between two consecutive dressing changes or after 1 week of treatment [9]. Acute, high-dose systemic corticosteroid use likely has no clinically significant effect on wound healing, whereas chronic systemic steroids may impair wound healing in susceptible individuals [10]. The clinical effects of new antineoplastic agents on wound healing are complex and uncertain, with available recommendations based on database opinions and case reports [20]. Data are lacking to allow definitive conclusions on the use of tissue engineered biological augmentation for routine management of tendon ailments [46].

How It Works

Molecular and Cellular Mechanisms

No single mechanism accounts for the development of hypertrophic scars or their eventual spontaneous resolution [1]. Hypertrophic scarring and contractures arise from deep burns that take longer to heal, characterized by a dysregulated wound healing process involving altered extracellular matrix composition and profibrotic cytokine signaling [15]. Understanding these underlying biologic mechanisms, including the roles of cytokines like TGF-beta and CTGF, allows hand surgeons to better address these issues [14]. Inhibition of the canonical TGFβ signalling pathway blocks regeneration [2]. FOXOs are involved in maintaining the balance between oxidative stress and antioxidants, making them an important therapeutic target to enhance wound healing in diabetes and to avoid over scarring [24]. Platelets secrete growth factors and active metabolites that have a positive influence in clinical situations requiring rapid healing and tissue regeneration [17]. FGF gene expression is associated with improved patient-reported outcome and may be used as a predictor for healing after Achilles tendon repair [11].

Immune Response and Inflammation

Wound healing is a complex biological process where the immune system recognizes and combats antigens, participates in debridement, and contributes to tissue repair through innate and adaptive responses [22]. An altered immune response following burn and thoracic trauma was associated with a reduced capacity for wound healing [3]. Depletion of macrophages restricted to the early stage of the repair response significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimized scar formation [6]. Smoking has a transient effect on the tissue microenvironment and a prolonged effect on inflammatory and reparative cell functions leading to delayed healing and complications [34].

Systemic Factors and Comorbidities

Molecular cascades of cytokines and other factors are responsible for delayed wound healing in diabetic wounds [16]. Excisional wound healing is delayed in a murine model of chronic kidney disease [25]. Acute, high-dose systemic corticosteroid use likely has no clinically significant effect on wound healing, whereas chronic systemic steroids may impair wound healing in susceptible individuals [10].

Tissue-Specific Healing and Interventions

While basic science reports have identified various growth factors for flexor tendon wound healing, their clinical relevance for the practicing hand surgeon remains unclear [13]. Despite a substantial biologic response, the administration of basic fibroblast growth factor failed to produce improvements in either the mechanical or functional properties of the repair in a canine model of intrasynovial flexor tendon healing [23]. Tendon-to-bone healing in a rat model was dominated by scar formation, preventing any positive effects of the implanted biomimetic scaffold [26]. Ultrasound appears to improve some structural properties and to modestly increase scar crosssectional area and type I collagen present at 6 weeks after injury in a rabbit model of medial collateral ligament healing [18]. A clear wound healing goal must be determined for negative pressure wound therapy, and if no improvement is observed between two consecutive dressing changes or after 1 week of treatment, discontinuation should be considered [9].

What the Evidence Shows

Molecular and Cellular Mechanisms

Macrophage depletion restricted to the early stage of the repair response impairs epithelialization and results in minimized scar formation [6]. The TGF-β family comprises 33 genes in mammals, with TGF-β serving as the best-studied factor within this family due to its diverse roles in cell proliferation, differentiation, wound healing, and the immune system [50]. FOXOs are involved in maintaining the balance between oxidative stress and antioxidants, representing an important therapeutic target to enhance wound healing in diabetes and to avoid over scarring [24].

Immune and Systemic Influences

Ongoing studies of delayed wound healing in chronic kidney disease include the establishment of renal failure models in diabetic strains to study the combined effects of CKD and diabetes [25].

Scar Biology and Pathology

Hypertrophic scarring and contractures result from deep burns that take longer to heal [15]. These conditions involve a dysregulated wound healing process characterized by altered extracellular matrix composition and profibrotic cytokine signaling [15].

Therapeutic Interventions and Agents

Pharmacologic Agents: Methotrexate is effective for suppressing keloid formation after release of syndactyly and for controlling recurrence after surgery for keloid [37]. The administration of basic fibroblast growth factor failed to produce improvements in either the mechanical or functional properties of intrasynovial flexor tendon repair in a canine model [23]. The clinical effects of new antineoplastic agents on wound healing are complex and uncertain, with available recommendations based on database opinions and case reports [20].

Biologics and Regenerative Medicine: An atelocollagen injection had beneficial effects on the healing of nonoperatively treated Achilles tendon injuries in a rat model [40]. A PRP injection on the 7th postoperative day demonstrated superior therapeutic effects compared with injections at other time points for healing of the bone-tendon interface of the rotator cuff in a mouse model [43]. However, current data does not show consistent improvement in healing or clinical outcomes with bone marrow stimulation or leukocyte-rich PRP for rotator cuff repair [29]. Very few studies on the effectiveness of PRP are of sufficient methodological quality to enable evidence-based decision-making [32]. The developing benefits of using mesenchymal stem cells (MSCs) and other biologics have the potential to be disruptive to current treatment protocols in the approaches to healing rotator cuff tears [33].

Physical and Mechanical Therapies: Early controlled motion of stable or surgically stabilized joints appears to improve ligament scar behavior, although no treatment identified to date stimulates true ligament regeneration [38]. The predominant use of therapeutic ultrasound is in relation to tissue repair and soft tissue lesion management, where evidence supports its application in the inflammatory, proliferative and remodelling phases [31].

Wound Closure and Topical Agents: Silicone gel application was effective in improving height and color of the surgical wound after total knee arthroplasty [41]. The non-invasive skin closure system Medizip offers comparable scar results and complication rates to intracutaneous sutures while significantly reducing closure time and costs [28].

Wound Management and Clinical Considerations

The effectiveness of negative pressure wound therapy in the management of lower extremity trauma was comparable to standard dressing and wound coverage methods [42]. Future directions for anti-adhesive agents in tendon repair include implementing randomized controlled trials and developing multifunctional biomaterials to improve patient outcomes [36].

Practical Considerations

Molecular and Cellular Mechanisms

Systemic Factors and Patient Optimization

Systemic physiological states significantly influence fracture and wound healing trajectories. In a rat model of polytrauma, burn and thoracic trauma alter fracture healing, systemic inflammation, and leukocyte kinetics [3]. This altered immune response is associated with a reduced capacity for wound healing [3]. Regarding pharmacological interventions, available recommendations concerning the effect of antineoplastic agents on wound healing are based on database opinions and case reports [20].

Surgical Closure and Wound Management

Preoperative medical optimization and meticulous surgical technique are mandatory to prevent acute wound complications after total knee arthroplasty [39]. Surgeons must recognize a problem wound early to implement proper and expeditious wound management, thereby preventing complications and lessening the potential for infection [39]. Closure techniques demonstrate distinct perfusion and complication profiles:

Running Subcuticular Closure: This method enables the most robust perfusion after total knee arthroplasty [4]. However, the clinical importance of this perfusion advantage remains uncertain, as patients in the supporting study lacked risk factors for wound healing complications [4].

Staple Closure: Primary skin incision closure with staples demonstrates lower wound complications, decreased wound closure times, and an overall reduction in resource utilization after total knee arthroplasty [35].

Medizip System: The non-invasive skin closure system Medizip represents a safe option in the spectrum of surgical wound treatment [28]. It offers comparable scar results and complication rates to intracutaneous sutures [28]. Additionally, Medizip significantly reduces closure time and costs compared to intracutaneous sutures [28].

Adjunctive Therapies and Devices

Negative Pressure Wound Therapy: A clear wound healing goal must be determined when using negative pressure wound therapy [9]. If no improvement is observed between two consecutive dressing changes or after 1 week of treatment, discontinuation should be considered [9]. Specific indications for closed incision negative-pressure wound therapy continue to be defined [30]. Topical negative pressure wound management requires further investigation to evaluate whether this method has a place forward of Role 4 [21].

Biologics and Platelet-Rich Plasma: Very few studies on the effectiveness of platelet-rich plasma are of sufficient methodological quality to enable evidence-based decision-making [32]. The developing benefits of using mesenchymal stem cells and other biologics have the potential to be disruptive to current treatment protocols for rotator cuff tears [33].

Therapeutic Ultrasound: The predominant use of therapeutic ultrasound is in relation to tissue repair and soft tissue lesion management [31]. Evidence supports its application in the inflammatory, proliferative, and remodelling phases of tissue repair [31]. In a rabbit model of medial collateral ligament healing, ultrasound appears to improve some structural properties [18]. Specifically, it appears to modestly increase scar crosssectional area and type I collagen present at 6 weeks after injury [18].

General Principles and Evidence Gaps

Research in support of some of the techniques utilised within scar management programmes is limited [12]. Consequently, anecdotal evidence and clinical experience continue to prevail in the choice of treatment for scar management [12].

Key Evidence

  • [L5] Although no single mechanism is yet known to account for the development of hypertrophic scar, nor for its eventual spontaneous resolution, insights obtained during the past 5 to 10 years hold out hope that rational, drug-based, treatments may one day replace the invasive surgery and other physical treatments. [1] (10.1016/s0749-0712(21)00203-1)
  • [L5] Specific TGFβ isoforms and downstream mediators play different roles in determining the balance between scar formation and tissue regeneration, and inhibition of the canonical signalling pathway blocks regeneration. [2] (10.3390/jdb4020021)
  • [L5] This altered immune response that follows was associated with a reduced capacity for wound healing. [3] (10.1186/s13018-019-1082-4)
  • [L1] However, the clinical importance remains uncertain as patients lacked risk factors for wound healing complications. [4] (10.1007/s11999-015-4209-x)
  • [L5] A pivotal difference between normal scars and hypertrophic scars may be a lack or late induction of myofibroblast apoptotic cell death. [5] (10.1016/s0749-0712(21)00204-3)
  • [L5] Depletion of macrophages restricted to the early stage of the repair response significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimized scar formation. [6] (10.4049/jimmunol.0903356)
  • [L2] Surgical incisions that initially healed with good scar quality generally healed well following subsequent incision through the previous scar. [7] (10.2106/jbjs.15.01418)
  • [L5] Optimal wound healing requires adequate nutrition, as nutrition deficiencies impede the normal processes that allow progression through stages of wound healing. [8] (10.1177/0884533609358997)
  • [L4] A clear wound healing goal must be determined, and if no improvement is observed between two consecutive dressing changes or after 1 week of treatment, discontinuation should be considered. [9] (10.1016/j.otsr.2016.04.018)
  • [L4] Acute, high-dose systemic corticosteroid use likely has no clinically significant effect on wound healing, whereas chronic systemic steroids may impair wound healing in susceptible individuals. [10] (10.1016/j.amjsurg.2012.11.018)
  • [L2] FGF gene expression is associated with improved patient-reported outcome and may be used as a predictor for healing. [11] (10.1186/s40634-021-00335-0)
  • [L5] Research in support of some of the techniques utilised within scar management programmes is limited, with anecdotal evidence and clinical experience continuing to prevail in the choice of treatment. [12] (10.1177/175899830501000201)
  • [L5] The article reviews the molecular basis of flexor tendon wound healing and the role of growth factors, noting that while basic science reports have identified various factors, their clinical relevance for the practicing hand surgeon remains unclear. [13] (10.1016/j.jhsa.2004.04.020)
  • [L5] Understanding the underlying biologic mechanisms of scar and contracture, including the roles of cytokines like TGF-beta and CTGF, allows hand surgeons to better address these issues and suggests new avenues of research to improve patient outcomes. [14] (10.1016/j.hcl.2009.06.007)
  • [L5] Hypertrophic scarring and contractures result from deep burns that take longer to heal, involving a dysregulated wound healing process with altered extracellular matrix composition and profibrotic cytokine signaling. [15] (10.1016/j.hcl.2016.12.004)
  • [L5] This review focuses on the molecular cascades of cytokines and erstwhile factors responsible for delayed wound healing, molecular targets and recent advancements in complete healing and its cure. [16] (10.1016/j.biopha.2019.108615)
  • [L4] Platelets secrete growth factors and active metabolites that have a positive influence in clinical situations requiring rapid healing and tissue regeneration. [17] (10.1160/th03-07-0440)
  • [L5] Ultrasound appears to improve some structural properties and to modestly increase scar crosssectional area and type I collagen present at 6 weeks after injury in this model. [18] (10.1177/0363546504267356)
  • [L5] The review highlights the complex and uncertain clinical effects of new antineoplastic agents on wound healing, noting that available recommendations are based on database opinions and case reports. [20] (10.5435/jaaos-d-24-00097)
  • [L2] This review supports the requirement for further investigation to evaluate whether this method of wound management has a place forward of Role 4. [21] (10.1016/j.injury.2010.02.027)
  • [L5] Wound healing is a complex biological process where the immune system recognizes and combats antigens, participates in debridement, and contributes to tissue repair through innate and adaptive responses. [22] (10.1016/j.injury.2006.02.035)
  • [L5] Despite a substantial biologic response, the administration of basic fibroblast growth factor failed to produce improvements in either the mechanical or functional properties of the repair. [23] (10.2106/jbjs.i.01601)
  • [L5] FOXOs are involved in maintaining the balance between oxidative stress and antioxidants, making them an important therapeutic target to enhance wound healing in diabetes and to avoid over scarring. [24] (10.1007/s12079-018-0484-0)
  • [Paper] Ongoing studies of this significantly delayed wound healing phenotype include the establishment of renal failure model in diabetic strains to study the combined effects of CKD and diabetes. [25] (10.1371/journal.pone.0059979)
  • [L5] Tendon-to-bone healing in this rat model was dominated by scar formation, preventing any positive effects of the implanted biomimetic scaffold. [26] (10.1089/ten.tea.2015.0101)
  • [L5] Wound management is a significant healthcare and financial burden requiring a multidisciplinary approach; orthopaedic surgeons must be familiar with fundamental principles and evidenced-based concepts for managing acute and chronic wounds to optimize outcomes. [27] (10.5435/jaaos-d-17-00024)
  • [L1] The non-invasive skin closure system Medizip represents a safe option in the spectrum of surgical wound treatment, offering comparable scar results and complication rates to intracutaneous sutures while significantly reducing closure time and costs. [28] (10.1007/s004020100308)
  • [L5] Current data does not show consistent improvement in healing or clinical outcomes with bone marrow stimulation or leukocyte-rich PRP. [29] (10.5435/jaaos-d-25-00069)
  • [L4] ciNPWT has been shown to be clinically effective for incisions at high risk for perioperative complications, although specific indications continue to be defined. [30] (10.5435/jaaos-d-17-00054)
  • [L5] The predominant use of therapeutic ultrasound is in relation to tissue repair and soft tissue lesion management, where the evidence would support its application in the inflammatory, proliferative and remodelling phases. [31] (10.1016/j.ultras.2008.02.004)
  • [L5] The authors note that very few studies on the effectiveness of PRP are of sufficient methodological quality to enable evidence-based decision-making. [32] (10.1136/bjsm.2010.079822)
  • [L4] The developing benefits of using mesenchymal stem cells (MSCs) and other biologics have the potential to be disruptive to current treatment protocols in the approaches to healing rotator cuff tears (RCTs). [33] (10.5772/intechopen.70270)
  • [L2] Smoking has a transient effect on the tissue microenvironment and a prolonged effect on inflammatory and reparative cell functions leading to delayed healing and complications. [34] (10.1097/sla.0b013e31824f632d)
  • [L1] Primary skin incision closure with staples demonstrated lower wound complications, decreased wound closure times, and an overall reduction in resource utilization. [35] (10.1016/j.arth.2017.04.004)
  • [L5] Future directions include implementing randomized controlled trials and developing multifunctional biomaterials to improve patient outcomes. [36] (10.1186/s13018-025-06436-1)
  • [L4] The use of methotrexate to suppress keloid formation after release of syndactyly and for control of recurrence after surgery for keloid is effective. [37] (10.1177/1753193411402146)
  • [L5] Early controlled motion of stable or surgically stabilized joints appears to improve ligament scar behavior, but no treatment identified to date stimulates true ligament regeneration. [38] (10.5435/00124635-199603000-00002)
  • [L4] Surgeons must address patient preoperative medical optimization, use meticulous surgical technique, and recognize a problem wound early to implement proper and expeditious wound management to prevent complications and lessen the potential for infection. [39] (10.5435/jaaos-d-15-00402)
  • [L5] An atelocollagen injection had beneficial effects on the healing of nonoperatively treated Achilles tendon injuries. [40] (10.1177/23259671231200933)
  • [L1] However, silicone gel application was effective in improving height and color of the surgical wound. [41] (10.1007/s00402-014-1942-7)
  • [Paper] Effectiveness was comparable to the standard dressing and wound coverage methods. [42] (10.1016/j.injury.2007.10.029)
  • [L5] A PRP injection on the 7th postoperative day demonstrated superior therapeutic effects compared with injections at other time points. [43] (10.1177/23259671231219812)
  • [L3] NPWT provides effective temporary wound coverage, but does not allow a delay in definitive free-flap reconstruction. [45] (10.1016/j.injury.2011.09.003)
  • [L4] Data are lacking to allow definitive conclusions on the use of these techniques for routine management of tendon ailments. [46] (10.1093/bmb/ldq030)
  • [L5] This review introduces the TGF-β family, comprising 33 genes in mammals, and highlights TGF-β as the best-studied factor with diverse roles in cell proliferation, differentiation, wound healing, and the immune system. [50] (10.1101/cshperspect.a021873)

References

[1] MOLECULAR AND CELLULAR ASPECTS OF FIBROSIS FOLLOWING THERMAL INJURY. Hand Clinics. 2000. DOI: 10.1016/s0749-0712(21)00203-1

[2] Signalling by Transforming Growth Factor Beta Isoforms in Wound Healing and Tissue Regeneration. Journal of Developmental Biology. 2016. DOI: 10.3390/jdb4020021

[3] Burn and thoracic trauma alters fracture healing, systemic inflammation, and leukocyte kinetics in a rat model of polytrauma. Journal of Orthopaedic Surgery and Research. 2019. DOI: 10.1186/s13018-019-1082-4

[4] The Chitranjan Ranawat Award: Running Subcuticular Closure Enables the Most Robust Perfusion After TKA: A Randomized Clinical Trial. Clinical Orthopaedics & Related Research. 2016. DOI: 10.1007/s11999-015-4209-x

[5] CONTROL OF WOUND CONTRACTION. Hand Clinics. 2000. DOI: 10.1016/s0749-0712(21)00204-3

[6] Differential Roles of Macrophages in Diverse Phases of Skin Repair. The Journal of Immunology. 2010. DOI: 10.4049/jimmunol.0903356

[7] Outcomes of Cutaneous Scar Revision During Surgical Implant Removal in Children with Cerebral Palsy. Journal of Bone and Joint Surgery. 2016. DOI: 10.2106/jbjs.15.01418

[8] Understanding the Role of Nutrition and Wound Healing. Nutrition in Clinical Practice. 2010. DOI: 10.1177/0884533609358997

[9] Negative pressure wound therapy in orthopaedic surgery. Orthopaedics & Traumatology: Surgery & Research. 2017. DOI: 10.1016/j.otsr.2016.04.018

[10] Corticosteroids and wound healing: clinical considerations in the perioperative period. The American Journal of Surgery. 2013. DOI: 10.1016/j.amjsurg.2012.11.018

[11] FGF gene expression in injured tendons as a prognostic biomarker of 1‐year patient outcome after Achilles tendon repair. Journal of Experimental Orthopaedics. 2021. DOI: 10.1186/s40634-021-00335-0

[12] Scar Management in Hand Therapy – is our Practice Evidence Based?. The British Journal of Hand Therapy. 2005. DOI: 10.1177/175899830501000201

[13] Clinical implications of growth factors in flexor tendon wound healing. The Journal of Hand Surgery. 2004. DOI: 10.1016/j.jhsa.2004.04.020

[14] Scar and Contracture: Biological Principles. Hand Clinics. 2009. DOI: 10.1016/j.hcl.2009.06.007

[15] Biological Principles of Scar and Contracture. Hand Clinics. 2017. DOI: 10.1016/j.hcl.2016.12.004

[16] Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomedicine & Pharmacotherapy. 2019. DOI: 10.1016/j.biopha.2019.108615

[17] Autologous platelets as a source of proteins for healing and tissue regeneration. Thrombosis and Haemostasis. 2004. DOI: 10.1160/th03-07-0440

[18] The Effects of Low-Intensity Ultrasound on Medial Collateral Ligament Healing in the Rabbit Model. The American Journal of Sports Medicine. 2005. DOI: 10.1177/0363546504267356

[20] Wound-Healing Effects of Common Antineoplastic Agents and Perioperative Considerations for the Orthopaedic Surgeon. Journal of the American Academy of Orthopaedic Surgeons. 2024. DOI: 10.5435/jaaos-d-24-00097

[21] Topical negative pressure and military wounds—A review of the evidence. Injury. 2011. DOI: 10.1016/j.injury.2010.02.027

[22] Wound healing: Immunological aspects. Injury. 2006. DOI: 10.1016/j.injury.2006.02.035

[23] The Effects of Exogenous Basic Fibroblast Growth Factor on Intrasynovial Flexor Tendon Healing in a Canine Model. Journal of Bone and Joint Surgery. 2010. DOI: 10.2106/jbjs.i.01601

[24] Understanding the perspectives of forkhead transcription factors in delayed wound healing. Journal of Cell Communication and Signaling. 2018. DOI: 10.1007/s12079-018-0484-0

[25] Excisional Wound Healing Is Delayed in a Murine Model of Chronic Kidney Disease. PLoS ONE. 2013. DOI: 10.1371/journal.pone.0059979

[26] In Vivo Evaluation of Adipose-Derived Stromal Cells Delivered with a Nanofiber Scaffold for Tendon-to-Bone Repair. Tissue Engineering Part A. 2015. DOI: 10.1089/ten.tea.2015.0101

[27] Advances in Wound Management. Journal of the American Academy of Orthopaedic Surgeons. 2018. DOI: 10.5435/jaaos-d-17-00024

[28] Results of a prospective randomised study comparing a non-invasive surgical zipper versus intracutaneous sutures for wound closure. Archives of Orthopaedic and Trauma Surgery. 2002. DOI: 10.1007/s004020100308

[29] Orthobiologic Augmentation to Improve Rotator Cuff Repair Outcomes: Current and Future Strategies. Journal of the American Academy of Orthopaedic Surgeons. 2025. DOI: 10.5435/jaaos-d-25-00069

[30] The Use of Closed Incision Negative-Pressure Wound Therapy in Orthopaedic Surgery. Journal of the American Academy of Orthopaedic Surgeons. 2018. DOI: 10.5435/jaaos-d-17-00054

[31] Ultrasound in contemporary physiotherapy practice. Ultrasonics. 2008. DOI: 10.1016/j.ultras.2008.02.004

[32] IOC consensus paper on the use of platelet-rich plasma in sports medicine. British Journal of Sports Medicine. 2010. DOI: 10.1136/bjsm.2010.079822

[33] Complete Rotator Cuff Tear: An Evidence-Based Conservative Management Approach. Advances in Shoulder Surgery. 2018. DOI: 10.5772/intechopen.70270

[34] Wound Healing and Infection in Surgery. Annals of Surgery. 2012. DOI: 10.1097/sla.0b013e31824f632d

[35] A Meta-Analysis and Systematic Review Evaluating Skin Closure After Total Knee Arthroplasty—What Is the Best Method?. The Journal of Arthroplasty. 2017. DOI: 10.1016/j.arth.2017.04.004

[36] Anti-adhesive agents in tendon repair: mechanisms, preclinical evidence, clinical challenges, and future perspectives—a narrative review. Journal of Orthopaedic Surgery and Research. 2025. DOI: 10.1186/s13018-025-06436-1

[37] Keloid formation after syndactyly release in patients with associated macrodactyly: management with methotrexate therapy. Journal of Hand Surgery (European Volume). 2011. DOI: 10.1177/1753193411402146

[38] Ligament Healing: Current Knowledge and Clinical Applications. Journal of the American Academy of Orthopaedic Surgeons. 1996. DOI: 10.5435/00124635-199603000-00002

[39] Acute Wound Complications After Total Knee Arthroplasty: Prevention and Management. Journal of the American Academy of Orthopaedic Surgeons. 2017. DOI: 10.5435/jaaos-d-15-00402

[40] An Atelocollagen Injection Enhances the Healing of Nonoperatively Treated Achilles Tendon Tears: An Experimental Study in Rats. Orthopaedic Journal of Sports Medicine. 2023. DOI: 10.1177/23259671231200933

[41] The effect of topical scar treatment on postoperative scar pain and pruritus after total knee arthroplasty. Archives of Orthopaedic and Trauma Surgery. 2014. DOI: 10.1007/s00402-014-1942-7

[42] The efficacy of negative pressure wound therapy in the management of lower extremity trauma: Review of clinical evidence. Injury. 2007. DOI: 10.1016/j.injury.2007.10.029

[43] Effect of Platelet-Rich Plasma at Different Initiation Times on Healing of the Bone-Tendon Interface of the Rotator Cuff in a Mouse Model. Orthopaedic Journal of Sports Medicine. 2024. DOI: 10.1177/23259671231219812

[45] Early soft tissue coverage and negative pressure wound therapy optimises patient outcomes in lower limb trauma. Injury. 2012. DOI: 10.1016/j.injury.2011.09.003

[46] Tissue engineered biological augmentation for tendon healing: a systematic review. British Medical Bulletin. 2010. DOI: 10.1093/bmb/ldq030

[50] TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harbor Perspectives in Biology. 2016. DOI: 10.1101/cshperspect.a021873

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d. Effective Technological Measures means those measures that, in the absence of proper authority, may not be circumvented under laws fulfilling obligations under Article 11 of the WIPO Copyright Treaty adopted on December 20, 1996, and/or similar international agreements.

e. Exceptions and Limitations means fair use, fair dealing, and/or any other exception or limitation to Copyright and Similar Rights that applies to Your use of the Licensed Material.

f. Licensed Material means the artistic or literary work, database, or other material to which the Licensor applied this Public License.

g. Licensed Rights means the rights granted to You subject to the terms and conditions of this Public License, which are limited to all Copyright and Similar Rights that apply to Your use of the Licensed Material and that the Licensor has authority to license.

h. Licensor means the individual(s) or entity(ies) granting rights under this Public License.

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.