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Tendon Biology and Healing

Overview

Tendon biology and healing present significant challenges that necessitate improved strategies to enhance repair and regeneration [1]. Understanding the biology, organization, and morphogenesis of native tendon tissue is necessary to improve current treatment modalities [10]. While basic science has identified various growth factors involved in flexor tendon wound healing, their clinical relevance for practicing hand surgeons remains unclear [4]. The basic biology of tendon tissues and recent repair proposals for tendon tears have been summarized in recent reviews [5], with key areas of study including biochemical pathways activated during tendon repair, experimental injury models, and parallels between tendon healing and development [7].

Healing of the tendon-bone insertion site after repair typically results in a reactive scar rather than a histologically normal tendon-bone insertion site [2]. The ultimate goal of stimulating a regenerative healing pathway is to improve healing at the tendon-bone insertion site [2]. Autologous bone marrow expanded mesenchymal stem cells (MSC) and leukocyte-poor platelet-rich plasma (LP-PRP) are being tested in a phase I/II randomized clinical trial for patellar tendinopathy to determine if they restore function [3]. Tendon regeneration is hypothesized to occur only in the MSC group, not the LP-PRP group, in the context of patellar tendinopathy treatment [3].

Controversy remains regarding the treatment of acute and chronic Achilles tendon ruptures despite a large body of evidence addressing these conditions [24]. Vascularization affects the tensile strength and rupture vulnerability of the healthy Achilles tendon [38], although it is unlikely to be the sole or most significant contributor to Achilles tendon rupture vulnerability [38]. Glucocorticoid injections are associated with significant long-term harms to tendon tissue and cells [9]. Early post-operative mobilization of digits is the only clinically justified method for preventing adhesions after tendon injury or repair [40], but the best method of early post-operative mobilization for adhesion prevention remains controversial [40]. A proposed nomenclature for skeletal muscle injuries integrates topographic location with histoarchitectonic features of damage to connective tissue structures [39]. This combined topographic and histoarchitectonic approach is considered essential for accurate prognosis and understanding recurrence in skeletal muscle injuries [39].

How It Works

Tendon healing results in a reactive scar rather than a histologically normal tendon-bone insertion site [2]. The tensile strength of a healing tendon improves over time but does not reach the levels of uninjured, normal tissue [14]. Consequently, the ultimate goal of tendon repair strategies is to stimulate a regenerative healing pathway [2]. Optimizing tendon healing requires understanding the biological processes of inflammation, repair, and remodeling [11].

Biological Modulators: * Matrix Metalloproteinases: All investigated matrix metalloproteinases (MMPs) and TIMP-1 make a pivotal contribution to the early human tendon healing process [26]. TIMP-2, -3, and -4 play a minor role in the early human tendon healing process [26]. * Stem Cells: Stem cells can have a positive effect on tendon healing, likely due to regeneration potential producing tissue similar to the preinjury state [8]. Results of stem cell therapy for tendon healing can be variable [8]. A phase I/II clinical trial hypothesis posits that while both MSC and LP-PRP will restore function, tendon regeneration will only be observed in the MSC group [3]. * Platelet-Rich Plasma: Platelet-rich plasma (PRP) manipulates tendon healing through specific molecular and cellular mechanisms [6].

Clinical Application and Limitations: The clinical relevance of various growth factors identified in basic science reports for flexor tendon wound healing remains unclear [4]. Currently, no strategies targeting growth factors for flexor tendon repair are routinely used in clinical practice [13]. Extrasynovial tendons heal more effectively than intrasynovial tendons [27].

Tissue Engineering and Biomaterials: Tendon tissue engineering approaches involve making new combinations of materials, designs, cells, and bioactive molecules to achieve personalized regeneration of a functional tendon [12]. Octacalcium phosphate might be beneficial for the healing of rotator cuff tendon to bone [18]. A greater understanding of molecular mechanisms involved in tendon development and natural healing, coupled with complex biomaterials, should lead to regenerative procedures that more closely recapitulate morphogenesis [25]. Biochemical pathways activated during repair, experimental injury models, and parallels between tendon healing and tendon development are key aspects of tendon healing biology [7]. Understanding the biology and organization of native tendon and the process of morphogenesis is necessary to improve current treatment modalities [10]. Challenges in tenocyte characterization exist, highlighting the need for improved strategies to enhance tendon repair and regeneration [1].

What the Evidence Shows

The ultimate goal of tendon healing strategies is to stimulate a regenerative healing pathway [2]. Optimizing tendon healing requires understanding the biological processes of inflammation, repair, and remodeling [11]. Biochemical pathways activated during repair, experimental injury models, and parallels between tendon healing and tendon development are key areas of study [7]. The review summarizes the basic biology of tendon tissues and provides an update on the latest repair proposals for tendon tears [5].

Biologic Therapies: * Stem Cells: Stem cells can have a positive effect on tendon healing, likely due to regeneration potential producing tissue similar to the preinjury state [8]. Results of stem cell therapy for tendon healing can be variable [8]. Autologous bone marrow expanded mesenchymal stem cells are hypothesized to restore function and induce tendon regeneration, whereas LP-PRP is only hypothesized to restore function [3]. * Platelet-Rich Plasma (PRP): PRP manipulates tendon healing through specific molecular and cellular mechanisms [6]. Primary use of glucocorticoids did not exert obvious deleterious side effects on the treated tendon but instead enhanced the regenerative effects of platelet-rich plasma in early inflammatory tendinopathy in a rabbit model [21]. * Scaffolds and Matrices: Few clinical trials have examined the effect of scaffolds on tendon-bone healing in well-designed, long-term follow-up studies with appropriate control groups [17]. Octacalcium phosphate might be beneficial for the healing of rotator cuff tendon to bone [18]. Demineralized cortical bone matrix control groups demonstrated similar outcomes to augmented repairs in a chronic rotator cuff tear model [33]. The treatment efficacy of Growth Differentiation Factor 8 (Myostatin) on early tendon repair remains to be defined [19]. * Glucocorticoids: Glucocorticoid injections are associated with significant long-term harms to tendon tissue and cells [9].

Biologic therapies facilitate the regeneration of the correct microarchitecture of the tendon attachment to the bone and reduce failures after surgical rotator cuff repair [32]. Although many biologic therapies have achieved some degree of success in improving structural, histological, and clinical outcomes after surgical tendon-bone enthesis repair, none have reliably and consistently led to clinical improvement [20]. No novel biologic healing approach has been successful in enhancing healing of the injured enthesis [31]. Biologic adjuvants have great potential to improve rotator cuff healing and reduce rates of reinjury, but current surgical treatments remain inadequate with high failure rates for large and massive tears [34]. The clinical relevance of various growth factors identified in basic science reports for flexor tendon wound healing remains unclear [4].

Mechanical and Rehabilitation Strategies: * Rotator Cuff: Numerous randomized controlled trials have shown no difference in healing rates between early mobilization and delayed rehabilitation protocols after rotator cuff repair [28]. * Flexor Tendons: Early controlled motion after flexor tendon repair has a favorable effect on the healing and remodeling response, resulting in stronger repairs and enabling greater excursion of the repaired tendon [29]. Recent research on flexor tendon repair has focused on using pharmacologic agents to modify the healing environment to increase the healing response within the tendon while decreasing adhesion formation between the tendon and its sheath [35]. * Achilles Tendon: Controversy remains regarding the treatment of acute and chronic Achilles tendon ruptures despite a large body of evidence [24].

Further investigation is needed to determine the most suitable methods of incorporating mechanical loading findings toward improving tendon repair, including optimal timing, parameters, and application in rehabilitation and tissue engineering [23]. Tendon tissue engineering approaches involve making new combinations of materials, designs, cells, and bioactive molecules to achieve personalized regeneration of a functional tendon [12]. New biologic strategies, such as cell-based strategies and tissue engineering, may be useful adjuncts to further improve current clinical outcomes in flexor tendon surgery [22]. Challenges in tenocyte characterization highlight the need for improved strategies to enhance tendon repair and regeneration [1]. The paper reviews challenges and opportunities for developing effective treatment strategies for enthesis repair, highlighting the need for better understanding of disease pathoetiology, improved outcome measures, and well-designed clinical trials to test repair augmentation strategies [16]. The review synthesizes literature to address historical controversies and evolving research in primary flexor tendon repair [15].

Practical Considerations

Primary repair remains the standard of care for tendon injuries [37]. The tensile strength of a healing tendon improves over time but does not reach the levels of uninjured, normal tissue [14]. Consequently, repaired tendon tissue rarely achieves functionality equal to that of the preinjured state [37].

Tenocyte characterisation presents challenges, necessitating improved strategies to enhance tendon repair and regeneration [1]. The ultimate goal of biologic augmentation in tendon-bone healing is to stimulate a regenerative healing pathway [2]. Developing effective treatment strategies for enthesis repair requires a better understanding of disease pathoetiology, improved outcome measures, and well-designed clinical trials [16].

Biologic Augmentation: * Platelet-Rich Plasma (PRP): PRP manipulates tendon healing through specific molecular and cellular mechanisms, which may explain differences in clinical trial outcomes for tendinopathy [6]. Primary use of glucocorticoids did not exert obvious deleterious side effects on the treated tendon and instead enhanced the regenerative effects of platelet-rich plasma in early inflammatory tendinopathy in a rabbit model [21]. * Stem Cells: Stem cells can have a positive effect on tendon healing, likely due to regeneration potential producing tissue similar to the preinjury state, although results can be variable [8]. A phase I/II randomized clinical trial protocol hypothesizes that mesenchymal stem cells (MSC) and leukocyte-poor platelet-rich plasma (LP-PRP) will restore function, with tendon regeneration expected only in the MSC group [3]. * Growth Factors: The clinical relevance of various growth factors identified in basic science reports for flexor tendon wound healing remains unclear for practicing hand surgeons [4]. The treatment efficacy of Growth Differentiation Factor 8 (Myostatin) on early tendon repair remains to be defined [19]. No strategies targeting growth factors in tendon repair are currently routinely used in clinical practice [13]. * Scaffolds: Few clinical trials have examined the effect of soft tissue scaffolds on tendon-bone healing in well-designed, long-term follow-up studies with appropriate control groups [17]. Generating tissue-engineered tendon constructs can be of considerable clinical benefit given the lack of adequate intrasynovial tendon graft sources, donor site morbidity, and the propensity for current repair methods to cause adhesion formation [36]. Developing functional, durable, and biocompatible scaffolds requires careful consideration of key aspects [36].

Many biologic therapies have achieved some degree of success in improving structural, histological, and clinical outcomes after surgical tendon-bone enthesis repair, but none have reliably and consistently led to clinical improvement [20]. New biologic strategies, such as cell-based strategies and tissue engineering, may be useful adjuncts to further improve current clinical outcomes in flexor tendon surgery [22]. Further investigation is needed to determine the most suitable methods of incorporating mechanical loading findings toward improving tendon repair, including optimal timing, parameters, and application in rehabilitation and tissue engineering [23].

Local Injections: Local glucocorticoid injections are associated with significant long-term harms to tendon tissue and cells [9].

Outcomes: Rotator cuff repair is cost-effective for all populations [30].

Key Evidence

  • [L5] The review emphasizes the challenges in tenocyte characterisation and the need for improved strategies to enhance tendon repair and regeneration. (10.1089/ten.teb.2016.0181)
  • [Paper] The review evaluates the use of biologics to improve healing of the tendon-bone insertion site after repair, noting that while the healing process results in a reactive scar rather than a histologically normal tendon-bone insertion site, the ultimate goal is to stimulate a regenerative healing pathway. (10.1016/j.csm.2012.07.003)
  • [L2] This document describes the protocol for a phase I/II randomized clinical trial designed to test the hypothesis that MSC and LP-PRP will restore function, but tendon regeneration will only be observed in the MSC group. (10.1186/s13018-019-1477-2)
  • [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. (10.1016/j.jhsa.2004.04.020)
  • [L4] The review summarizes the basic biology of tendon tissues and provides an update on the latest repair proposals for tendon tears. (10.1302/2058-5241.2.160075)
  • [L4] This review focuses on the specific molecular and cellular mechanisms by which PRP manipulates tendon healing to better understand how PRP affects tendinopathy and explore the reason for the differences in clinical trial outcomes. (10.3389/fbioe.2023.1187974)
  • [L5] Biochemical pathways activated during repair, experimental injury models, and parallels between tendon healing and tendon development are emphasized. (10.1146/annurev-bioeng-071811-150122)
  • [L4] The current evidence shows that stem cells can have a positive effect on tendon healing, likely due to regeneration potential producing tissue similar to the preinjury state, though results can be variable. (10.1016/j.arthro.2011.12.009)
  • [L4] This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections. (10.1016/j.semarthrit.2013.08.006)
  • [L5] Understanding the biology and organization of the native tendon and the process of morphogenesis of tendon tissue is necessary to improve current treatment modalities. (10.1016/j.jhsa.2007.09.007)
  • [L5] Optimising tendon healing requires understanding the biological processes of inflammation, repair, and remodelling. (10.1136/bjsm.36.5.315)
  • [L5] These approaches involve making new combinations of materials, designs, cells, and bioactive molecules to achieve personalized regeneration of a functional tendon. (10.1016/j.jconrel.2021.03.040)
  • [L5] Understanding the role that growth factors play in tendon repair should enable a more targeted approach to be developed to improve the results of flexor tendon repair, although currently no strategies are routinely used in clinical practice. (10.1177/1753193413509231)
  • [L4] Although the tensile strength of the healing tendon improves over time, it does not reach the levels of uninjured, normal tissue. (10.1016/j.jbiomech.2003.11.005)
  • [L4] The review synthesizes literature to address historical controversies and evolving research in primary flexor tendon repair. (10.4081/or.2015.6125)
  • [L5] The paper reviews challenges and opportunities for developing effective treatment strategies for enthesis repair, highlighting the need for better understanding of disease pathoetiology, improved outcome measures, and well-designed clinical trials to test repair augmentation strategies. (10.2106/jbjs.18.00200)
  • [L4] Few clinical trials have examined the effect of scaffolds on tendon-bone healing in well-designed, long-term follow-up studies with appropriate control groups. (10.1177/2325967115587495)
  • [L5] It might be beneficial for the healing of rotator cuff tendon to bone. (10.1016/j.jse.2015.01.011)
  • [L5] GDF-8's treatment efficacy of the early tendon repair remains to be defined. (10.1177/1558944718792708)
  • [L4] Although many biologic therapies have achieved some degree of success in improving structural, histological, and clinical outcomes after surgical tendon-bone enthesis repair, none have reliably and consistently led to clinical improvement. (10.5435/jaaos-d-20-01011)
  • [L5] The primary use of glucocorticoids did not exert any obvious deleterious side effects on the treated tendon but instead enhanced the regenerative effects of platelet-rich plasma in early inflammatory tendinopathy. (10.1177/03635465211037354)
  • [L5] Recent incremental improvements in clinical outcomes suggest that new biologic strategies, such as cell-based strategies and tissue engineering, may be useful adjuncts to further improve current clinical outcomes in flexor tendon surgery. (10.1016/j.hcl.2005.01.001)
  • [L5] Further investigation with a focus on improving clinical outcomes is needed to determine the most suitable methods of incorporating mechanical loading findings toward improving tendon repair, including optimal timing, parameters, and application in rehabilitation and tissue engineering. (10.2106/jbjs.l.01004)
  • [L5] There is a large body of evidence addressing treatment of acute and chronic Achilles tendon ruptures; however, controversy remains. (10.2106/jbjs.o.00002)
  • [L5] A greater understanding of the molecular mechanisms involved in tendon and ligament development and natural healing, coupled with the capability of producing complex biomaterials, should lead to regenerative procedures that more closely recapitulate morphogenesis. (10.1002/bdrc.21041)
  • [L4] The study demonstrates a pivotal contribution of all investigated MMPs and TIMP-1, but a minor role of TIMP-2, -3, and -4, in the early human tendon healing process. (10.3390/ijms18102199)
  • [L5] These differences reveal mechanisms through which extrasynovial tendons heal more effectively than do intrasynovial tendons. (10.2106/jbjs.20.01253)
  • [L2] Numerous randomized controlled trials have shown no difference in healing rates between early mobilization and delayed rehabilitation protocols. (10.1016/j.ocl.2015.08.017)
  • [L5] Early controlled motion after flexor tendon repair has a favorable effect on the healing and remodeling response, resulting in stronger repairs and enabling greater excursion of the repaired tendon. (10.1016/s0749-0712(21)00284-5)
  • [L4] Rotator cuff repair is cost-effective for all populations. (10.2106/jbjs.l.01495)
  • [L5] No novel biologic healing approach has been successful in enhancing healing of the injured enthesis. (10.1016/j.jse.2017.10.030)
  • [L2] Biological therapies facilitate the regeneration of the correct microarchitecture of the tendon attachment to the bone and reduce failures after surgical rotator cuff repair. (10.1530/eor-24-0012)
  • [L5] The control group demonstrated a similar outcome to augmented repairs. (10.1016/j.jse.2017.01.003)
  • [L5] Biologic adjuvants have great potential to improve rotator cuff healing and reduce rates of reinjury, but current surgical treatments remain inadequate with high failure rates for large and massive tears. (10.1177/2325967116636586)
  • [L5] Recent research has been focused on using pharmacologic agents to modify the healing environment to increase the healing response within the tendon while decreasing the adhesion formation between the tendon and its sheath. (10.1016/j.ocl.2015.08.019)
  • [L5] Generating tissue engineered tendon constructs can be of considerable clinical benefit given the lack of adequate intrasynovial tendon graft sources, donor site morbidity, and the propensity for current methods of repair to cause adhesion formation, though this requires careful consideration of key aspects of developing a functional, durable, and biocompatible scaffold. (10.1177/1753193413512432)
  • [L5] Primary repair remains the standard of care, but repaired tendon tissue rarely achieves functionality equal to that of the preinjured state. (10.5435/00124635-201103000-00002)
  • [L5] Whilst no definitive conclusion was reached, it was concluded that the vascularisation does affect the tensile strength and so rupture vulnerability of the healthy Achilles tendon, although it is unlikely to be either the sole, or most significant, contributor. (10.1016/j.injury.2005.02.012)
  • [L5] The authors propose a nomenclature for skeletal muscle injuries that integrates topographic location with histoarchitectonic features of the damage to connective tissue structures, arguing that this combined approach is essential for accurate prognosis and understanding recurrence. (10.1177/2325967120909090)
  • [L4] The only thing that appears clinically justified in adhesion prevention is the need for early post-operative mobilization of digits after tendon injury or repair but the best method of mobilization remains controversial. (10.1093/bmb/ldp013)

References

[1] A Clinical, Biological, and Biomaterials Perspective into Tendon Injuries and Regeneration. Tissue Engineering Part B: Reviews. 2016. DOI: 10.1089/ten.teb.2016.0181

[2] Biologics in the Management of Rotator Cuff Surgery. Clinics in Sports Medicine. 2012. DOI: 10.1016/j.csm.2012.07.003

[3] Autologous bone marrow expanded mesenchymal stem cells in patellar tendinopathy: protocol for a phase I/II, single-centre, randomized with active control PRP, double-blinded clinical trial. Journal of Orthopaedic Surgery and Research. 2019. DOI: 10.1186/s13018-019-1477-2

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

[5] Tendon injuries. EFORT Open Reviews. 2017. DOI: 10.1302/2058-5241.2.160075

[6] Platelet-rich plasma in the pathologic processes of tendinopathy: a review of basic science studies. Frontiers in Bioengineering and Biotechnology. 2023. DOI: 10.3389/fbioe.2023.1187974

[7] Tendon Healing: Repair and Regeneration. Annual Review of Biomedical Engineering. 2012. DOI: 10.1146/annurev-bioeng-071811-150122

[8] Exploring the Application of Stem Cells in Tendon Repair and Regeneration. Arthroscopy. 2012. DOI: 10.1016/j.arthro.2011.12.009

[9] The risks and benefits of glucocorticoid treatment for tendinopathy: A systematic review of the effects of local glucocorticoid on tendon. Seminars in Arthritis and Rheumatism. 2014. DOI: 10.1016/j.semarthrit.2013.08.006

[10] Tendon: Biology, Biomechanics, Repair, Growth Factors, and Evolving Treatment Options. The Journal of Hand Surgery. 2008. DOI: 10.1016/j.jhsa.2007.09.007

[11] Tendon healing: can it be optimised?. British Journal of Sports Medicine. 2002. DOI: 10.1136/bjsm.36.5.315

[12] Tendon tissue engineering: Cells, growth factors, scaffolds and production techniques. Journal of Controlled Release. 2021. DOI: 10.1016/j.jconrel.2021.03.040

[13] The growth factors involved in flexor tendon repair and adhesion formation. Journal of Hand Surgery (European Volume). 2013. DOI: 10.1177/1753193413509231

[14] Biomechanics of tendon injury and repair. Journal of Biomechanics. 2004. DOI: 10.1016/j.jbiomech.2003.11.005

[15] A review of current concepts in flexor tendon repair: physiology, biomechanics, surgical technique and rehabilitation.. Orthopedic Review. 2015. DOI: 10.4081/or.2015.6125

[16] Enthesis Repair. Journal of Bone and Joint Surgery. 2018. DOI: 10.2106/jbjs.18.00200

[17] Augmentation of Rotator Cuff Repair With Soft Tissue Scaffolds. Orthopaedic Journal of Sports Medicine. 2015. DOI: 10.1177/2325967115587495

[18] The role of an octacalcium phosphate in the re-formation of infraspinatus tendon insertion. Journal of Shoulder and Elbow Surgery. 2015. DOI: 10.1016/j.jse.2015.01.011

[19] The Effect of Growth Differentiation Factor 8 (Myostatin) on Bone Marrow–Derived Stem Cell–Coated Bioactive Sutures in a Rabbit Tendon Repair Model. HAND. 2018. DOI: 10.1177/1558944718792708

[20] Augmentation of Rotator Cuff Healing With Orthobiologics. Journal of the American Academy of Orthopaedic Surgeons. 2021. DOI: 10.5435/jaaos-d-20-01011

[21] Early-Stage Primary Anti-inflammatory Therapy Enhances the Regenerative Efficacy of Platelet-Rich Plasma in a Rabbit Achilles Tendinopathy Model. The American Journal of Sports Medicine. 2021. DOI: 10.1177/03635465211037354

[22] The Future of Flexor Tendon Surgery. Hand Clinics. 2005. DOI: 10.1016/j.hcl.2005.01.001

[23] The Role of Mechanical Loading in Tendon Development, Maintenance, Injury, and Repair. Journal of Bone and Joint Surgery. 2013. DOI: 10.2106/jbjs.l.01004

[24] Everything Achilles: Knowledge Update and Current Concepts in Management. The Journal of Bone and Joint Surgery-American Volume. 2015. DOI: 10.2106/jbjs.o.00002

[25] Tendon and ligament regeneration and repair: Clinical relevance and developmental paradigm. Birth Defects Research Part C: Embryo Today: Reviews. 2013. DOI: 10.1002/bdrc.21041

[26] Time-Dependent Alterations of MMPs, TIMPs and Tendon Structure in Human Achilles Tendons after Acute Rupture. International Journal of Molecular Sciences. 2017. DOI: 10.3390/ijms18102199

[27] Flexor Tendon Injury and Repair. Journal of Bone and Joint Surgery. 2021. DOI: 10.2106/jbjs.20.01253

[28] Immobilization After Rotator Cuff Repair. Orthopedic Clinics of North America. 2016. DOI: 10.1016/j.ocl.2015.08.017

[29] EARLY MOTION AFTER FLEXOR TENDON SURGERY. Hand Clinics. 1996. DOI: 10.1016/s0749-0712(21)00284-5

[30] The Societal and Economic Value of Rotator Cuff Repair. Journal of Bone and Joint Surgery. 2013. DOI: 10.2106/jbjs.l.01495

[31] Assembly, maturation, and degradation of the supraspinatus enthesis. Journal of Shoulder and Elbow Surgery. 2018. DOI: 10.1016/j.jse.2017.10.030

[32] Biological strategies in rotator cuff repair: a clinical application and molecular background. EFORT Open Reviews. 2024. DOI: 10.1530/eor-24-0012

[33] The effectiveness of demineralized cortical bone matrix in a chronic rotator cuff tear model. Journal of Shoulder and Elbow Surgery. 2017. DOI: 10.1016/j.jse.2017.01.003

[34] Biologic Treatments for Sports Injuries II Think Tank—Current Concepts, Future Research, and Barriers to Advancement, Part 2. Orthopaedic Journal of Sports Medicine. 2016. DOI: 10.1177/2325967116636586

[35] Flexor Tendon Repair. Orthopedic Clinics of North America. 2016. DOI: 10.1016/j.ocl.2015.08.019

[36] Tissue engineering in flexor tendon surgery: current state and future advances. Journal of Hand Surgery (European Volume). 2013. DOI: 10.1177/1753193413512432

[37] Tissue Engineering Solutions for Tendon Repair. American Academy of Orthopaedic Surgeon. 2011. DOI: 10.5435/00124635-201103000-00002

[38] Review of the vascularisation of the human Achilles tendon. Injury. 2005. DOI: 10.1016/j.injury.2005.02.012

[39] A Histoarchitectural Approach to Skeletal Muscle Injury: Searching for a Common Nomenclature. Orthopaedic Journal of Sports Medicine. 2020. DOI: 10.1177/2325967120909090

[40] Prevention of adhesions in surgery of the flexor tendons of the hand: what is the evidence?. British Medical Bulletin. 2009. DOI: 10.1093/bmb/ldp013

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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.