Optimizing repair of tendon ruptures and chronic tendinopathies: Integrating the use of biomarkers with biological interventions to improve patient outcomes and clinical trial design

Abstract

Tendons are dense connective tissues of the musculoskeletal system that link bones with muscles to foster mobility. They have complex structures and exist in varying biomechanical, metabolic and biological environments. In addition, tendon composition and mechanical properties can change over the lifespan as an individual ages. Many tendons function in high stress conditions with a low vascular and neuronal supply, conditions often leading to development of chronic tendinopathies, and in some cases, overt rupture of the tissues. Given their essential nature for human mobility and navigation through the environment, the effective repair and regeneration of different tendons after injury or damage is critical for quality of life, and for elite athletes, the return to sport participation at a high level. However, for mainly unknown reasons, the outcomes following injury are not always successful and lead to functional compromise and risk for re-injury. Thus, there is a need to identify those patients who are at risk for developing tendon problems, as well those at risk for poor outcomes after injury and to design interventions to improve outcomes after injury or rupture to specific tendons. This review will discuss recent advances in the identification of biomarkers prognostic for successful and less successful outcomes after tendon injury, and the mechanistic implications of such biomarkers, as well as the potential for specific biologic interventions to enhance outcomes to improve both quality of life and a return to participation in sports. In addition, the implication of these biomarkers for clinical trial design is discussed, as is the issue of whether such biomarkers for successful healing of one tendon can be extended to all tendons or are valid only for tendons in specific biomechanical and biological environments. As maintaining an active lifestyle is critical for health, the successful implementation of these advances will benefit the large number of individuals at risk.

Optimizing tendon repair and regeneration: how does the in vivo environment shape outcomes following rupture of a tendon such as the Achilles tendon?

“…Thus, repair of a tendon such as a flexor tendon of the hand that functions in the context of a sheath, adhesions can develop post-surgery leading to loss of function [discussed in Kuroiwa and Amadio (2023)], a condition that can be influenced by a variety of interventions (Wiig et al, 2014;Edsfeldt et al, 2017;Jiang K. et al, 2023). In the case of the AT, some individuals heal naturally after surgery with a long-term good outcome, while others provided the same surgical procedure ± later versus early loading experience a much less satisfactory outcome [ (Addevico et al, 2019;Chen et al, 2021;Saarensilta et al, 2023a); discussed in (Hart et al, 2023)]. However, even with surgery the repaired tendon may still be compromised at 2 years post-surgery (Geremia et al, 2015), and thus functional repair likely does not yield regeneration.…”

“…If one suffers a transection or complete rupture of a tendon such as the AT or the flexor tendons of the hand, this injury often requires surgical repair followed by a period of immobilization [discussed in Ackermann et al (2023); Hart et al (2023)]. Furthermore, the faster the patients can receive the surgery, the better the outcomes (Svedman et al, 2018).…”

“…Even with a surgical intervention to join the torn ends of the AT together, patients can experience a good to excellent outcome at 1-year post-injury, or a poor outcome based on validated criteria [discussed in Chen et al (2022); Chen et al (2023); Hart et al (2023)]. Recently, Chen et al ( 2022) and Wu et al (2023) reported that using proteomic approaches and shards of tissue from the torn ends of ruptured AT taken at the time of surgery led to the identification of biomarkers of good versus poor outcomes at 1-year post-injury.…”

“…In conservative treatment protocols, early mobilization is likely recommended compared to prolonged immobilization via casting (Kangas et al, 2003;Van der Eng et al, 2013), but issues around re-rupture rate and other complications still remain to be resolved in detail. Given the heterogeneity in patient outcomes even within the surgical treatment cohorts [ (Svedman et al, 2018); discussed in Hart et al (2023)], it is also likely, but not proven, that heterogeneity may also exist within the conservative treatment population as well. Thus, comparing two heterogeneous populations within both the surgical and non-surgical groups may lead to an obscuring of differences in outcomes.…”

“…While the interventions identified above are quite diverse in their chemical, biochemical and cellular basis, their impact on improving clinical outcomes is variable, in part due to the heterogeneity of the patients and the quality of the local postinjury environment (discussed in the last paragraph of the Introduction section), as well as the fact that nearly all patients receiving cellular interventions (i.e., PRP, stem cells, and other cellular preparations) prefer to receive autologous materials which may not be optimal to impact outcomes [discussed in Kydd and Hart (2020); Hart and Nakamura (2022)]. Going forward, using tools such as biomarkers of good versus poor clinical outcomes could enhance the use of some of those interventions identified above to improve the outcomes of selected patient subsets (Hart et al, 2023).…”