Combat- and non-combat related musculoskeletal injuries (MSKIs) are major causes of lost duty days within the United States Armed Forces. The amount of MSKI-related medically-restricted duty time is a significant impediment to the medical readiness of the United States Armed Forces. While combat-related MSKIs are often more severe, non-combat-related musculoskeletal injuries are more common and account for the majority of the lost duty time (Schneider et al., 2000). MSKIs affect approximately 500,000 Service members annually (Armed Forces Health Surveillance Branch, 2020), and account for 65% of the medical non-deployable population (Molloy et al., 2020). The total economic impact of musculoskeletal injuries within the United States Armed Forces is estimated at $3.7 billion per year, of which direct medical related costs exceed $700 million (Nindl et al., 2013). MSKIs are an even larger burden among United States civilians, with an estimated 1 in 2 adults afflicted with a musculoskeletal disorder, burdening society to the tune of $874 billion annually (United States Bone and Joint Initiative, 2016).

Owing to the body’s endogenous capacity to repair some damaged tissues, the majority of MSKIs result in eventual return-to-duty/activity with no long-term limitations. This is especially true for those on the minor end of the severity spectrum. As such, traditional non-surgical treatment approaches for MSKIs focus on pain management, immobilization, managing inflammation, and physical rehabilitation (Wascher and Bulthuis, 2014). Even with these treatment approaches, recovery is often a long process. For the most common MSKIs, recovery times result in more than 14 limited duty days per injury, with some resulting in 120 limited duty days (Ruscio et al., 2010). During this time, physical activity is commonly limited in a manner that reduces Service member’s function and their ability to perform required duties. As such, there exists an urgent clinically unmet need to expedite tissue healing kinetics following MSKI. Stated differently, the ability to accelerate MSKI healing rate would greatly benefit military and civilian populations alike.

The pressing need to accelerate the endogenous MSKSI recovery timelines requires the development and evaluation of novel therapeutic agents. Traditionally, this type of development lifecycle would require an extensive investment of time and resources into the research and development pipeline needed to develop novel therapeutics (e.g., small molecules and/or orthobiologics) de novo. However, given the current existence of a broad portfolio of interventions already under regulatory approval for other indications, there potentially exists an opportunity to leverage or repurpose existing clinically available agents for the accelerated healing of MSKIs to enable near-term, clinically meaningful improvements in the current standard of care, subsequent MSKI outcomes, and readiness of the United States Armed Forces. Notably, historic efforts which utilize a repurposed intervention are up to 10 times less expensive to bring to market and do so in about half the amount of time, compared to novel interventions (Pushpakom et al., 2019). Thus, Repurposing Existing Products to Accelerate Injury Recovery (REPAIR) may be the ideal paradigm for making near-term progress for decreasing the burden of MSKIs within the United States Armed Forces. To that end, the intent of this perspective is to provide a theoretical framework for the types of MSKIs that could be addressed, potential targets of opportunity for further research, and practical considerations for REPAIR.

In the United States Armed Forces, the most common acute MSKIs are sprains/strains (48.5%), contusion/superficial injuries (13.9%), and fractures (10.5%) (Stahlman and Taubman, 2018). Acute MSKIs occur when mechanical properties of a tissue are exceeded and tissue rupture occurs. This can occur due to forces generated within the body (e.g., non-contact anterior cruciate ligament sprain) or from an outside traumatic force (e.g., laceration). Acute MSKIs follow the typical four-phased wound healing process of hemostasis, inflammation, proliferation, and remodeling (Velnar et al., 2009). Dysfunction in the endogenous repair process or repeated re-injury before repair is complete can cause acute MSKIs to become chronic and may result in them adopting pathophysiological characteristics of overuse MSKIs (Arendt-Nielsen et al., 2011).

Overuse MSKIs are four times more common than acute MSKIs in Service members and most commonly include stress fractures, tendinitis, bursitis, and fasciitis (Hauret et al., 2010). These injuries are caused by repeated physical activity that exceeds the body’s ability to adapt. This may be due to normal tissue repair being insufficient for the rate of tissue breakdown or from dysfunction of the tissue repair process itself (Aicale et al., 2018). Regardless, insufficient tissue repair results in degeneration of musculoskeletal tissues, causing inflammation and pain.

Acute and overuse MSKIs present unique challenges that likely require different treatment modalities (Walsh et al., 2008; Dhillon et al., 2017). A successful MSKI therapeutic (or combination thereof) will likely need to be tailored to both the affected tissues and the cause of injury. Not only do tissues contain unique cell populations that respond differently to specific signals, but their function and organization also vastly differ. Histologically, tissues can have drastic differences such as a tissue that provides passive structure and is mostly extracellular matrix (e.g., bone), or a tissue that is highly cellular whose major function is movement (e.g., skeletal muscle) (Betts et al., 2013). There are differences in other fundamental traits, such as vascularity—e.g., cartilage is avascular and skeletal muscle is highly vascular (Betts et al., 2013).

To this end, performing research using the REPAIR paradigm has the potential to identify therapeutics that target endogenous musculoskeletal recovery mechanisms. By developing these candidates for specific MSKI indications, they can aid in the faster healing of injured tissue and a more timely return of function to pre-injury levels. Doing so would culminate in earlier return-to-duty/activity and mitigate re-injury risks, further reducing long term loss of duty.

The following sections provide high-level overviews of some physiologic targets of opportunity for potential REPAIR candidates which may warrant consideration for further research investigations. Information is summarized in Table 1.

There are several important design criteria for scientists and clinicians to consider when evaluating potential REPAIR-themed candidates (Table 2). As stated previously, a majority of MSKIs eventually recover on their own and Service members return-to-duty/activity with little/no limitations. As such, adverse side effects from a therapeutic should be as minimal as possible (if at all), as to not exceed the therapies’ expected benefit(s). Any developed REPAIR therapeutic would ideally be additive or synergistic with current treatments of rehabilitation, surgery, and pain management. To meet the high demand imposed by MSKIs, a treatment would need to be mass produced and cost effective. The complexity of the therapeutic should be kept low. Ideally, a REPAIR therapeutic can be self-administered. If increasing the dose at the site of injury while minimizing off target effects is needed, localized approaches such as a topical cream or patch, or at a higher complexity, an injection, might be useful. A REPAIR treatment that requires a medical professional to administer is best if limited to the need of a single administration to avoid repeated visits. An ideal effective treatment would be kept in stock at medical facilities and perhaps even carried by a field medic and thus a long shelf-life and ease of storage, small size, and stable across a range of temperatures, are desired.

In addition to the efficacy of a REPAIR therapeutic accelerating MSKI recovery time, consideration should also be taken for long (er)-term implications. MSKIs can increase the risk for a subsequent MSKI by seven times (Schneider et al., 2000). A specific example is the risk of developing osteoarthritis, the leading cause of disability discharge (Cameron et al., 2016), is greatly increased by a joint MSKI (Buckwalter and Brown, 2004; Wang et al., 2020). Thus, mitigating secondary and tertiary injury risks via improved recovery could yield long-term benefits for lost duty by the reduction in total injury occurrence. Research using risk factors for future injuries as an outcome metric would be beneficial in addition to metrics related to regain of function from the current injury.

MSKIs result in a significant burden on the United States Armed Forces in terms of both costs and lost duty time, and thus are a major impediment to readiness (Schneider et al., 2000; Nindl et al., 2013)^,. There is an unmet need for therapies that accelerate MSKI recovery time and mitigate MSKI recurrence risks. There are existing therapies for other indications that, pending beneficial efficacy data from needed research investigations, may fill this need. Notably, if/when forthcoming research data support its use, rather than the monumental investment of resources (i.e., time and money) needed to develop and evaluate an intervention de novo, the REPAIR paradigm described herein has the benefit of leveraging prior investments, often from the federal sector (e.g., National Institute of Health, Department of Defense), such that research and design of potential MSKI specific indications would occur in a more cost and time effective manner. Thus, utilizing the REPAIR paradigm to leverage existing technologies for the development of treatments for common MSKIs could make more significant near-term progress at decreasing the present MSKI burden and increasing overall military readiness.