Reptiles are the only amniotes that maintain the capacity to regenerate appendages. This study presents the first anatomical and histological evidence of tail repair with regrowth in an archosaur, the American alligator. The regrown alligator tails constituted approximately 6–18% of the total body length and were morphologically distinct from original tail segments. Gross dissection, radiographs, and magnetic resonance imaging revealed that caudal vertebrae were replaced by a ventrally-positioned, unsegmented endoskeleton. This contrasts with lepidosaurs, where the regenerated tail is radially organized around a central endoskeleton. Furthermore, the regrown alligator tail lacked skeletal muscle and instead consisted of fibrous connective tissue composed of type I and type III collagen fibers. The overproduction of connective tissue shares features with mammalian wound healing or fibrosis. The lack of skeletal muscle contrasts with lizards, but shares similarities with regenerated tails in the tuatara and regenerated limbs in Xenopus adult frogs, which have a cartilaginous endoskeleton surrounded by connective tissue, but lack skeletal muscle. Overall, this study of wild-caught, juvenile American alligator tails identifies a distinct pattern of wound repair in mammals while exhibiting features in common with regeneration in lepidosaurs and amphibia.
Volumetric muscle loss (VML)—defined as the irrecoverable loss of skeletal muscle tissue with associated persistent functional deficits—is among the most common and highly debilitating combat-related extremity injuries. This is particularly true in cases of severe polytrauma wherein multiple extremities may be involved as a result of high energy wounding mechanisms. As such, significant investment and effort has been made toward developing a clinically viable intervention capable of restoring the form and function of the affected musculature. While these investigations conducted to date have varied with respect to the species, breed, and sex of the chosen pre-clinical in-vivo model system, the majority of these studies have been performed in unilateral injury models, an aspect which may not fully exemplify the clinical representation of the multiply injured patient. Furthermore, while various components of the basal pathophysiology of VML (e.g., fibrosis and inflammation) have been investigated, relatively little effort has focused on how the pathophysiology and efficacy of pro-regenerative technologies is altered when there are multiple VML injuries. Thus, the purpose of this study was two-fold: (1) to investigate if/how the pathophysiology of unilateral VML injuries differs from bilateral VML injuries and (2) to interrogate the effect of bilateral VML injuries on the efficacy of a well-characterized regenerative therapy, minced muscle autograft (MMG). In contrast to our hypothesis, we show that bilateral VML injuries exhibit a similar systemic inflammatory response and improved muscle functional recovery, compared to unilateral injured animals. Furthermore, MMG treatment was found to only be effective at promoting an increase in functional outcomes in unilateral VML injuries. The findings presented herein add to the growing knowledge base of the pathophysiology of VML, and, importantly, reiterate the importance of comprehensively characterizing preclinical models which are utilized for early-stage screening of putative therapies as they can directly influence the translational research pipeline.
Musculoskeletal injuries (MSKIs) are a great hindrance to the readiness of the United States Armed Forces through lost duty time and reduced operational capabilities. While most musculoskeletal injuries result in return-to-duty/activity with no (functional) limitations, the healing process is often long. Long healing times coupled with the high frequency of musculoskeletal injuries make them a primary cause of lost/limited duty days. Thus, there exists an urgent, clinically unmet need for interventions to expedite tissue healing kinetics following musculoskeletal injuries to lessen their impact on military readiness and society as a whole. There exist several treatments with regulatory approval for other indications that have pro-regenerative/healing properties, but few have an approved indication for treating musculoskeletal injuries. With the immediate need for treatment options for musculoskeletal injuries, we propose a paradigm of Repurposing Existing Products to Accelerate Injury Recovery (REPAIR). Developing treatments via repurposing existing therapeutics for other indications has shown monumental advantages in both cost effectiveness and reduced time to bring to market compared to novel candidates. Thus, undertaking the needed research efforts to evaluate the effectiveness of promising REPAIR-themed candidates has the potential to enable near-term solutions for optimizing musculoskeletal injuries recovery, thereby addressing a top priority within the United States. Armed Forces. Herein, the REPAIR paradigm is presented, including example targets of opportunity as well as practical considerations for potential technical solutions for the translation of existing therapeutics into clinical practice for musculoskeletal injuries.
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