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 inXenopusadult 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.

Volumetric muscle loss (VML) is a severe injury resulting in substantial skeletal muscle loss, leading to a complex pathology that culminates in suboptimal tissue repair and significant long-term functional deficits. This study employs a rodent model of VML to investigate the impact of biological sex on the injury pathobiology and its potential influence on the response to autologous minced muscle grafting (MMG) as a regenerative therapy. While no significant differences were observed between the end-stage male and female responses to VML, both male and female subjects appeared to benefit from MMG treatment. Females demonstrated improved neuromuscular function, while males exhibited reduced fibrosis at the site of injury. Additional differences in the wound healing response included distinct variations in myofiber characteristics, with females exhibiting a lower proportion of Type 2a fibers and elevated levels of myogenin. These findings suggest that regenerative therapies, such as MMG, may exhibit sex-specific benefits. Future studies will further explore sexual dimorphism in the acute response to injury to identify potential therapeutic targets that may yield greater therapeutic efficacy for each sex.

Volumetric muscle loss (VML) represents a devastating extremity injury which leads to chronic functional deficits and disability and is unrecoverable through normal healing pathways. When left untreated, the VML pathophysiology creates many challenges towards successful treatment, such as altered residual muscle architecture, excessive fibrosis, and contracture(s). As such, innovative approaches and technologies are needed to prevent or reverse these adverse sequelae. Development of a rationally designed biomaterial technology which is intended to be acutely placed within a VML defect – i.e., to serve as a muscle void filler (MVF) by maintaining the VML defect – could address this clinical unmet need by preventing these adverse sequelae as well as enabling multi-staged treatment approaches. To that end, three biomaterials were evaluated for their ability to serve as a provisional MVF treatment intended to stabilize a VML defect in a rat model for an extended period (28 days): polyvinyl alcohol (PVA), hyaluronic acid and polyethylene glycol combination (HA + PEG), and silicone, a clinically used soft tissue void filler. HA + PEG biomaterial showed signs of deformation, while both PVA and silicone did not. There were no differences between treatment groups for their effects on adjacent muscle fiber count and size distribution. Not surprisingly, silicone elicited robust fibrotic response resulting in a fibrotic barrier with a large infiltration of macrophages, a response not seen with either the PVA or HA + PEG. Taken together, PVA was found to be the best material to be used as a provisional MVF for maintaining VML defect volume while minimizing adverse effects on the surrounding muscle.

Treatment of volumetric muscle loss (VML) faces challenges due to its unique pathobiology and lower priority in severe musculoskeletal injury management. Consequently, a need exists for multi-stage VML treatment strategies to accommodate delayed interventions owing to comorbidity management or prolonged casualty care in combat settings. To this end, polyvinyl alcohol (PVA) was used at concentrations of 5%, 7.5%, and 10% to generate provisional muscle void fillers (MVFs) of varying stiffness values (1.125 kPa, 3.700 kPa, and 7.699 kPa) to stabilize VML injuries as part of a two-stage approach. These were implanted into a rat model for a duration of 4 weeks, then explanted and either left untreated (control) or treated through minced muscle grafting (MMG). Additional benchmarks included acute MMG and unrepaired groups. At the MVF explant, the 7.5% PVA group exhibited superior neuromuscular function compared to the 5% and 10% PVA groups, the least fibrosis, and the largest median myofiber size among all groups at the 12-week endpoint. Despite the 7.5% PVA’s superiority amongst the two-stage treatment groups, neuromuscular function was neither improved nor impaired relative to acute treatment benchmarks. This suggests that the future success of a two-stage VML treatment strategy will necessitate a more effective definitive intervention.

Aims: This study aimed to assess the effects of chondrogenic agents kartogenin (KGN) and KA9 in combination with anakinra (ANR), an interleukin (IL) 1 receptor antagonist (IL1RA) on post-traumatic osteoarthritis (PTOA) progression following intra-articular fractures (IAF). The hypothesis was that this immunoregenerative approach would promote osteochondral healing and alleviate PTOA more effectively than individual treatments or controls. Methods: Male Lewis rats (n = 78) underwent IAF, followed by weekly intra-articular injection of saline (control), KGN, or KA9 in conjunction with the systemic administration of saline (control) or ANR via osmotic pumps. Inflammatory and osteochondral markers were assessed through serum and synovial fluid analysis, micro-CT (µCT) for bone parameters, contrast-enhanced µCT for cartilage evaluation, histopathological analysis, and immunohistochemistry (IHC). Results: Immunoregenerative treatments did not adversely affect animal wellbeing. While local inflammation markers were minimally affected, some osteochondral remodelling markers indicated that KGN, KA9, and their combination with ANR reduced markers of osteochondral degradation. Bone analysis showed improved trabecular morphometry parameters and reduced bone surface with some treatments, and cartilage composition and thickness improved with treatments, although the effects were inconsistent across groups. Osteoarthritis Research Society International scores revealed location-specific variations in pathology, and IHC staining demonstrated intergroup differences in protein expression at different timepoints. Conclusion: This study suggests that KGN and KA9 may offer some protection against PTOA by influencing cartilage and subchondral bone health, and that the combination with ANR shows potential for enhanced effects. However, the results were mixed, with no treatment group consistently demonstrating positive improvements across all outcomes. The complexity of developing a novel immunoregenerative therapy for PTOA is highlighted by the variability in treatment response. Cite this article: Bone Joint Res 2026;15(3):264–277.