The superior healing capacity of MRL tendons is minimally influenced by the systemic environment of the MRL mouse.

Murphy Roths Large mice (MRL) exhibit improved tendon healing and are often described as a "super-healer" strain. The underlying mechanisms that drive the superior healing response of MRL remain a controversial subject. We utilized a tendon transplantation model between MRL and "normal-healer" B6-mice to differentiate between the contribution of MRL's innate tendon and systemic environment to its improved healing capacity. Patellar tendons with a midsubstance punch injury were transplanted back into the same animal (autograft) or into an animal of the other strain (allograft). Findings at 4 weeks showed that the innate MRL tendon environment drives its improved healing capacity as demonstrated by improved stiffness and maximum load in MRL-grafts-in-B6-host-allografts compared to B6-autografts, and higher modulus in MRL-autografts compared to B6-graft-in-MRL-host-allografts. Groups with an MRL component showed an increase in pro-inflammatory cytokines in the 3 days after injury, suggesting an early enhanced inflammatory profile in MRL that ultimately resolves. A preserved range of motion of the knee joint in all MRL animals suggests a systemic "shielding effect" of MRL in regard to joint adhesiveness. Our findings 4-weeks post injury are consistent with previous studies showing tissue-driven improved healing and suggest that the systemic environment contributes to the overall healing process.

Histological and immunohistochemical guide to tendon tissue.

Tendons are unique dense connective tissues with discrete zones having specific structure and function. They are juxtaposed with other tissues (e.g., bone, muscle, and fat) with different compositional, structural, and mechanical properties. Additionally, tendon properties change drastically with growth and development, disease, aging, and injury. Consequently, there are unique challenges to performing high quality histological assessment of this tissue. To address this need, histological assessment was one of the breakout session topics at the 2022 Orthopaedic Research Society (ORS) Tendon Conference hosted at the University of Pennsylvania. The purpose of the breakout session was to discuss needs from members of the ORS Tendon Section related to histological procedures, data presentation, knowledge dissemination, and guidelines for future work. Therefore, this review provides a brief overview of the outcomes of this discussion and provides a set of guidelines, based on the perspectives from our laboratories, for histological assessment to assist researchers in their quest to utilize these techniques to enhance the outcomes and interpretations of their studies.

Mechanobiological considerations in colorectal stapling: Implications for technology development.

Technological advancements in minimally invasive surgery have led to significant improvements in patient outcomes. One such technology is surgical stapling, which has evolved into a key component of many operating rooms by facilitating ease and efficacy in resection and repair of diseased or otherwise compromised tissue. Despite such advancements, adverse post-operative outcomes such as anastomotic leak remain a persistent problem in surgical stapling and its correlates (i.e., hand-sewing), most notably in low colorectal or coloanal procedures. Many factors may drive anastomotic leaks, including tissue perfusion, microbiome composition, and patient factors such as pre-existing disease. Surgical intervention induces complex acute and chronic changes to the mechanical environment of the tissue; however, roles of mechanical forces in post-operative healing remain poorly characterized. It is well known that cells sense and respond to their local mechanical environment and that dysfunction of this "mechanosensing" phenomenon contributes to a myriad of diseases. Mechanosensing has been investigated in wound healing contexts such as dermal incisional and excisional wounds and development of pressure ulcers; however, reports investigating roles of mechanical forces in adverse post-operative gastrointestinal wound healing are lacking. To understand this relationship well, it is critical to understand: 1) the intraoperative material responses of tissue to surgical intervention, and 2) the post-operative mechanobiological response of the tissue to surgically imposed forces. In this review, we summarize the state of the field in each of these contexts while highlighting areas of opportunity for discovery and innovation which can positively impact patient outcomes in minimally invasive surgery.

Enhanced healing outcomes in MRL/MpJ mouse tissues conserved in insertion site following surgical repair.

BACKGROUND: Surgical repair of supraspinatus tendons (SSTs) has a high failure rate at the insertion site. A significant hurdle to therapeutic development is that effective intrinsic healing mechanisms are unknown. The MRL/MpJ (MRL) mouse exhibits tissue-specific enhanced healing; however, these tissues exhibit disparate properties from the complex SST. The extent of SST healing in the complex environment of the rotator cuff is unknown. We hypothesized that MRL mice would exhibit enhanced restoration of the structurally complex insertion site, resulting in functional improvements. METHODS: B6 and MRL mice underwent SST detachment and immediate surgical repair. Mice were analyzed for gait assessment after either 2 or 6 weeks and were then killed humanely for immunohistologic analysis. RESULTS: MRL SSTs demonstrated enhanced recovery of zonal architecture and bone structure compared with B6 SSTs. MRL SSTs exhibited decreased levels of type III collagen at 2 weeks and increased levels of type I procollagen at 6 weeks compared with B6 SSTs. MRL mice experienced initial gait deficits at 2 weeks that had recovered by 6 weeks. DISCUSSION: The temporal balance of collagen in MRL mice suggests recovery toward naive composition. Initial gait deficits in MRL mice may provide a protective loading environment that is ultimately beneficial. The mechanisms of enhanced healing observed previously in MRL mice may be conserved in the complex SST, providing a platform to interrogate specific aspects of improved healing.

The role of the tendon ECM in mechanotransduction: disruption and repair following overuse.

Purpose: Tendon overuse injuries are prevalent conditions with limited therapeutic options to halt disease progression. The specialized extracellular matrix (ECM) both enables joint function and mediates mechanical signals to tendon cells, driving biological responses to exercise or injury. With overuse, tendon ECM composition and structure changes at multiple scales, disrupting mechanotransduction and resulting in inadequate repair and disease progression. This review highlights the multiscale ECM changes that occur with tendon overuse and corresponding effects on cell-matrix interactions and cellular response to load.Results: Different functional joint requirements and tendon types experience a wide range of loading profiles, creating varied downstream mechanical stimuli. Distinct ECM structure and mechanical properties within the fascicle matrix, interfascicle matrix, and enthesis and their varied disruption with overuse are considered. The pericellular matrix (PCM) comprising the microscale tendon cell environment has a unique composition that changes with overuse injury and exercise, suggesting an important role in mechanotransduction and promoting repair. Cell-matrix interactions are mediated by structures including cilia, integrins, connexins and cytoskeleton that signal downstream homeostasis, adaptation, or repair. ECM disruption with tendon overuse may cause altered mechanical loading and cell-matrix interactions, resulting in mechanobiological understimulation, apoptosis, and ineffective repair. Current interventions to promote repair of tendon overuse injuries including exercise, targeting cell signaling, and modulating inflammation are considered.Conclusion: Future therapeutics should be assessed with regard of their effects on multiscale mechanotransduction in addition to joint function, with consideration of the central role of ECM.