Co-delivery of a laminin-111 supplemented hyaluronic acid based hydrogel with minced muscle graft in the treatment of volumetric muscle loss injury

Abstract

Minced muscle autografting mediates de novo myofiber regeneration and promotes partial recovery of neuromuscular strength after volumetric muscle loss injury (VML). A major limitation of this approach is the availability of sufficient donor tissue for the treatment of relatively large VMLs without inducing donor site morbidity. This study evaluated a laminin-111 supplemented hyaluronic acid based hydrogel (HA+LMN) as a putative myoconductive scaffolding to be co-delivered with minced muscle grafts. In a rat tibialis anterior muscle VML model, delivery of a reduced dose of minced muscle graft (50% of VML defect) within HA+LMN resulted in a 42% improvement of peak tetanic torque production over unrepaired VML affected limbs. However, the improvement in strength was not improved compared to a 50% minced graft-only control group. Moreover, histological analysis revealed that the improvement in in vivo functional capacity mediated by minced grafts in HA+LMN was not accompanied by a particularly robust graft mediated regenerative response as determined through donor cell tracking of the GFP+ grafting material. Characterization of the spatial distribution and density of macrophage and satellite cell populations indicated that the combination therapy damps the heightened macrophage response while re-establishing satellite content 14 days after VML to a level consistent with an endogenously healing ischemia-reperfusion induced muscle injury. Moreover, regional analysis revealed that the combination therapy increased satellite cell density mostly in the remaining musculature, as opposed to the defect area. Based on the results, the following salient conclusions were drawn: 1) functional recovery mediated by the combination therapy is likely due to a superposition of de novo muscle fiber regeneration and augmented repair of muscle fibers within the remaining musculature, and 2) The capacity for VML therapies to augment regeneration and repair within the remaining musculature may have significant clinical impact and warrants further exploration.

Biomimetic sponges for regeneration of skeletal muscle following trauma

“…Many of the tissue‐engineered scaffolds are either mechanically unsuitable or fail to enhance tissue‐resident stem cell activity . We are only aware of one other study where LM‐111 was delivered to the site of VML injury using hydrogels composed of hyaluronic acid and poly(ethylene glycol) . The study reported little to no cellular infiltration into the defect owing to the largely intact and undegraded hydrogels.…”

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

“…132,133,[158][159][160][161][162] In a subsequent study, Corona and coworkers investigated a laminin-111 supplemented PEG-hyaluronic acidbased hydrogel as a delivery vehicle for minced muscle grafts for VML injuries. 163 At 8 weeks, the hydrogels were found to be wholly intact and did not support cellular infiltration into the defect site. The lack of cellular infiltration was associated 3 1255 with impaired muscle regeneration and function.…”

“…In a subsequent study, Corona and coworkers investigated a laminin‐111 supplemented PEG‐hyaluronic acid‐based hydrogel as a delivery vehicle for minced muscle grafts for VML injuries . At 8 weeks, the hydrogels were found to be wholly intact and did not support cellular infiltration into the defect site.…”

Musculoskeletal Regeneration, Rehabilitation, and Plasticity Following Traumatic Injury

“…The permanent loss of muscle fibers is due to a fundamental loss of native regenerative elements required for skeletal muscle regeneration, such as the basal lamina and satellite cells [75][76][77]. Additionally, rodent and porcine animal models of VML injury have observed a heightened and prolonged inflammatory response [78,79] that significantly deviates from that observed in recoverable injury models such as ischemia reperfusion injury [80]. The prolonged inflammatory response after VML injury appears to drive extracellular matrix protein production and deposition, resulting in extensive compartmental fibrosis [81,82].…”