Decellularized extracellular matrix repair of volumetric muscle loss injury impairs adjacent bone healing in a rat model of complex musculoskeletal trauma

Abstract

Background: Traumatic muscle loss (i.e., volumetric muscle loss [VML] injury) impairs adjacent fracture healing but is often left untreated. A promising therapy for this application is a decellularized extracellular matrix (ECM) because of their capacity to regenerate a vascularized tissue bed. This study tested the hypothesis that repair of VML concomitant to fracture with a small intestine submucosa (SIS)-ECM improves musculoskeletal healing.

Methods: In male Lewis rats (~375 g), a 3-mm segmental bone defect (SBD) was created in concomitance with a 6-mm, full-thickness VML injury to the adjacent tibialis anterior (TA) muscle. For all rats (n = 10), the SBD was treated with internal plate fixation and delivery of recombinant human bone morphogenetic protein 2 (1 μg) on a collagen sponge. The VML either had no repair or SIS-ECM repair (n = 5/group). Bone regeneration within the SBD (BV/TV [bone volume as a fraction of total volume]) was assessed via in vivo micro-computed tomography at 2, 4, and 6 weeks and histology at 6 weeks after injury. Tibialis anterior muscle in vivo strength and histologic assessments were performed at 6 weeks after injury.

Results: Compared with no repair, SIS-ECM presented -21% (p = 0.09) and -27% (p = 0.004) BV/TV at 4 and 6 weeks after injury, respectively. At 6 weeks, the SBD gap length was shorter for the no repair than that for the SIS-ECM (2.64 ± 0.30 and 3.67 ± 0.41 mm, respectively; p = 0.09), whereas the distances from the end of each cortical segment to the center of the first stabilization screw were longer (1.86 ± 0.25 and 0.85 ± 0.30 mm, respectively; p = 0.035), indicating enhanced resorption in the SIS-ECM group. Both groups presented similar magnitude TA muscle strength deficits compared with their contralateral limbs (10-150 Hz: no repair, -58% to 67%; SIS-ECM, -51% to 74%). The TA muscle of the SIS-ECM group was remarkable for its presentation of fibrosis, edema, and immune cell presence.

Conclusions: Small intestine submucosa-ECM VML repair impaired open fracture healing and failed to improve skeletal muscle strength.