Xenogeneic extracellular matrix as an inductive scaffold for regeneration of a functioning musculotendinous junction.

The prevailing dogma in tissue engineering is cell-centric. One shortcoming of this approach is the failure to provide the implanted cells with a suitable in vivo microenvironment that promotes tissue reconstruction. Extracellular matrix (ECM)-based scaffolds provide a three-dimensional microenvironment that can promote constructive and functional tissue remodeling rather than inflammation and scarring even in the absence of any implanted cells. The objective of this study was to determine the ability of an ECM-based scaffold to facilitate functional restoration of the distal gastrocnemius musculotendinous junction in a canine model after complete resection of the tissue. Within 6 months, vascularized, innervated skeletal muscle that was similar to normal muscle tissue had formed at the ECM-scaffold implantation site. This neo-tissue generated 48% of the contractile force of contralateral musculotendinous junction and represents the first report of de novo formation of contractile, vascularized, and innervated skeletal muscle in situ after significant tissue loss.

Constructive remodeling of biologic scaffolds is dependent on early exposure to physiologic bladder filling in a canine partial cystectomy model.

Biologic scaffolds composed of extracellular matrix (ECM) have been used to facilitate the constructive remodeling of several tissue types. Previous studies suggest that the ECM scaffold remodeling process is dependent on microenvironmental factors, including tissue-specific biomechanical loading. The objective of the present study was to evaluate the effects of long-term catheterization (LTC), with its associated inhibition of bladder filling and physiologic biomechanical loading, on ECM scaffold remodeling following partial cystectomy in a canine model. Reconstruction of the partial cystectomy site was performed using ECM scaffolds prepared from porcine small intestinal submucosa (SIS) or porcine urinary bladder matrix (UBM). Animals were randomly assigned to either a long-term catheterization (LTC) group (n=5, catheterized 28 d) or a short-term catheterization group (STC, n=5, catheterized 24 h), and scaffold remodeling was assessed by histologic methods at 4 and 12 wk postoperatively. By 4 wk, animals in the STC group showed a well-developed and highly differentiated urothelium, a robust vascularization network, abundant smooth muscle actin (SMA), and smooth muscle myosin heavy chain (smMHC) expressing spindle-shaped cells, and many neuronal processes associated with newly formed arterioles. In contrast, at 4 wk the scaffolds in LTC animals were not epithelialized, and did not express neuronal markers. The scaffolds in the LTC group developed a dense granulation tissue containing SMA+, smMHC-, spindle-shaped cells that were morphologically and phenotypically consistent with myofibroblasts, but not smooth muscle cells. By 12 wk postoperatively, the ECM scaffolds in the STC animals showed a constructive remodeling response, with a differentiated urothelium and islands of smooth muscle cells within the remodeled scaffold. In contrast, at 12 wk the scaffolds in LTC animals had a remodeling response more consistent with fibrosis even though catheters had been removed 8 wk earlier. These findings show that early exposure of site-appropriate mechanical loading (i.e., bladder filling) mediates a constructive remodeling response after ECM repair in a canine partial cystectomy model.