Tendinopathy results in progressive tendon degeneration and is associated with pain, progressive muscle weakness, and ultimately tendon failure. In the shoulder, tendinopathy of the rotator cuff affects 30% of individuals over 60 years of age, and impairs their ability to perform common activities of daily living. These injuries are managed conservatively and/or surgically. Tendon tear size, chronicity, muscle retraction, fatty muscle atrophy, and fibrosis are interrelated characteristics of rotator cuff tears and are associated with poor outcomes. Importantly, these muscle changes appear to be insensitive to rehabilitation even in the presence of a successful surgical repair of the tendon. We have recently developed an injectable, tissue specific extracellular matrix (ECM) hydrogel, which is derived from decellularized porcine skeletal muscle, and have shown that it promotes muscle regeneration via increasing vascularization, enhancing the recruitment and proliferation of muscle progenitors, and reducing cell death. These findings lead to our overall theoretical framework for a high impact intervention aimed at improving muscle recovery and ultimately functional outcomes. Specifically, progressive tendon degeneration leads to progressive muscle retraction, which ultimately causes overwhelming degeneration. Therefore, a regenerative stimulus at the time of muscle reloading (surgical tendon repair) is required to initiate long-term tissue recovery. Our broad central hypothesis is that chronic muscle atrophy and degeneration are reversible with surgical tendon repair plus an injection of a skeletal muscle ECM hydrogel.
Specific Aim 1 will measure acute (5 days) histological, protein, and gene expression changes in a rabbit model of chronically degenerated muscle after surgical rotator cuff tendon repair and ECM hydrogel injections.
Specific Aim 2 will measure subacute (8 weeks post-repair) physiological, histological, and protein changes in these chronically degenerated muscles after surgical tendon repair and ECM hydrogel injections. These experiments will determine if muscle recovery occurs after delivering a supplemental, low-cost, non cell-based regenerative therapy during surgical tendon repair in a chronically degenerated muscle. We expect a near term impact on surgery and rehabilitation because these findings will provide evidence for preliminary human trials. Together, the PIs have a long-standing history of productivity in preclinical and human experiments for rotator cuff disease, and translation of ECM hydrogels into patients, so we are well suited to execute and rapidly translate these experiments to humans.
Tendinopathy results in progressive tendon degeneration and is associated with pain and progressive muscle degeneration and weakness. Surgical repair and rehabilitation yields relatively poor outcomes as muscle size and strength do not recover. Here we propose that chronic muscle atrophy and degeneration are reversible with surgical tendon repair plus an injection of muscle-derived ECM hydrogel.
