Timed Delivery of Therapy Enhances Functional Muscle Regeneration

Abstract

Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Typically, previous investigations have focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here we study how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell engraftment and the functional repair of severely injured muscle. Delivery of a biomaterial-based therapy timed with the peak of injury-induced inflammation leads to potent early and long-term regenerative benefits. Diminished inflammation and fibrosis, enhanced angiogenesis, and increased cell engraftment are seen during the acute stage following optimally timed treatment. Over the long-term, treatment during peak inflammation leads to enhanced functional regeneration, as indicated by reduced chronic inflammation and fibrosis and increased tissue perfusion and muscle contractile force. Treatments initiated immediately after injury or after inflammation had largely resolved provided more limited benefits. These results demonstrate the importance of appropriately timing the delivery of biologic therapy in the context of muscle regeneration. Biomaterial-based timed delivery can likely be applied to other tissues and is of potential wide utility in regenerative medicine.

CD4 T-cells regulate angiogenesis and myogenesis

“…Immediately after vessel ligation, the calf muscle of the ischemic limb, consisting of the gastrocnemius, plantaris, and soleus muscles, was injected with 50 μL of the alginate gel, consisting of concentrated CM from 2 million T-cells. Injection into the distal limb was done to simultaneously induce angiogenesis and myogenesis in the degenerating ischemic skeletal muscle in the distal limb, as previously described [21, 22]. At days 3 and 6 after vessel ligation, the injections were repeated.…”

Cell therapy to improve regeneration of skeletal muscle injuries

“…Owing to the complexity of the healing cascade and its precise spatiotemporal regulation, it is unlikely that a single molecular factor is able to rescue a tissue from degeneration. Thus, the timed delivery of multiple growth factors could be required . In this regard, Borselli et al .…”

“…Thus, the timed delivery of multiple growth factors could be required. 89 In this regard, Borselli et al have shown that the simultaneous delivery of myogenic (IGF-1) and angiogenic growth factors (VEGF) can promote functional regeneration of ischaemic muscle tissues. 90 However, it is pertinent to note that while this combination of growth factors demonstrated significant benefit in ischaemia, no apparent benefit was observed with the same dose of growth factors in a crush muscle injury model.…”

A multi-functional SiO32−-releasing hydrogel with bioinspired mechanical properties and biodegradability for vascularized skeletal muscle regeneration

“…12 The biological activities of silicate ions relied on their release kinetics from the SRH, 36 which was tested by immersing samples in deionized water for up to 7 days and the critical time period for the delivery of therapy to enhance muscle regeneration. 37 All hydrogels showed an efficient release of silicate ions on the first day (Fig. 2D) when minimal degradation occurred, indicating the ease of silicate ion transport through the hydrogel network.…”