Severe skeletal muscle trauma resulting from ischemic damage, nerve transection injuries, or volumetric defects is an intractable problem. Dysfunction and disability owing to the latter are an increasingly significant clinical burden. To address this challenge, this proposal seeks to develop biomaterial delivery systems that regulate the micro-environmental factors that harness the pro-regenerative functions of recruited blood monocytes to enhance volumetric muscle healing outcomes. In a pre-clinical model of volumetric muscle loss, we have shown that delivery of immune modulatory small molecules targeted to bioactive lipid receptors increases wound repair macrophages within the injury niche and enhances repair mechanisms such as angiogenesis, matrix deposition, and muscle fiber regrowth. The overall hypothesis for the proposed research is that local pharmacological targeting of sphingosine 1-phosphate (S1P) receptors uniquely recruits Ly6Clo monocytes directly from blood to the injury niche where they serve as biased progenitors of wound healing macrophages within injured muscle.
Our specific aims are as follows:
Aim 1 : To characterize inflammatory infiltrate into the murine spinotrapezius volumetric muscle loss model and immune cell interactions with muscle satellite cells;
Aim 2 : To assess the impact of local delivery of S1P receptor targeted small molecules from polymer scaffolds on myeloid cell accumulation and behavior after skeletal muscle injury;
Aim 3 : To evaluate functional outcomes within a critical-sized volumetric defect in the murine quadriceps in response to local delivery of S1P receptor targeted small molecules. As the sequelae of muscle injuries increases at a disproportionate rate with advancing age, the burden of muscle injury on an aging domestic population will be increasingly severe. Thud, mechanisms surrounding the healing of volumetric muscle defects must be elucidated in order to advance translational therapeutics.
Rotator cuff tears (RCTs) are present in up to 39% of the asymptomatic population and 64% of the population presenting symptoms such as shoulder pain and decreased strength and range of motion. Failed repairs result in significantly more muscle degeneration, and even successful repairs fail to reverse or reduce this pathological process. Muscle degeneration is a strong predictor of patient outcomes: fatty infiltration and atrophy of the muscle correlate with pain, functional deficits, and post-surgical tear recurrence. Thus, therapies that slow or reverse muscle degeneration promise to improve clinical outcomes after RCT and decrease total societal costs.
| Tellier, L E; Krieger, J R; Brimeyer, A L et al. (2018) Localized SDF-1? Delivery Increases Pro-Healing Bone Marrow-Derived Cells in the Supraspinatus Muscle Following Severe Rotator Cuff Injury. Regen Eng Transl Med 4:92-103 |
| Krieger, Jack R; Sok, Mary Caitlin P; Turner, Thomas C et al. (2018) Delivery of Immunomodulatory Microparticles in a Murine Model of Rotator Cuff Tear. MRS Adv 3:1341-1346 |
