Keshav Shah
BME PhD Proposal Presentation
Date: 2023-09-13
Time: 1:15 PM
Location / Meeting Link: Children's Healthcare of Atlanta Seminar Room, EBB / https://gatech.zoom.us/j/93347241397
Committee Members:
Johnna Temenoff, PhD (advisor); Ahmet Coskun, PhD; Melissa Kemp, PhD; Young Jang, PhD; Nick Willett, PhD
Title: Biomaterial-Based Mesenchymal Stromal Cell Delivery for the Treatment of Spatially Variant Muscle Degeneration after Rotator Cuff Tear
Abstract:
Rotator cuff tear (RCT) is a significant clinical problem, and its prevalence increases with increasing age. Following rotator cuff tendon tear, the associated muscle undergoes degeneration in the form of fatty and fibrous infiltration and muscle atrophy. Surgical intervention fails to address muscle degeneration, yet this attribute has been correlated with poor clinical outcomes following treatment. Additionally, rotator cuff muscle has been shown to degenerate asymmetrically, a characteristic that is also not addressed clinically. Therefore, a better understanding of spatially variant muscle degeneration could facilitate the development of more efficacious therapies for these injuries. Recent studies have demonstrated a reduction in rotator cuff muscle degeneration after transplantation of mesenchymal stromal cells (MSCs). However, MSC-based therapies for musculoskeletal diseases have been plagued in part by a lack of effective methods to retain and assess cells at the site of injury once transplanted. Thus, the long-term goal of this research is to develop improved biomaterial-based strategies for delivery of MSCs to facilitate repair of rotator cuff muscle after massive rotator cuff tears. Towards attainment of this goal, the objectives of this work are to 1) design hydrogel microcarriers that promote pro-regenerative activity of MSCs in vitro and 2) utilize a spatial multiomics pipeline to investigate how delivery of MSCs on microcarriers influences spatially variant muscle de-/regeneration in vivo following severe RCT in a rat model. Towards the first objective, an enzymatically-degradable hydrogel microcarrier system will be used to study MSC bioactivity in an inflammatory in vitro microenvironment. Then, towards the second objective, the effects of localized MSC-microcarrier delivery on healing outcomes and intercellular signaling in the supraspinatus muscle will be assessed via both immunohistochemistry and spatially-resolved transcriptomic and proteomic analyses up to two weeks after rotator cuff tear. Long-term, the results of this work could be used to inform future biomaterial-based cell therapies and improve clinical outcomes of patients after severe rotator cuff tear.