ORCID
http://orcid.org/0000-0002-8827-5257
Date of Award
Spring 5-15-2020
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Post-traumatic elbow contracture is a multi-tissue pathology which develops in up to 50% of patients following elbow trauma (e.g., fracture, dislocation). It is unclear which periarticular soft tissues are driving the functional deficit following injury because it is not possible in clinical settings to isolate each soft tissues’ mechanical and biological contributions to elbow contracture. Therefore, an animal model is needed to identify the primary periarticular soft tissue(s) which contribute to contracture. The first animal models of contracture were developed in the knee; however, these studies are not generalizable to the elbow due to anatomical and functional differences between these two joints. Thus, we developed a model of post-traumatic elbow contracture in the rat and can now investigate each periarticular soft tissues’ contribution to motion loss, which will ultimately inform the development of tissue targeted treatment strategies. Current strategies to manage elbow contracture (e.g., physical therapy, surgery) rarely restore range-of-motion to pre-injury levels. These strategies are often not effective because they physically disrupt the periarticular soft tissues rather than treat the underlying pathology. Previously, stem cells have been used in animal models of soft tissue fibrosis in an effort to prevent tissue hypertrophy and functional loss. However, these treatments exhibited unpredictable results which ranged from transient benefits to amplified pathology. Hence, a mechanism is needed to improve stem cell efficacy following injection. In this work, mechanical memory will be used to direct stem cells toward positively influencing tissue regeneration in vivo. The studies presented in this dissertation aimed (1) to evaluate mechanical and biological changes in the periarticular soft tissues from our rat model of elbow contracture to ultimately identify the primary contributor(s) to motion loss, and (2) to determine in vitro if adipose-derived stem cells (ASCs) exhibit mechanical memory and to examine if treatment with soft primed ASCs will reduce fibrosis and improve elbow function in our rat model after injury. Following injury, flexion-extension and pronation-supination developed motion loss differently throughout immobilization and uniquely responded to joint reloading during subsequent free mobilization in our rat elbow contracture model. However, the motion lost was more severe in flexion-extension than in pronation-supination. The anterior capsule, ligaments, and cartilage were identified as the primary contributors to contracture in flexion-extension. Physiological testing confirmed that muscle was not a permanent contributor to elbow contracture in our rat model. Biological characterization of the anterior capsule and lateral collateral ligament identified that hypertrophy as a result of fibrosis likely caused the deficit in joint mechanics. To prevent fibrosis in these tissues, a biological treatment strategy was developed using mechanically primed ASCs. Soft primed ASCs displayed a delayed stiffness response demonstrating that these cells exhibit mechanical memory in vitro. Injecting these soft primed ASCs into the anterior capsule of our rat elbow contracture model decreased capsular fibrosis and hypertrophy and increased range-of-motion compared to untreated animals. Overall, this work has significantly advanced our understanding of post-traumatic elbow contracture as well as presented a biologically motivated treatment strategy to prevent motion loss following elbow trauma in our rat model.
Language
English (en)
Chair
Spencer Lake
Committee Members
Gretchen Meyer, Aaron Chamberlain, Amit Pathak, Lori Setton,
Comments
Permanent URL: https://doi.org/10.7936/dxhc-c095