Post-traumatic joint stiffness (PTJS), a common cause of pain and disability, is a challenging clinical problem because injury severity often doesn't correlate with loss-of-function, making it difficult to predict patient risk. PTJS is especially problematic in the elbow because of high susceptibility to loss of motion and a lack of viable treatment options. The key factors responsible for the initiation, progression, and persistence of PTJS remain unclear. While capsule stiffening likely contributes, the role of other periarticular structures (e.g., ligaments, muscle, tendon, cartilage, bone) is unknown. We recently developed a model of PTJS in Long-Evans rats by inducing relevant elbow injuries followed by six-weeks of immobilization. This protocol led to impaired joint mechanics that persisted even after remobilization, thereby mimicking symptoms of the human condition. Objective: use this animal model to correlate joint dysfunction with tissue-level alterations in periarticular structures that contribute to the development of PTJS. Hypothesis: dysregulation of normal healing will lead to a fibrogenic biological response, abnormal and excessive extracellular matrix (ECM) production/deposition, and mechanical stiffening of several periarticular tissues that together will cause debilitating joint contracture. SA1: Determine contributors to joint contracture by identifying mechanical, biological and morphological changes that occur in the periarticular structures of stiff elbows. Rationale: A rat elbow model of PTJS wil be used to identify which periarticular joint structures exhibit altered tissue-level mechanics and determine what biological, organizational and morphological changes accompany these differences. Targeted mechanical testing, qPCR, and histology will be used to evaluate periarticular soft tissues and -CT imaging/histology to evaluate bone. Hypothesis: Joint contracture is caused by a maladaptive fibrotic response in several periarticular structures (mediated by TGF- signaling and leading to improper ECM regulation) demonstrating the multifactorial nature of PTJS pathophysiology. SA2: Elucidate causes of stiffness/contracture by correlating improvements in altered properties of periarticular structures following remobilization with subsequent recovery of joint function. Rationale: Correlation of impaired joint mechanics with time-dependent improvements to periarticular tissues will elucidate which anatomical structures contribute to long-term PTJS. Hypothesis: Joint- and tissue-level properties will improve following remobilization, but persistent joint dysfunction will correlate with permanently altered tissue- level properties of several periarticular structures (e.g., increased stiffness of ligament/tendon, proliferation of capsule/scar, ECM dysregulation in muscle, abnormal bone morphology/remodeling, cartilage degeneration). This study will elucidate tissue-specific changes that cause the development and progression of PTJS. Results will provide insight towards developing improved prevention/treatment strategies that directly target affected periarticular tissues, and will enable future study of other common elbow pathologies (e.g., instability and OA).

Public Health Relevance

Post-traumatic joint stiffness (PTJS), a common clinical problem that causes pain and loss of motion, is especially challenging in the elbow because of high susceptibility to injury and a lack of adequate treatment options. The objective of this study is to use an animal model of PTJS to identify which anatomical structures near the joint (e.g., capsule, ligament, muscle, tendon, cartilage, bone) contribute to the development of elbow stiffness/contracture, and correlate changes in tissue-level properties with functional impairment of the joint in order to identify targets for prevention/treatment strategies. The long-term resultof this work will be to greatly improve fundamental understanding of joint health, which will have significant potential to improve the treatment of common injuries and decrease the occurrence and impact of PTJS in the elbow.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR067504-03
Application #
9295958
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Washabaugh, Charles H
Project Start
2015-08-01
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Dunham, Chelsey L; Castile, Ryan M; Chamberlain, Aaron M et al. (2017) Pronation-Supination Motion Is Altered in a Rat Model of Post-Traumatic Elbow Contracture. J Biomech Eng 139:
Dunham, Chelsey L; Castile, Ryan M; Havlioglu, Necat et al. (2017) Persistent motion loss after free joint mobilization in a rat model of post-traumatic elbow contracture. J Shoulder Elbow Surg 26:611-618