Research Projects
The Orthopedic Genetic Host Variation Lab has several research projects underway.
Demographic, imaging and surgical characteristics of patients with arthrofibrosis
The overarching goal of this research project is to understand causal factors associated with arthrofibrosis risk, severity and subsequent need for manipulation under anesthesia or revision of total knee arthroplasty, or both. These factors include patient demographics, preoperative physical exam results, intraoperative surgical features, and preoperative and postoperative imaging findings. To accomplish this goal, we're capitalizing on comprehensive electronic health records (EHRs), serial multimodal imaging and registry-based follow-up data on patients at Mayo Clinic with total knee arthroplasty (TKA).
Pathophysiology of acquired idiopathic stiffness
These studies tackle a major knowledge gap by addressing the central hypothesis that arthrofibrosis is initiated in vivo by local alterations in tissue repair processes after joint surgery and that it's linked to inflammation. We propose that biological alterations deregulate the formation of mechanoprotective transient connective tissues that normally stabilize injured joints to facilitate healing. We also propose that arthrofibrosis is in part cell autonomous and reflected by deregulation of the growth, differentiation and activity of mesenchymal stromal cells.
Genetic predisposition to arthrofibrosis
People with fibrotic phenotypes may possess predisposing genetic variations associated with arthrofibrosis. Initial whole-exome sequencing (WES) studies by our research team suggest that genetic variants may promote arthrofibrosis after total knee arthroplasty. We're now expanding these WES studies by acquiring and analyzing additional samples from patients with TKA undergoing revision for arthrofibrosis and matched control participants from several sources. Genomic studies on these samples will collectively identify genetic variants that instigate arthrofibrosis after surgery.
Molecular characterization of arthrofibrotic pathways
Myofibroblasts are postulated to be the key effector cells in the arthrofibrotic cascade and may be derived from fibroblasts that are stimulated by mechanical tension and arthrofibrotic growth factors. We're investigating the pathogenesis of human and animal myofibroblasts by examining the mechanisms that control cell growth and differentiation of protomyofibroblasts and their interactions within the local environment. We use cellular and functional analyses of biopsies and primary cell cultures from patients undergoing revision TKA for arthrofibrosis and established in vitro models for mesenchymal stromal cell activity in culture.
Arthrofibrosis animal models
Our lab has previously developed and validated an animal model of arthrofibrosis in the rabbit. This rabbit model has been used to demonstrate that pharmacologic interventions can be employed to reduce the severity of arthrofibrosis. Our current efforts are focused on assessing the efficacy of single and multiple drug strategies in our arthrofibrosis established rabbit model and development of small animal arthrofibrosis models for genetic- and drug-based studies.
Applications of artificial intelligence
We're creating deep learning-based algorithms to identify TKA patients at risk of developing arthrofibrosis based on radiographic assessment. We're also defining key histologic features indicative of fibrotic processes in tissue samples derived from patients with arthrofibrosis.