Fabrice Bernard

PhD Defense Presentation

Date: Monday, April 26th 2021

Time: 10:00 AM

Location: https://bluejeans.com/208282976

Thesis Advisors:

J. Brandon Dixon, PhD

Georgia Institute of Technology, GW Woodruff School of Mechanical Engineering

Nick Willett, PhD

Emory University School of Medicine, Department of Orthopaedics

Thesis Committee:

Kyle Allen, PhD

University of Florida, J. Crayton Pruitt Family Department of Biomedical Engineering

James Dahlman, PhD

Georgia Institute of Technology, WH Coulter Department of Biomedical Engineering

Andrés Garcia, PhD

Georgia Institute of Technology, GW Woodruff School of Mechanical Engineering

Susan Thomas, PhD

Georgia Institute of Technology, GW Woodruff School of Mechanical Engineering

Title: The Role of Microvascular Clearance in the Progression of Osteoarthritis

Abstract:

Osteoarthritis (OA) is the most common disease of the knee. OA is characterized by damage to the articular cartilage, underlying bone, and chronic inflammation of the joint tissues, leading to the progressive loss of joint function, increased disability, and reduced quality of life. In OA, the role of chronic low-grade inflammation has been implicated in disease progression. In wound healing, lymphangiogenesis, or the formation of new lymphatic vessels, is central to inflammation resolution. However, in the osteoarthritic synovium, lymphatic vessel density is decreased in later stages of OA, and changes in the microcirculatory environment may be responsible for joint dysfunction. Blood vessels and lymphatic vessels (the microvasculature) play a critical role in tissue maintenance and have been implicated in OA development and treatment strategies. Therefore, our objective was to understand joint clearance mechanisms under normal and diseased conditions. This thesis's long-term goal was to establish biomolecular engineering strategies to assess microvascular function in normal and OA joints.

In Aim 1, we used near-infrared (NIR) imaging techniques to non-invasively evaluate venous and lymphatic drainage in the naïve knee joint in vivo. We then perturbed joint homeostasis using exercise or endothelin-1, a cytokine elevated in human OA with strong vascular tonic activity, and investigated the effects on microvascular function and clearance mechanisms. In Aim 2, we used these techniques to determine how microvascular clearance changes during OA progression in a post-traumatic OA model in the rat. In Aim 3, we used human OA synovial fluid to study lymphatic collecting vessel contractility and lymphangiogenesis using two ex vivo platforms.

Collectively, we found that 1) joint clearance can be significantly altered by exercise or ET-1, 2) OA induction in the rat has differential effects on venous and lymphatic clearance, and 3) treatment with human OA synovial fluid reduces lymphatic collecting vessel contractility and growth ex vivo. These studies increased the fundamental knowledge about the role of the microvasculature, and specifically lymphatics, in normal joint function and during OA progression.