Mechanobiology of Cartilaginous Tissues
Our group initiated a series of studies to quantify the effects of mechanical forces on intact organ culture explants of cartilage. While the general phenomena was well known from previously published animal and tissue studies, the cell signaling pathways/mechanisms and biophysical stimuli were not well understood. We published one of the first in vitro studies showing that moderate dynamic compression of cartilage explants stimulated chondrocyte biosynthesis, while static compression downregulated biosynthesis. In addition, we discovered that moderate dynamic compression could inhibit protease-mediated matrix degradation in normal intact cartilage induced by the combination of injurious mechanical compression and inflammatory cytokine challenge using an in vitro organ culture model of traumatic joint injury. More recently, we have expanded this approach to new single tissue culture models, such as tendon, and several multi-tissue cultures designed to mimic intra-tissue interactions, including the first ever bone-tendon-muscle co-culture model of the shoulder rotator cuff.

Nanomolecular Rheology
The macroscopic biomechanical properties of tissues such as cartilage and tendon are well understood. However, measurement of such properties at the nanoscale (using nanometer-scale deformations less than the size of individual matrix molecules) was needed to connect tissue properties to the structure of constituent ECM.

Our group recently developed AFM-based methodologies to quantify ECM molecular mechanics, and we confirmed for the first time that poroelastic dynamics govern cartilage mechanics even at nanometer-scale deformations. Using a novel AFM system developed in the lab, we are studying murine knee models of post-traumatic OA, matrix remodeling using genetically engineered mice, and murine tendon and skin poro-viscoelastic behavior.

Drug Delivery for Osteoarthritis
Osteoarthritis (OA) affects hundreds of millions of people worldwide but no disease modifying OA drug has yet been approved by the FDA for patients. One of the biggest challenges is to devise a method for local and safe delivery of potential therapeutics into cartilage to minimize their systemic side effects and to increase their residence time for sustained delivery inside such a dense, avascular tissue. Intra-articular injection, the most commonly used delivery method by Orthopaedic surgeons, suffers from rapid clearance of drugs from the joint, within a matter of hours. We are developing cartilage-targeted nanoparticle-based drug delivery mechanisms for treating post-traumatic OA. Since cartilage is heavily negatively charged (due to the dense packing of aggrecan proteoglycans in the tissue matrix), electrostatic interactions can be used to augment transport, binding and retention of drug carrying particles or, alternatively, drugs functionalized with cationic (e.g., heparin binding) domains. This project focuses on: (1) investigating the effects of electrostatic interactions on the partitioning, uptake and binding of drugs and drug delivery carriers within cartilage; (2) determining optimally charged carriers for delivering drugs that have either intracellular or extracellular targets; (3) testing drug-carrier conjugates in both in vitro and animal models of post-traumatic OA.

PTOA: Prevention, Drug Effects, and Repair
It is well known that traumatic joint injury progresses to post-traumatic osteoarthritis (PTOA) at a very high rate, especially in young women suffering sports injuries. Yet the mechanisms leading to cartilage degeneration, the hallmark of OA, are still not well understood, and there are no disease-modifying drugs, only drugs for symptomatic pain relief. We are investigating the effects of small molecule glucocorticoids and a variety of biologic drugs on healthy and diseased cartilage to aid in the prevention of PTOA. In vitro organ culture models include application of single impact compressive injury to cartilage (simulating effects of total joint injury) followed by long term culture with inflammatory cytokines to emulate the effects of joint inflammation on cartilage degradation (a silent process, since cartilage has no nerve supply). Proteomic and metabolomic analyses are being used to identify biomarkers of disease and to study molecular/cellular pathways that may aid in development of therapeutics. Complementary studies use a novel self-assembling peptide hydrogel in animal studies of cartilage defects to enhance local growth factor delivery and enhance migration of marrow progenitor cells into the wound site.


Joints in Space: Organ on a Chip
Our mission in this program is to bring experimental and computational approaches to study the effects of space flight and therapeutic interventions on the musculoskeletal system, focusing on cartilage, bone and synovium. Experiments are being carried by SpaceX to the International Space Station (ISS) for 1-month tests.  In this joint project with NIH and CASIS/NASA, we are studying the effects of micro-gravity and reactive oxygen species (caused by the enhanced ionizing radiation environment in the ISS) on PTOA progression using an organ-on-a-chip joint model. Post-traumatic osteoarthritis (PTOA) is an all too common condition initiated in otherwise healthy (young to middle-aged) individuals who suffer a joint injury. The interactions between cartilage, bone and synovium in human joints are critically important for joint function and human motion on earth and in long-term space flight. Upon traumatic joint injury, there is an immediate upregulation of inflammatory cytokines in the synovial fluid that are secreted primarily by cells in the synovial membrane. When combined with mechanical trauma to cartilage accompanying joint injury, degradation of cartilage as well as subchondral bone often progresses to PTOA.No efficacious disease-modifying osteoarthritis drugs (DMOADS) are yet available which alter halt the progression of OA/PTOA. 

Such injuries are not uncommon amongst astronauts: exercise-related injuries are the most frequent source of injuries for astronauts living aboard the International Space Station and, historically, injury rates of astronauts in the Shuttle program were 3-fold higher during the astronauts’ mission period (defined as 1-year preflight to 1-year post flight). We have developed an organ co-culture microphysiological system (osteochondral plugs with joint capsule synovium explants harvested from human donors) to study joint disease and its progression, and to test the efficacy of several potential disease modifying therapeutics for response biomarkers on earth as well as during the astronaut mission period.