Research

The Cartilage Bioengineering Laboratory studies the prevention of post-traumatic osteoarthritis, cartilage biomechanics, mechanotransduction of chondrocytes, lubrication of temporomandibular joint, and rehabilitation after cartilage repair surgeries. Our long term goal is to exploit therapeutic techniques for osteoarthritis treatment.

In Vitro Cartilage Lesion Repair

At the early stage of osteoarthritis (OA), a small hole usually appears in the articular surface. Since cartilage has little ability to heal spontaneously, even a minor lesion, if left untreated, can hinder the joint movement, induce pain, and cause deterioration to the entire joint surface. Microfracture is an arthroscopic procedure attempt to promote on-site repair of a cartilage lesion through the involvement of subchondral bone marrow. This minimally invasive, technically simple, and low-cost technique remains the first-line option for small cartilage lesion treatment in knee joints. However, clinical trials and animal studies have yielded variable and unpredictable healing results after microfracture surgery. Soft fibrous scar tissue, instead of hyaline cartilage, often insufficiently filled the defect with central degeneration. Using human or large animal subjects, invasive tissue evaluation methods, such as histology, biochemical and biomechanical tests, were ethically and practically difficult to be adopted in the longitudinal assessment of repaired tissue. Therefore little is known about the precise mechanisms of tissue repair after microfracture procedure. In this project, we are aiming to simulate, understand and improve the microfracture surgery using an in vitro bioreactor system.

Schematic of microfrature surgery (Adopted form Mithoefer et. Al, Am J Sports Med, 2009)
Bioreactor for cartilage-bone organ culture
Viability of chondrocytes after long term co-culture with bone

Mechano-Biology of Chondrocytes

The chondrocytes in cartilage are constantly exposed to physical forces and these can influence the biological behaviors of cells, including gene expression, phenotype, paracrine or autocrine factor secretion, and metabolism. These mechanically induced cellular alterations may constitute major factors affecting the physiological and pathological conditions of the organism. This new approach is known as mechanobiology because it requires the use of cellular/molecular biology methods to identify the various steps or stages by which changes occur in the cells and tissues as a result of the applied mechanical forces. This new avenue of research, crucial for understanding tissue remodeling phenomena or pathological processes like osteoarthritis (OA), or to develop new strategies for tissue regeneration, requires understanding mechanisms of mechanotransduction through which physical stimuli are transformed into cellular responses. We are focusing on the calcium signaling and its related pathways in chondrocytes under fluid shear stress, hydrostatic pressure, osmotic stress, electric field and mechanical compression.

Physical stimuli on chondrocytes
Calcium signaling pathway
Calcium responses of chondrocytes under different mechanical stimuli and pathway inhibitors

TMJ Biomechanics

The temporomandibular joint (TMJ) is the only movable joint in our heads that connects the lower jaw (mandible) to the temporal bone of the skull. TMJ is also the only joint in our body which has a disc between the two articular surfaces besides knee joint. The joints have a high degree of freedom, allowing our jaw to move up and down and side to side and enabling us to talk, eat, and yawn. Over 10 million Americans are affected by the disorder of TMJ, also known as TMD. Little is known about the etiology of TMD. It is conjectured that TMD is related to the tissue in the joints. In this project, using micro-indenter, tribometer and mixture theory for soft tissue, we aim to understand the function-structure relationship of the cartilaginous tissue in TMJ and the interaction between the disc and condylar cartilage.

Healthy TMJ disc that fully covers the condylar head
3D Contour of Condylar Cartilage by microCT
A custom-built tribometer to measure the friction coefficient of tissue in TMJ
The TMJ disc has different friction coefficients with the condylar cartilage.

Mixture Theory for Articular Cartilage

Articular cartilage is a layer of low friction, load-bearing, soft tissue that overlies the articulating bony surfaces in diarthrodial joints. It provides a nearly frictionless surface for the transmission and distribution of joint load, exhibiting little to no wear over decades of use. This remarkable function of cartilage is granted by its unique composition and the microstructure of the fluid-filled extracellular matrix or by the multiphasic nature of articular cartilage. In engineering terms, the tissue is a porous viscoelastic material consisting of two principal phases: a fluid phase primarily composed of water with dissolved solutes and mobile ions in it, and a solid phase composed of a densely woven, strong, collagen fibrillar network enmeshed with proteoglycan macromolecules.

Various constitutive models have been used to describe articular cartilage. The most successful theories for cartilage biomechanics are the mixture theories based on poroelasticity, i.e., biphasic and triphasic theories. The biphasic theory models the soft hydrated tissues as composite materials consisting of two continuum and immiscible phases: solid phase and fluid phase. Besides Young’s modulus and Poisson’s ratio, hydraulic permeability of ECM is the third critical parameter to determine the compressive viscoelastic behavior of the tissue. The relative movement between the two phases and resultant frictional drag were described by Darcy’s law. To account for the Donnan osmotic pressure, ion transport, and other electrokineticrelated effects, the ions were separated from the fluid phase as a third phase. This generates the triphasic mixture theory.

In this project, we developed a correspondence principle which makes the usage of triphasic constitutive laws as simple as linear elastic theory. The nonlinear complicate governing equations were also linearized into standard parabolic partial differential equations. Using triphasic theory and the indentation technique, we are able to determine the three mechanical properties of articular cartilage and its proteoglycan content simultaneously. The results were verified with those from commercial GAG assay kit. Indentation is the regarded as the most popular nondestructive testing method for most in vivo and in situ studies and small animal models. The biphasic and triphasic indentation solutions can simultaneously determine the aggregate modulus, Poisson’s ratio, permeability, and FCD of cartilage without removal from the subchondral bone.

The triphasic theory is also essential for our tissue repair and cartilage mechanotransduction studies. To investigate the mechano-biology of chondrocytes in cartilage, it is necessary to first understand the mechano-electrochemical environment of surrounding chondrocytes in natural articular cartilage. Mixture theory provides significant advantages to capture the structure-function relationships of articular cartilage and to identify the physical and chemical fields surrounding the cells.

Schematic of Triphasic Mixture Theory for articular cartilage
Fluid pressure field inside cartilage under mechanical compression
A custom-built micro-indenter for cartilage indentation
Close-up of indentation test