Microphysiological joint-on-chip platform for the study of arthritic diseases - PROJECT SUMMARY / ABSTRACT The objective of this proposal is to establish a new microphysiological ‘joint-on-chip’ system, with structural biomimicry and biomechanical function, that can support mechanistic study of arthritic diseases and rapidly test candidate treatments. Recent advances in the development of on-chip technologies have shown potential to miniaturize musculoskeletal tissues and emulate key aspects of a healthy joint. One primary goal of on-chip technologies is to create robust and reliable human models of the joint so that the study of disease pathogenesis and screening of promising drug treatment candidates is possible with high throughput. No disease modifying treatments are available to address osteoarthritis (OA), a health burden that afflicts millions of people in the United States. With the development of on-chip technologies, pharmaceutical companies would be positioned to ‘fail fast’, and advance or accelerate only the most promising candidate drug therapies toward clinical trials. Unfortunately, realistic joint-on-chip models currently lack minimal essential functionality that is necessary for the study of arthritic diseases and evaluation of treatment candidates. Challenges include the need for human- derived biomaterial inks that support tissue-specific mechanical and cellular responses, and the need to recapitulate the complexity of the human joint, including crosstalk between multiple tissue types, and movement- induced biomechanical stimuli like frictional sliding that mimics the in vivo environment. To improve realistic joint- on-chip models, our lab has developed human-derived biomaterial inks – particulated allograft extracellular matrix with a unique crosslinking technology – to enable 3D bioprinting of tissues that more closely mimic the natural structure of cartilage, bone, and synovium. We have additionally demonstrated that differential biomechanical stimuli (e.g., compression and frictional sliding) promote distinct cellular responses that are characteristic of healthy tissue and needed in the engineering of a miniaturized version of the human joint. We now plan to develop a joint-on-chip with minimal essential functionality using human-sourced tissues and cells to study arthritic diseases and drug treatment candidates. We will optimize human biomaterials to recreate essential tissue structure and function, and engineer necessary biomechanical stimulation that is currently lacking in on-chip technology. We will pursue three related specific aims. In Aim 1, we will optimize a library of particulated and human-derived biomaterial inks for 3D joint-on-chip printing. In Aim 2, we will establish a human joint-on-chip platform with minimal essential functionality. In Aim 3, we will quantify the joint-on-chip pathogenic response to biomechanical injury and inflammatory challenge. If successful, we will for the first time create a realistic joint-on-chip model with essential functionality that is useful to study arthritic diseases and evaluate treatment candidates.
