Human Organ-on-a-Chip Microphysiological Systems to Model Musculoskeletal Pathologies and Accelerate Therapeutic Discovery

Abstract

Human Microphysiological Systems (hMPS), otherwise known as organ- and tissue-on-a-chip models, are an emerging technology with the potential to replace in vivo animal studies with in vitro models that emulate human physiology at basic levels. hMPS platforms are designed to overcome limitations of two-dimensional (2D) cell culture systems by mimicking 3D tissue organization and microenvironmental cues that are physiologically and clinically relevant. Unlike animal studies, hMPS models can be configured for high content or high throughput screening in preclinical drug development. Applications in modeling acute and chronic injuries in the musculoskeletal system are slowly developing. However, the complexity and load bearing nature of musculoskeletal tissues and joints present unique challenges related to our limited understanding of disease mechanisms and the lack of consensus biomarkers to guide biological therapy development. With emphasis on examples of modeling musculoskeletal tissues, joints on chips, and organoids, this review highlights current trends of microphysiological systems technology. The review surveys state-of-the-art design and fabrication considerations inspired by lessons from bioreactors and biological variables emphasizing the role of induced pluripotent stem cells and genetic engineering in creating isogenic, patient-specific multicellular hMPS. The major challenges in modeling musculoskeletal tissues using hMPS chips are identified, including incorporating biological barriers, simulating joint compartments and heterogenous tissue interfaces, simulating immune interactions and inflammatory factors, simulating effects of in vivo loading, recording nociceptors responses as surrogates for pain outcomes, modeling the dynamic injury and healing responses by monitoring secreted proteins in real time, and creating arrayed formats for robotic high throughput screens. Overcoming these barriers will revolutionize musculoskeletal research by enabling physiologically relevant, predictive models of human tissues and joint diseases to accelerate and de-risk therapeutic discovery and translation to the clinic.

Organ‐on‐a‐chip technologies for biomedical research and drug development: A focus on the vasculature

“…The main challenge within this system is to mimic the wide range of complexity, highly organized structure, and load bearing capacity of these tissues. Recent literature reviews the current efforts to improve our understanding of the musculoskeletal system and its pathologies using OOC technologies 44–46 . Particularly, the development focuses on OOC models of tendons, 47,48 joints, 49,50 and vascularized bone 51 …”

“…Recent literature reviews the current efforts to improve our understanding of the musculoskeletal system and its pathologies using OOC technologies. [44][45][46] Particularly, the development focuses on OOC models of tendons, 47,48 joints, 49,50 and vascularized bone. 51…”

Evolution of functional tissue engineering for tendon and ligament repair

“…Early research using auto‐, allo‐ and xenografts has evolved into exciting basic studies in mechanobiology, cell signaling and enthesis formation (e.g., Passini et al., 2021; Fang et al., 2020; and Assaraf et al., 2020) as well as more applied efforts to create devices focused on tissue engineering scaffold‐free collagen (Mubyana & Corr, 2018) and implantation of bone marrow‐derived stem cell implants in large animal models (Mahalingam et al., 2016). Other exciting examples include use of 3‐D robotics to mimic ADLs (Bates et al., 2015; Rudy et al., 1996; Sakane et al., 1997; Woo et al., 1998), microphysiological systems to model local pathologies and healing (Ajalik et al., 2022), endogenous stem cells to stimulate an intrinsic progenitor cell niche (Depres‐tremblay et al., 2016), and clinical trials for the Bridge‐Enhanced ACL Restoration (BEAR) implant (BEAR) (Murray et al., 2019, 2020). Maybe this “dot” in Figure 13a will need to be even more centered with larger diverse teams (including patients; Dr. C. Zhao recommendation), new strategies, and major funding!…”

Sourcing cells for in vitro models of human vascular barriers of inflammation

“…The musculoskeletal system encompasses numerous tissues with varying types and levels of vascularization. As tissue chip models of musculoskeletal tissues become more sophisticated, it is important to consider the accurate representation of vascular barriers and their roles within these tissues ( 160 ). Tissues such as muscles ( 161 ), bone ( 162 ), synovium ( 163 ), and menisci ( 164 ) are vascularized while other tissues such as tendons and ligaments ( 165 , 166 ), intervertebral discs ( 167 ), and cartilage ( 163 , 168 ) generally have very little or no vascularization.…”

“…Therefore, ECs are an important component for researchers to consider when creating in vitro models of musculoskeletal tissues. Most existing musculoskeletal tissue chips with vasculature components utilize HUVECs, and other sources for musculoskeletal tissue ECs are rare ( 160 ). However, accurate representation of musculoskeletal EC function will facilitate more physiologically relevant tissue systems, particularly in disease and injury models.…”