Tissue Engineering for Musculoskeletal Regeneration and Disease Modeling

Zhong, Li; Xiang, Shiqi; Li, Eileen N.; Fritch, Madalyn R.; Alexander, Peter G.; Lin, Hang; Tuan, Rocky S.

doi:10.1007/164_2020_377

Cited by 12 publications

(9 citation statements)

References 189 publications

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“…The application of laboratory-based functional tools is essential to validate a target and to elucidate one when fine-mapping draws a blank. Going forward, the use of cells with enhanced chondrogenic potential 85 combined with three dimensional (3D) models of cartilage, and of cartilage with bone 86 , will provide more robust and realistic cell and organ models for the functional analyses of OA SNPs and their target genes. These models will also enable the inclusion of mechanical load as an experimental parameter, further aligning them with the in vivo reality of an articulating joint 87 .…”

Section: Discussionmentioning

confidence: 99%

Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.

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Section: Discussionmentioning

confidence: 99%

Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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“…Limitations of these approaches include the difficulty in recreating cell-ECM interactions in vivo and biomechanically matching the tissue of interest with a biomaterial scaffold. Although not thoroughly covered here, others have extensively reviewed the biomaterials and fabrication methods which are key components in successful representation of musculoskeletal disease models ( Cunniffe et al, 2019 ; Li et al, 2021 ).…”

Section: Considerations For Building Musculoskeletal Microphysiologic...mentioning

confidence: 99%

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

Ajalik

Alenchery

Cognetti

et al. 2022

Front. Bioeng. Biotechnol.

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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.

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“…Organoids are ex-vivo generated 3 dimensional (3D) cell structures that resemble an organ structure and cellular complexity ( 36 ). They have recently become of interest to the field of regenerative medicine as they could potentially mimic the organ of interest in vitro better than traditional 2D culture systems.…”

Section: Cell Types and Cell-based Productsmentioning

confidence: 99%

Cell Therapy in Veterinary Medicine as a Proof-of-Concept for Human Therapies: Perspectives From the North American Veterinary Regenerative Medicine Association

et al. 2021

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In the past decade, the potential to translate scientific discoveries in the area of regenerative therapeutics in veterinary species to novel, effective human therapies has gained interest from the scientific and public domains. Translational research using a One Health approach provides a fundamental link between basic biomedical research and medical clinical practice, with the goal of developing strategies for curing or preventing disease and ameliorating pain and suffering in companion animals and humans alike. Veterinary clinical trials in client-owned companion animals affected with naturally occurring, spontaneous disease can inform human clinical trials and significantly improve their outcomes. Innovative cell therapies are an area of rapid development that can benefit from non-traditional and clinically relevant animal models of disease. This manuscript outlines cell types and therapeutic applications that are currently being investigated in companion animals that are affected by naturally occurring diseases. We further discuss how such investigations impact translational efforts into the human medical field, including a critical evaluation of their benefits and shortcomings. Here, leaders in the field of veterinary regenerative medicine argue that experience gained through the use of cell therapies in companion animals with naturally occurring diseases represent a unique and under-utilized resource that could serve as a critical bridge between laboratory/preclinical models and successful human clinical trials through a One-Health approach.

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Tissue Engineering for Musculoskeletal Regeneration and Disease Modeling

Cited by 12 publications

References 189 publications

Genetics of osteoarthritis

Genetics of osteoarthritis

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

Cell Therapy in Veterinary Medicine as a Proof-of-Concept for Human Therapies: Perspectives From the North American Veterinary Regenerative Medicine Association

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