Translational cell fate reprogramming and regenerative medicine enabled by microphysiological systems.

Recent advances in genetic engineering and in vivo reprogramming have opened transformative possibilities for controlling cell fate in tissue repair and regeneration. However, clinical translation remains constrained by the limited predictive value of animal models and traditional in vitro systems, which often fail to fully recapitulate human responses, including the physiological consequences of genetic manipulations. Emerging microphysiological systems, exemplified by three-dimensional organoids and organs-on-chips (OoCs) systems, help bridge this gap by recreating key aspects of human physiology while enabling precise bioengineering of the niche to modulate cell fate decisions and plasticity. Organoids derived from induced pluripotent stem cells, adult stem cells, primary tissues, or directly reprogrammed cells preserve the patient-specific genetic background, facilitating mechanistic studies of development and disease and the evaluation of gene correction and reprogramming strategies in a human-relevant context. Complementarily, OoC platforms provide regulated perfusion, tissue vascularization, mechanical forces, molecular gradients, and immune cell integration to promote tissue maturation, functional readouts, and quantitative assessment of therapeutic responses that are difficult to achieve in static cultures. In this review, we discuss how organoids and OoC-based platforms are being leveraged to study and enhance cell fate reprogramming, repair, and regeneration across multiple tissues. We highlight recent reports where these systems informed the design, optimization, and safety evaluation of gene and cell therapies. Finally, we outline current limitations, including scalability, standardization, and biomaterial constraints, and propose future directions for integrating organoids, OoC, and gene-modulation technologies to enable more predictive, personalized, and clinically translatable regenerative medicine.

Duke Scholars

Author Samira Musah Biomedical Engineering