Bioengineering platforms for cell therapeutics derived from pluripotent and direct reprogramming

Abstract

Pluripotent and direct reprogramming technologies hold great potential for tissue repair and restoration of tissue and organ function. The implementation of induced pluripotent stem cells and directly reprogrammed cells in biomedical research has resulted in a significant leap forward in the highly promising area of regenerative medicine. While these therapeutic strategies are promising, there are several obstacles to overcome prior to the introduction of these therapies into clinical settings. Bioengineering technologies, such as biomaterials, bioprinting, microfluidic devices, and biostimulatory systems, can enhance cell viability, differentiation, and function, in turn the efficacy of cell therapeutics generated via pluripotent and direct reprogramming. Therefore, cellular reprogramming technologies, in combination with tissue-engineering platforms, are poised to overcome current bottlenecks associated with cell-based therapies and create new ways of producing engineered tissue substitutes.

FIG. 1.

Bioengineering strategies to advance reprogrammed cell-based research. Promising technologies for improving the therapeutic efficacy and utility of the reprogrammed cells include biomaterial scaffolds, bioprinting, microfabricated devices, and biostimulatory systems.

FIG. 2.

Diverse applications of microdevice platforms in induced pluripotent and direct reprogramming and differentiation. (a) Generation of human iPSCs at a higher efficiency of reprogramming in the microfluidic cell culture system. Reprinted by permission from Luni et al., Nat. Methods 13(5), 446–452 (2016). Copyright 2016 Springer Nature Customer Service Center GmbH: Springer Nature. (b) Formation of motor neuronal and vascular networks in a multichannel microfluidic device in the presence of perfusion culture. Adapted with permission from Osaki et al., Sci. Rep. 8, 5168 (2018). Copyright 2018 Authors, licensed under a Creative Commons Attribution (CC BY) license. (c) A 3D organotypic Alzheimer's disease (AD) model by triculture of AD neurons, astrocytes, and microglia in a 3D microfluidic platform. Reprinted by permission from Park et al., Nat. Neurosci. 21(7), 941–951 (2018). Copyright 2018 Springer Nature Customer Service Center GmbH: Springer Nature. (d) Construction of 3D vascularized induced hepatic tissues generated in a 3D microfluidic system under flow conditions. Generation of a multiorgan model by tri-culturing 3D hepatic tissues, intestinal organoids, and stomach organoids in a high‐throughput microfluidic device. Adapted with permission from Jin et al., Adv. Funct. Mater. 28, 1801954 (2018). Copyright 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. (e) In situ generation of liver organoids using a 3D perfusable chip. Republished with permission from Wang et al., Lab Chip 18, 23 (2018). Copyright 2018 Clearance Center, Inc. (f) Development of vascularized and mature renal organoids by placing them on ECM within a perfusable millifluidic chip. Reprinted by permission from Homan et al., Nat. Methods 16(3), 255–262 (2019). Copyright 2019 Springer Nature Customer Service Center GmbH: Springer Nature.

FIG. 3.

Biostimulatory platforms to promote induced pluripotent and direct reprogramming and maturation. (a) Stiffness of hydrogels affects mesenchymal–epithelial transition and reprogramming efficiencies of generating iPSCs. Adapted with permission from Choi et al., Macromol. Biosci. 16, 199 (2015). Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) Microgroove patterned substrates affect fibroblast morphology and iPSC generation. Reprinted by permission from Downing et al., Nat. Mater. 12(12), 1154–1162 (2013). Copyright 2013 Springer Nature Customer Service Center GmbH: Springer Nature. (c) Afterload promotes maturation of engineered heart muscles. Reprinted with permission from Leonard et al., J. Mol. Cell. Cardiol. 118, 147–158 (2018). Copyright 2018 Elsevier. (d) Control of axonal growth of iN cells by receptor conjugated-magnetic nanoparticles (MNP) and gradient magnetic field (GMF). Adapted with permission from Jin et al., Nano Lett. 19, 6517 (2019). Copyright 2019 American Chemical Society. (e) Gradual increase in frequency during electrical stimulation of iPSC-CMs encapsulated in fibrin hydrogel promotes cardiac maturation. Reprinted by permission from Ronaldson-Bouchard et al., Nature 556(7700), 239–243 (2018). Copyright 2018 Springer Nature Customer Service Center GmbH: Springer Nature. (f) Hydrazide-functionalized carbon nanotube-pericardial matrix (PMCNT)-derived conductive hydrogel enhances cardiac maturation. Republished with permission from Roshanbinfar et al., Biomater. Sci. 7, 9 (2019). Copyright 2019 Clearance Center, Inc.