Biomaterials-assisted spheroid engineering for regenerative therapy

Abstract

Cell-based therapy is a promising approach in the field of regenerative medicine. As cells are formed into spheroids, their survival, functions, and engraftment in the transplanted site are significantly improved compared to single cell transplantation. To improve the therapeutic effect of cell spheroids even further, various biomaterials (e.g., nano- or microparticles, fibers, and hydrogels) have been developed for spheroid engineering. These biomaterials not only can control the overall spheroid formation (e.g., size, shape, aggregation speed, and degree of compaction), but also can regulate cell-to-cell and cell-to-matrix interactions in spheroids. Therefore, cell spheroids in synergy with biomaterials have recently emerged for cell-based regenerative therapy. Biomaterials-assisted spheroid engineering has been extensively studied for regeneration of bone or/and cartilage defects, critical limb ischemia, and myocardial infarction. Furthermore, it has been expanded to pancreas islets and hair follicle transplantation. This paper comprehensively reviews biomaterials-assisted spheroid engineering for regenerative therapy. [BMB Reports 2021; 54(7): 356-367].

Fig. 1

Differences between 2D monolayer culture and 3D spheroid culture for potential clinical applications.

Fig. 2

Methods of spheroid formation.

Fig. 3

Principles of biomaterials-based spheroid engineering.

Fig. 4

Cardiac spheroids formation with silicon nanowires and maturation with external electrical stimulation. (A) Schematic illustrations of a setup for external electrical stimulation to cardiac spheroids. (B) Timeline of in vitro conditioning. (C) Silicon nanowire incorporation to spheroids could improve maturation with electrical stimulation to be beneficial for cardiac repair. (D-F) Transmission electron micrograph images showing (D) structures of n-type doped silicon nanowires (scale bar, 100 nm), (E) composite spheroids formed with human induced pluripotent stem cells (hiPSCs) and silicon nanowires (scale bar, 100 μm), and (F) silicon nanowires located in extracellular space (scale bar, 500 nm). (G) Expression of genes related to contractile machinery in hiPSC cardiac spheroids (beta myosin heavy chain, MYH7; alpha myosin heavy chain, MYH6). NC, unwired spheroid; WC, wired spheroid; NS, unwired spheroid with stimulation; WS, wired spheroid with stimulation. (H) Beat rate of hiPSC cardiac spheroids, showing that electrical stimulation significantly reduced spontaneous beat rate in spheroids incorporating silicon nanowires and electrically stimulated (WS). Taken together, tissue level functional development would be beneficial for reduced pacemaking and arrhythmic risk after transplantation. Adapted with permission from Richards et al. (70). Copyright (2016) American Chemical Society.