Bio-assembling and Bioprinting for Engineering Microvessels from the Bottom Up

Abstract

Blood vessels are essential in transporting nutrients, oxygen, metabolic wastes, and maintaining the homeostasis of the whole human body. Mass of engineered microvessels is required to deliver nutrients to the cells included in the constructed large three-dimensional (3D) functional tissues by diffusion. It is a formidable challenge to regenerate microvessels and build a microvascular network, mimicking the cellular viabilities and activities in the engineered organs with traditional or existing manufacturing techniques. Modular tissue engineering adopting the "bottom-up" approach builds one-dimensional (1D) or two-dimensional (2D) modular tissues in micro scale first and then uses these modules as building blocks to generate large tissues and organs with complex but indispensable microstructural features. Building the microvascular network utilizing this approach could be appropriate and adequate. In this review, we introduced existing methods using the "bottom-up" concept developed to fabricate microvessels including bio-assembling powered by different micromanipulation techniques and bioprinting utilizing varied solidification mechanisms. We compared and discussed the features of the artificial microvessels engineered by these two strategies from multiple aspects. Regarding the future development of engineering the microvessels from the bottom up, potential directions were also concluded.

Keywords: Bio-assembling; Bioprinting; Bottom-up; Microvessels; Tissue engineering.

Figure 1

Artificial microvessels by modular tissue engineering: bio-assembling and bioprinting microvessels from the bottom up.

Figure 2

The fabrication process of several kinds of modules. (A) Six fabrication methods of cell spheroids modules[34], including (A1) suspension cell culture, (A2) hanging drop, (A3) microwell, (A4) microwell array from micropatterned agarose wells (Republished with permission from Rivron NC, Vrij EJ, Rouwkema J, et al., Proc Natl Acad Sci, 2012, 109:6886–91.[35]), and finally, (A5) microchannel forming (Reproduced from ref. 36 with permission from The Royal Society of Chemistry). (B) Fabrication process of fiber module by microchannels[30]. (C) Fabrication process of microplates and rings by (C1) photolithography (Republished with permission from Teshima T, Onoe H, Kuribayashiashiashias K, et al., Small, © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim[38]). and (C2) dielectrophoresis (from ref.[39] licensed under Creative Commons Creative Commons Attribution License). (D) Layer-by-layer fabrication process of cell sheets[44].

Figure 3

Bio-assembling powered by micromanipulations. (A) Building microvessels by pick-and-place of the cell spheroids and the piezo-driven two-finger microhand for high speed pick-and-place assembly (Republished with permission from Ramadan AA, Takubo T, Mae Y, et al., IEEE Trans Ind Electron, 56:1121–35.[58]). (B) Construction of the microvessels by wrapping a cell sheet[60]. (C) A 4-layer PDMS microfluidic device for microfluidic self-assembly of ring-shaped modules (left, reproduced from ref 63 with permission from The Royal Society of Chemistry), and automated assembly of microvascular structures using a multimicromanipulator system (Republished with permission, from Liu X, Shi Q, Wang H, et al. IEEE/ASME Trans Mechatron, 2018, 23:667–78[65]). (D) Semi-automatic fabrication of microvascular structures by spinning fibers containing cells (Reproduced from ref. 66 with permission from the Royal Society of Chemistry). (E) Construction of microvessels using cell origami based on the self-folding driven by cell traction force (from ref.[39] licensed under Creative Commons Creative Commons Attribution License). (F) The cells are electrically assembled to a microvascular structure on the capillary surface by applying an electrical potential and extracting the rods from the collagen gel[22,76].

Figure 4

Devices developed for bioprinting microvessels. (A) Microvascular structures could be built by bioprinting based on inkjet, extraction, and direct laser writing (from ref.[77] licensed under Creative Commons Attribution License. Copyright © Mary Ann Liebert). (B) Direct bioprinting of microvascular structures based on the coaxial nozzle, and microscopic view of L929 mouse fibroblasts encapsulated by tubular alginate (Republished with permission from reference[88]). (C) Experimental setup and fabrication of engineered tissues containing microvascular structures using optical stereolithography[93]. (D) Microscopic photograph of a microheater array used to perform thermal stereolithography (Republished with permission, from Kojima M, Horade M, Takata S, et al., IEEE International Conference on Cyborg and Bionic Systems, IEEE, 2018.[97]).