Alginate microfibers as therapeutic delivery scaffolds and tissue mimics

Abstract

Alginate, a naturally occurring polysaccharide, has been widely used in cell encapsulation, 3D culture, cell therapy, tissue engineering, and regenerative medicine. Alginate's frequent use comes from its biocompatibility and ability to easily form hydrogel in a variety of forms (e.g. microcapsules, microfibers, and porous scaffolds), which can provide immunoprotection for cell therapy and mimic the extracellular matrix for tissue engineering. During the past 15 years, alginate hydrogel microfibers have attracted more and more attention due to its continuous thin tubular structures (diameter or shell thickness ⩽ 200 µm), high-density cell growth, high handleability and retrievability, and scalability. This review article provides a concise overview of alginate and its resultant hydrogel microfibers for the purpose of promoting multidisciplinary, collaborative, and convergent research in the field. It starts with a historical review of alginate as biomaterials and provides basics about alginate structure, properties, and mechanisms of hydrogel formation, followed by current challenges in effective cell delivery and functional tissue engineering. In particular, this work discusses how alginate microfiber technology could provide solutions to unmet needs with a focus on the current state of the art of alginate microfiber technology and its applications in 3D cell culture, cell delivery, and tissue engineering. At last, we discuss future directions in the perspective of alginate-based advanced technology development in biology and medicine.

Keywords: 3D culture; Alginate; cell delivery; hydrogel; microfiber; stem cell; tissue engineering.

Figure 1.

Survey of alginate-related papers in PubMed. (A) Increasing number of alginate-related papers published each year. (B) Spherical alginate hydrogels (e.g. microcapsules, microbeads, microspheres, microparticles, and microcarriers) dominating their biological and biomedical applications in comparison to alginate microfibers (e.g. microfibers, microtubes, microstrands, and microribbons), nanofibers, porous matrices or scaffolds, hydrogel sheets, and bulk hydrogels. (A color version of this figure is available in the online journal.)

Figure 2.

Timelines of the key alginate-based biotechnology developments. The white dashed line indicates the start of a new era of alginate as biomaterials for 3D cell culture, cell therapy, and tissue regeneration. (A color version of this figure is available in the online journal.)

Figure 3.

Representative versatile alginate hydrogel systems. (A) Optical image of alginate microcapsules. Scale bar = 100 µm. (B) Photo of alginate core (left), one-layer (middle), and two-layer onion-like hydrogel capsules (right). (Adapted from Zarket and Raghavan, https://creativecommons.org/licenses/by/4.0/.) (C) Confocal image of multicompartmental alginate microparticles. Scale bar = 1000 µm. (Reproduced from Lu et al. with permission from the Royal Society of Chemistry.) (D) Optical image of alginate hydrogel microfibers. Scale bar = 300 µm. (E) Photo of the preformed alginate microtube. Scale bar = 4000 µm. (Adapted from Jorgensen et al.) (F) Optical image of the cavity microfiber. Scale bar = 400 µm. (Adapted from Tian et al., https://creativecommons.org/licenses/by/4.0/.) (G) Confocal image of multicompartmental microfibers. Insert: Cross-sectional view. Scale bar = 200 µm. (Adapted from Cheng et al., Copyright © 2016 American Chemical Society.) (H) Scanning electron microscopy (SEM) image electrospun alginate nanofibers. Scale bar = 1 µm. (I) SEM image of the IPN hydrogels composed of 15% PF127/0.25% alginate. (Adapted from Chou et al.) (J) SEM image of alginate cryogel. (Adapted from Bencherif et al.) (K) SEM image of bioprinted alginate hydrogel with minimal porosity. (Adapted from Chaji et al., https://creativecommons.org/licenses/by/4.0/.) (I–K) Scale bar = 100 µm.

Figure 4.

A simple egg-box model of calcium alginate hydrogel. G: α-l-guluronate residue; M: β-d-mannuronate residue. (A color version of this figure is available in the online journal.)

Figure 5.

Versatile fabrication methods to make alginate hydrogel microfibers (A–D), core–shell microfibers or microtubes (E–G), or bead-in-microfiber structures (H–J). (A) Coaxial glass microfluidics embedded in a PDMS substrate. (Reprinted with permission from Shin et al., Copyright © 2007 American Chemical Society.) (B) Coaxial cylindrical PDMS microfluidic device. (Reprinted from Jun et al., Copyright (2013), with permission from Elsevier.) (C) Wet spinning. (Adapted from Yang et al., http://creativecommons.org/licenses/by/4.0/.) (D) Extrusion. (Reprinted from Unser et al., Copyright (2015), with permission from Elsevier.) (E) Multicoaxial glass capillary microfluidics for making core–shell microfibers. (Reprinted from Zuo et al., Copyright (2016), with permission from Elsevier.) (F) Multicoaxial PDMS microfluidics for making core–shell microfibers or co-cultured cell fibers. (Reprinted from Yamada et al., Copyright (2012), with permission from Elsevier.) (G) Extrusion through a needle-in-needle device to fabricate premade alginate microtubes. (Reprinted with permission from Jorgensen et al., Copyright © 2021 IOP Publishing Ltd.) (H) Coaxial glass capillary gas-in-water microfluidics to fabricate cavity microfibers. (Adapted with permission from Tian et al. Copyright © 2018 American Chemical Society.) (I) Vertical, coaxial glass capillary microfluidics to fabricate oil droplet-filled microfibers that can be tuned by varying oil-phase flow rates. (Reprinted from Chaurasia et al., Copyright (2016), with permission from Elsevier.) (J) All-in-water microfluidics to fabricate aqueous-droplet-filled hydrogel microfibers. (Adapted with permission from Wang et al., Copyright © 2021 American Chemical Society.)

Figure 6.

Perspectives of alginate hydrogel microfibers for cell delivery and tissue mimics. (A color version of this figure is available in the online journal.)