Hydrogels for Tissue Engineering: Addressing Key Design Needs Toward Clinical Translation

Abstract

While the soft mechanics and tunable cell interactions facilitated by hydrogels have attracted significant interest in the development of functional hydrogel-based tissue engineering scaffolds, translating the many positive results observed in the lab into the clinic remains a slow process. In this review, we address the key design criteria in terms of the materials, crosslinkers, and fabrication techniques useful for fabricating translationally-relevant tissue engineering hydrogels, with particular attention to three emerging fabrication techniques that enable simultaneous scaffold fabrication and cell loading: 3D printing, in situ tissue engineering, and cell electrospinning. In particular, we emphasize strategies for manufacturing tissue engineering hydrogels in which both macroporous scaffold fabrication and cell loading can be conducted in a single manufacturing step - electrospinning, 3D printing, and in situ tissue engineering. We suggest that combining such integrated fabrication approaches with the lessons learned from previously successful translational experiences with other hydrogels represents a promising strategy to accelerate the implementation of hydrogels for tissue engineering in the clinic.

Keywords: Biomaterials; Bioprinting; Electrospinning; Hydrogels; Tissue Engineering.

FIGURE 1

Design of functional hydrogels for tissue engineering. Selected constituent images reproduced with permission from references (Jin et al., 2011; Fuoco et al., 2014; Fang et al., 2016; Grigoryan et al., 2019; Mirdamadi et al., 2020; Li et al., 2021).

FIGURE 2

Venn diagram describing the key properties of natural and synthetic polymers most commonly used for fabricating hydrogel-based tissue scaffolds.

FIGURE 3

Schematic of techniques to fabricate hydrogel-based macroporous scaffolds for tissue engineering. (Inset) Spider plot of the relative advantages of different macroporous scaffold formation techniques (scale 1–5: 1 = least advantageous, 5 = most advantageous) Note that the cryogelation plot overlaps with the salt leaching plot such that it is not clearly visible in the graph.

FIGURE 4

Schematic of ex vivo and in vivo bioprinting techniques (* represents the viscosity range of bioinks useful for each bioprinting technique).

FIGURE 5

Examples of emerging 3D printing approaches: (A) 3D bioprinting system with a microfluidic printhead that can load multiple biomaterials in different channels (Reproduced with permission from Dickman et al., 2020). (B) Schematic and images of FRESH printed alginate gels embedded in gelatin slurry bath. Scale bar = 1 cm (Reproduced with permission from Hinton et al., 2015). (C) Extruded FRESH printing of HA hydrogel into self-healing support hydrogel bath. Scale bar = 200 μm (Reproduced with permission from Highley et al., 2015).

FIGURE 6

Strategies for cell electrospinning: (A) reactive electrospinning of 3T3 mouse fibroblasts and C2C12 mouse myoblasts in POEGMA hydrogel nanofibers; (B) cell-laden electrospinning of C2C12 myoblasts in fibrin scaffolds; (C) combining cell printing and cell electrospinning to encapsulate C2C12 myoblasts in alginate scaffolds. Reproduced with permission (Xu et al., 2018; Yeo and Kim, 2018; Guo et al., 2019).

FIGURE 7

(A) Design of the handheld Biopen to print gelatin methacrylamide and hyaluronic acid methacrylate (HA-GelMa) hydrogel scaffolds with core-shell structure. Reproduced with permission (di Bella et al., 2018). (B) In situ bioprinting to fabricate HA hydrogels for chondral defect repair. Reproduced with permission (Li et al., 2017). (C) In situ formation of fibrin-HA/collagen sheet for skin tissue regeneration. Reproduced with permission (Hakimi et al., 2018). (D) In situ bioprinting of mesenchymal stromal cells and nano-hydroxyapatite collagen for in vivo bone tissue regeneration. Reproduced with permission (Keriquel et al., 2017).