Natural-Based Hydrogels for Tissue Engineering Applications

Abstract

In the field of tissue engineering and regenerative medicine, hydrogels are used as biomaterials to support cell attachment and promote tissue regeneration due to their unique biomimetic characteristics. The use of natural-origin materials significantly influenced the origin and progress of the field due to their ability to mimic the native tissues' extracellular matrix and biocompatibility. However, the majority of these natural materials failed to provide satisfactory cues to guide cell differentiation toward the formation of new tissues. In addition, the integration of technological advances, such as 3D printing, microfluidics and nanotechnology, in tissue engineering has obsoleted the first generation of natural-origin hydrogels. During the last decade, a new generation of hydrogels has emerged to meet the specific tissue necessities, to be used with state-of-the-art techniques and to capitalize the intrinsic characteristics of natural-based materials. In this review, we briefly examine important hydrogel crosslinking mechanisms. Then, the latest developments in engineering natural-based hydrogels are investigated and major applications in the field of tissue engineering and regenerative medicine are highlighted. Finally, the current limitations, future challenges and opportunities in this field are discussed to encourage realistic developments for the clinical translation of tissue engineering strategies.

Keywords: DNA; anisotropy; biomimetic; blood derivatives; decellularized tissue; extracellular matrix; glycosaminoglycans; nanoparticles; proteins; supramolecular crosslinking.

Figure 1

Crosslinking of hydrogels. (A) Thermally induced entanglement of polymer chains; (B) molecular self-assembly; (C) ionic gelation; (D) electrostatic interaction; (E) chemical crosslinking. Reproduced with permission from [7], copyright 2016 by American Association for the Advancement of Science.

Figure 2

Examples of the use of natural proteins and polysaccharides for 3D bioprinting strategies. (A) Organ-scale 3D printing of collagen. Reproduced with permission from [21], copyright 2019, Springer Nature; (B) Volumetric bioprinting using gelatin with methacryloyl residues (GelMA). Reproduced with permission from [24] copyright 2019, The Authors; (C) Bioprinting of covalently crosslinked hyaluronic acid (HA) hydrogels. Reproduced with permission from [66], copyright 2018, Wiley Periodicals, Inc.

Figure 3

Representation of 3D printing using specific cell-laden dECM bioinks within a support framework. Reproduced with permission from [72], copyright 2014, Springer Nature.

Figure 4

Schematic representation of the liposome–DNA hydrogel and its stimuli-responsive release behavior. Reproduced with permission from [85], copyright 2018, WILEY-VCH Verlag GmbH & Co.

Figure 5

Supramolecular biomaterials formed by crosslinking of polymeric precursors through (A) host–guest complexation using macrocyclic hosts (B) coordination of metals with ligands (end-terminated or grafted on polymer chains), and (C) multiple hydrogen-bonding motifs. Reproduced with permissions from: (A) [11], copyright 2018, The Royal Society of Chemistry; (B) [135], copyright 2011, Nature Publishing Group; (C) [136], copyright 2005, Nature Publishing Group.

Figure 6

Examples of advanced nanocomposite hydrogels showing reinforced, smart or anisotropic characteristics. (A) Injectable hyaluronic acid (HA) hydrogels mechanically reinforced with cellulose nanocrystals (CNC). Reproduced with permission from [149], copyright 2015, American Chemical Society; (B) gelatin-based hydrogels with high electrical conductivity due to the incorporation of gold nanorods (GNRs). Adapted with permission from [166], copyright 2016, Elsevier; (C) anisotropic gelatin hydrogels produced by the magnetic alignment of magnetic-responsive particles (peg-mCNC). Reproduced with permission from [176], copyright 2019, American Chemical Society.