Click Chemistry-Based Injectable Hydrogels and Bioprinting Inks for Tissue Engineering Applications

Abstract

Background: The tissue engineering and regenerative medicine approach require biomaterials which are biocompatible, easily reproducible in less time, biodegradable and should be able to generate complex three-dimensional (3D) structures to mimic the native tissue structures. Click chemistry offers the much-needed multifunctional hydrogel materials which are interesting biomaterials for the tissue engineering and bioprinting inks applications owing to their excellent ability to form hydrogels with printability instantly and to retain the live cells in their 3D network without losing the mechanical integrity even under swollen state.

Methods: In this review, we present the recent developments of in situ hydrogel in the field of click chemistry reported for the tissue engineering and 3D bioinks applications, by mainly covering the diverse types of click chemistry methods such as Diels-Alder reaction, strain-promoted azide-alkyne cycloaddition reactions, thiol-ene reactions, oxime reactions and other interrelated reactions, excluding enzyme-based reactions.

Results: The click chemistry-based hydrogels are formed spontaneously on mixing of reactive compounds and can encapsulate live cells with high viability for a long time. The recent works reported by combining the advantages of click chemistry and 3D bioprinting technology have shown to produce 3D tissue constructs with high resolution using biocompatible hydrogels as bioinks and in situ injectable forms.

Conclusion: Interestingly, the emergence of click chemistry reactions in bioink synthesis for 3D bioprinting have shown the massive potential of these reaction methods in creating 3D tissue constructs. However, the limitations and challenges involved in the click chemistry reactions should be analyzed and bettered to be applied to tissue engineering and 3D bioinks. The future scope of these materials is promising, including their applications in in situ 3D bioprinting for tissue or organ regeneration.

Keywords: 3D bioprinting; Click chemistry; Hydrogels; Regenerative medicine; Tissue engineering.

Fig. 1

Example methods of click chemistry-based hydrogels discussed in this article

Fig. 2

General click chemistry-related chemical reactions for formation of hydrogels focused in this article. Adopted and reprinted from [4] Copyright (2018), with permission from Elsevier

Fig. 3

Dual cross-linked injectable chondroitin sulphate-based hydrogel loaded with bone morphogenetic protein-4 via DA based click chemistry for restoration of rat cranial defect. Reprinted from [17] Copyright (2017), with permission from Elsevier

Fig. 4

A Hyaluronic acid-based copper-free click chemistry hydrogels implanted in Balb-c mice for up to 35 days for cartilage regeneration. B Volume of hydrogel in vivo at different time and C White solid tissue like hydrogels with chondrocytes removed from mice. Reproduced from [73] with permission from the Royal Society of Chemistry

Fig. 5

Amino-yne click chemistry-based hydrogels: pH-sensitive mechanism. Reprinted (redrawn) with permission from [113]. Copyright 2018 American Chemical Society