Abstract
Bioprinting techniques allow for the recreation of 3D tissue-like structures. By deposition of hydrogels combined with cells (bioinks) in a spatially controlled way, one can create complex and multiscale structures. Despite this promise, the ability to deposit customizable cell-laden structures for soft tissues is still limited. Traditionally, bioprinting relies on hydrogels comprised of covalent or mostly static crosslinks. Yet, soft tissues and the extracellular matrix (ECM) possess viscoelastic properties, which can be more appropriately mimicked with hydrogels containing reversible crosslinks. In this study, we have investigated aldehyde containing oxidized alginate (ox-alg), combined with different cross-linkers, to develop a small library of viscoelastic, self-healing, and bioprintable hydrogels. By using distinctly different imine-type dynamic covalent chemistries (DCvC), (oxime, semicarbazone, and hydrazone), rational tuning of rheological and mechanical properties was possible. While all materials showed biocompatibility, we observed that the nature of imine type crosslink had a marked influence on hydrogel stiffness, viscoelasticity, self-healing, cell morphology, and printability. The semicarbazone and hydrazone crosslinks were found to be viscoelastic, self-healing, and printable—without the need for additional Ca2+ crosslinking—while also promoting the adhesion and spreading of fibroblasts. In contrast, the oxime cross-linked gels were found to be mostly elastic and showed neither self-healing, suitable printability, nor fibroblast spreading. The semicarbazone and hydrazone gels hold great potential as dynamic 3D cell culture systems, for therapeutics and cell delivery, and a newer generation of smart bioinks.
Highlights
As we strive to recapitulate the complexity of native tissues and organs, bioprinting (BP)has emerged as a promising group of technologies for fields ranging from fundamental cell biology to clinically relevant tissue engineering [1]
We have investigated the suitability of hydrogels based on oxidized alginate with imine type crosslinks as an injectable and printable biomaterials platform
The viscoelasticity could be tuned by selecting the imine type of crosslinks: Oxime with lowest off rate (k−1 ) behaved like an elastic gel and hydrazone with highest off rate (k−1 ) behaved like a viscoelastic gel
Summary
Has emerged as a promising group of technologies for fields ranging from fundamental cell biology to clinically relevant tissue engineering [1]. BP allows the printing of various materials, cells, and biological molecules in defined space. These technologies have allowed progress toward the custom 3D construction of both soft and hard tissues including skin, heart, kidney, and bone [1,2]. Bioprinting of high modulus materials (> 1 MPa range) for hard tissues, such as bone [3], has already been successfully demonstrated on a clinical scale for a wide range of polymeric materials. The bioprinting of biological constructs for softer tissues with complex architecture remains limited. Though several key studies have recently shown strategies to design hydrogels with enhanced capacity to self-support bioprinted structures for soft tissues [8,9,10], the demand for customizable bioinks with tissue relevant viscoelasticity and shear-thinning properties required for bioprinting remains unfulfilled
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