This review provides a detailed overview of the rapidly advancing field of biofabrication, particularly with regards to the use of photo-cross-linking (i.e., light-based) techniques. The major emphasis of this review is on the fundamentals of photo-cross-linking and key criteria identified for the successful design and implementation of photo-cross-linked bioinks and bioresins in extrusion-based and lithography-based bioprinting. The general mechanisms associated with photo-cross-linking (e.g., free-radical chain polymerization, thiol–ene, photomediated redox) of natural and synthetic materials are described to inform bioink and bioresin design, which includes the selection of polymers, functional group modifications, photoinitiators, and light sources that enable facile and cytocompatible photo-cross-linking. Depending on material selection and the bioprinting technique of interest, we describe the specific bioink or bioresin properties and criteria that must be achieved to ensure optimal printability and utility. Finally, examples of current state-of-the-art applications of light-based bioprinting for in vitro tissue models, tissue engineering, and regenerative medicine are provided to further motivate future opportunities within the bioprinting landscape that are facilitated with light.
In this study, the cyto‐compatibility and cellular functionality of cell‐laden gelatin‐methacryloyl (Gel‐MA) hydrogels fabricated using a set of photo‐initiators which absorb in 400–450 nm of the visible light range are investigated. Gel‐MA hydrogels cross‐linked using ruthenium (Ru) and sodium persulfate (SPS), are characterized to have comparable physico‐mechanical properties as Gel‐MA gels photo‐polymerized using more conventionally adopted photo‐initiators, such as 1‐[4‐(2‐hydroxyethoxy)‐phenyl]‐2‐hydroxy‐2‐methyl‐1‐propan‐1‐one (Irgacure 2959) and lithium phenyl(2,4,6‐trimethylbenzoyl) phosphinate (LAP). It is demonstrated that the Ru/SPS system has a less adverse effect on the viability and metabolic activity of human articular chondrocytes encapsulated in Gel‐MA hydrogels for up to 35 days. Furthermore, cell‐laden constructs cross‐linked using the Ru/SPS system have significantly higher glycosaminoglycan content and re‐differentiation capacity as compared to cells encapsulated using I2959 and LAP. Moreover, the Ru/SPS system offers significantly greater light penetration depth as compared to the I2959 system, allowing thick (10 mm) Gel‐MA hydrogels to be fabricated with homogenous cross‐linking density throughout the construct. These results demonstrate the considerable advantages of the Ru/SPS system over traditional UV polymerizing systems in terms of clinical relevance and practicability for applications such as cell encapsulation, biofabrication, and in situ cross‐linking of injectable hydrogels.
Extrusion‐based 3D bioprinting is hampered by the inability to print materials of low‐viscosity. In this study, a single initiating system based on ruthenium (Ru) and sodium persulfate (SPS) is utilized for a sequential dual‐step crosslinking approach: 1) primary (partial) crosslinking in absence of light to alter the bioink's rheological profile for print fidelity, and 2) subsequent secondary post‐printing crosslinking for shape maintenance. Allyl‐functionalized gelatin (Gel‐AGE) is used as a bioink, allowing thiol‐ene click reaction between allyl moieties and thiolated crosslinkers. A systematic investigation of primary crosslinking reveals that a thiol‐persulfate redox reaction facilitates thiol‐ene crosslinking, mediating an increase in bioink viscosity that is controllable by tailoring the Ru/SPS, crosslinker, and/or Gel‐AGE concentrations. Thereafter, subsequent photoinitiated secondary crosslinking then facilitates maximum conversion of thiol‐ene bonds between AGE and thiol groups. The dual‐step crosslinking method is applicable to a wide biofabrication window (3–10 wt% Gel‐AGE) and is demonstrated to allow printing of low‐density (3 wt%) Gel‐AGE, normally exhibiting low viscosity (4 mPa s), with high shape fidelity and high cell viability (>80%) over 7 days of culture. The presented approach can therefore be used as a one‐pot system for printing low‐viscous bioinks without the need for multiple initiating systems, viscosity enhancers, or complex chemical modifications.
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