Strategies to use fibrinogen as bioink for 3D bioprinting fibrin-based soft and hard tissues

Fibrin gel has been widely used for engineering various types of tissues due to its biocompatible nature, biodegradability, and tunable mechanical and nanofibrous structural properties. Despite their promising regenerative capacity and extensive biocompatibility with various tissue types, fibrin-based biomaterials are often notoriously known as burdensome candidates for 3D biofabrication and bioprinting. The high viscosity of fibrin (crosslinked form) hinders proper ink extrusion, and its pre-polymer form, fibrinogen, is not capable of maintaining shape fidelity. To overcome these limitations and empower fibrinogen-based bioinks for fibrin biomimetics and regenerative applications, different strategies can be practiced. The aim of this review is to report the strategies that bring fabrication compatibility to these bioinks through mixing fibrinogen with printable biomaterials, using supporting bath supplemented with crosslinking agents, and crosslinking fibrin in situ. Moreover, the review discusses some of the recent advances in 3D bioprinting of biomimetic soft and hard tissues using fibrinogen-based bioinks, and highlights the impacts of these strategies on fibrin properties, its bioactivity, and the functionality of the consequent biomimetic tissue. Statement of Significance Due to its biocompatible nature, biodegradability, and tunable mechanical and nanofibrous structural properties, fibrin gel has been widely employed in tissue engineering and more recently, used as in 3D bioprinting. The fibrinogen's poor printable properties make it difficult to maintain the 3D shape of bioprinted constructs. Our work describes the strategies employed in tissue engineering to allow the 3D bioprinting of fibrinogen-based bioinks, such as the combination of fibrinogen with printable biomaterials, the in situ fibrin crosslinking, and the use of supporting bath supplemented with crosslinking agents. Further, this review discuss the application of 3D bioprinting technology to biofabricate fibrin-based soft and hard tissues for biomedical applications, and discuss current limitations and future of such in vitro models.