Production of gelatin methacrylate by flow chemistry and investigation of its suitability as a biomaterial†

Abstract

Biopolymers such as gelatin, hyaluronic acid, and chitin are used in the form of hydrogels as scaffolds for tissue engineering and as bioinks for bioprinting. The biopolymers themselves tend to be weak and hence are usually chemically functionalized to improve their stability and tenacity. The chemical functionalization is currently conducted using batch methods, which are time-consuming, difficult to scale up, and have batch-to-batch variation. Flow chemistry, on the other hand, is more efficient, safer, reproducible, easy to scale up, and can give much higher space–time yields compared to batch reactions. In this study, a flow chemistry protocol was developed for the synthesis of the commonly used biomaterial gelatin methacrylate (GelMA), and the resulting GelMA was used in bioprinting and as a hydrogel in cell culture studies to investigate its ability to support cell attachment and expansion. It was found that conversion of gelatin into GelMA proceeded rapidly and optimally at 60 °C, giving reproducible and high degrees of substitution (65–85%) and high yields in up to 20 minutes of reaction. Scale-up of the reaction was also demonstrated. The resulting GelMA was characterized by oscillatory shear rheometry and was found to be capable of extrusion bioprinting, yielding self-supporting and defect-free hydrogel patterns. The GelMA hydrogels were also found to be able to support the proliferation of primary endometrial cells over 6 days of culture. The GelMA produced by flow chemistry, therefore, was shown to be suitable for use as a bioink and as a hydrogel substrate for cell culture, demonstrating the potential of flow chemistry as an efficient method to produce biomaterials for bioprinting and tissue engineering applications.