Mechanistic understanding of enhancing bioactivity via bio-ionic liquid functionalization of biomaterials

• The role of bio-ionic liquids (BILs) as cell adhesion molecules for enhancing the bioactivity of bio-inert biomaterials has been investigated. • A bio-inert polyethylene glycol diacrylate (PEGDA) was bio-activated with an acrylated choline BIL to form highly cytocompatible BioPEG hydrogels. • Molecular dynamics (MD) simulations revealed stable electrostatic and van der Waals interactions between BIL in BioPEG and the lipid bilayer of cell membranes. • Advanced manufacturing of cytocompatible BioPEG scaffolds was achieved via digital light processing (DLP)-based optical 3D printing. The selection of biomaterials is a pivotal criterion for designing tissue engineering scaffolds, crucial for diverse biomedical applications. While natural biomaterials offer inherent bioactivity and biocompatibility, fine-tuning their properties for specific applications poses challenges. Conversely, synthetic biomaterials, while highly customizable, are often bio-inert. Functionalizing materials with bioactive molecules can improve cell-material interactions. Prevailing approaches utilizing RGD peptides or natural/synthetic composites have drawbacks including cost and immunogenicity. Bio-ionic liquids (BILs), a class of biocompatible ionic liquids derived from natural or synthetic biomolecules, offer a potential alternative. Herein, we present the biofunctionalization of a bio-inert polyethylene glycol diacrylate (PEGDA) with an acrylated choline-based BIL (“BioPEG”) as a method for enhancing the bioactivity of biomaterials. Cell studies using mouse myoblast C2C12 and human mesenchymal stem cells (hMSCs) revealed the excellence of BioPEG hydrogels in promoting cell attachment, growth, proliferation, and differentiation. Computational molecular dynamics (MD) simulations elucidated the mechanism by which BIL facilitates cell interaction with PEGDA. 3D printability of BioPEG hydrogel was showcased using a digital light processing (DLP) bioprinter, with printed scaffolds demonstrating excellent cytocompatibility. Collectively, these findings present BIL as a versatile bioactive agent for augmenting cell adhesion to materials, thus enriching the repertoire of biomaterials for advanced tissue engineering.