Abstract
Zwitterionic polymeric hydrogels (polyampholytes) have shown promise as functional biomaterial platforms with resistance to nonspecific protein adsorption (non-biofouling) and as controlled release drug delivery materials. However, there are few zwitterionic cross-linkers to complement these materials and provide a fully zwitterionic material. To date, available zwitterionic cross-linkers have been limited to carboxybetaine or sulfobetaine acrylate/methacrylates and only one of these has been tested in vivo. Peptides offer a highly adaptable zwitterionic scaffold to imbed a series of desired functions. To investigate this hypothesis a simple N-Ser-Ser-C dimethacrylate cross-linker was synthesized. This novel cross-linker was incorporated into a polyampholyte hydrogel, and its physical properties and biocompatibility were compared against a polyampholyte hydrogel synthesized with an EG-based cross-linker to reveal increased non-fouling performance while promoting enhanced cellular adhesion to fibrinogen delivered from the hydrogel over commercial polyethylene glycol (PEG) cross-linkers. Therefore, these results suggest that the S-S cross-linker will demonstrate superior future performance for in vivo applications Continuing, a library of serine and lysine-based zwitterionic dimethacrylamide and mixed methacrylate/ methacrylamide zwitterionic dipeptide cross-linkers (Lys-Lys, Ser-Lys, Lys-Ser) have been developed to provide a tunable polymer platform that retains the desired non-fouling properties. Moreover, this strategy was employed to build tripeptide zwitterionic cross-linkers to extend the distance between the zwitterionic components, another key feature not amenable in the carboxy- or sulfobetaine based cross-linkers. Peptide-based cross-linkers can be synthesized following an ‘outside-in’ approach and the key to this route is the selective protection strategy of both N and C termini, peptide coupling, and semi-orthogonal protection and deprotection strategy. It has been hypothesized that molecular-level control over the length, charge spacing, charge density, and sidechains will lead to fully tunable polymer hydrogels for directed biomaterial scaffolds.