Tunable degradation of low-fouling carboxybetaine-hyaluronic acid hydrogels for applications in cell encapsulation

Low-fouling hydrogels with tunable degradation rates and biochemical environments have the potential to improve adoptive cell therapies for cancer immunotherapy and regenerative medicine. To this end, we developed in situ gelling hydrogels from low-fouling poly(carboxybetaine-co-maleimide) (pCBM) random copolymers and thiolated hyaluronic acid (HA-SH). pCBM-HA hydrogel enzymatic degradation rates were tuned 5 fold by altering pCBM composition (4, 11, and 16 maleimide mol%) and 2.3 fold by HA-SH concentration (1-2 wt%). pCBM-HA gels were low-fouling towards bovine serum albumin (BSA; adsorbed ∼20 μg cm^-2) and resisted fibroblast adhesion. To control pCBM-HA bioactivity, the cell adhesive peptide CGRGDS was immobilized on pCBM to promote fibroblast adhesion (39% decrease in circularity), which increased metabolic activity by ∼50%. pCBM-HA modified with CGRGDS enhanced the metabolic activity of encapsulated T cells by ∼21% compared to gels without HA, indicating their potential for immunotherapies. Low-fouling pCBM-HA hydrogels provide a vehicle with tunable degradation rates and biochemical environments for encapsulation applications in cell adoptive therapies.