Thioether-Functionalized Cellulose for the Fabrication of Oxidation-Responsive Biomaterial Coatings and Films

Implantable medical devices, such as subcutaneous drug delivery systems or deep brain stimulation electrodes, are powerful tools for disease treatment. However, implantation of these devices stimulates a multicellular foreign body response (FBR) leading to device encapsulation by fibrotic tissue, which attenuates device function. Biomaterial coatings, which adhere or bond to the device surface, or biomaterial films, which can be press-fit as a separate material layer onto devices, hold promise for both preventing premature failure of chronically implanted medical devices and enhancing the device functionality and performance. However, current hydrophilic polymers used in device coatings and films have significant drawbacks such as swelling and delamination. In this work, we address these limitations by developing an oxidation-responsive, bio-inspired polymer (HEC_MTP) which is synthesized by modifying hydroxyethyl cellulose (HEC), with 3-(methylthio)-propyl isothiocyanate (MTPI). HEC_MTP readily dissolves in dimethyl sulfoxide (DMSO) and blends of other green solvents. By tuning polymer solution viscosity through solvent and concentration selection, HEC_MTP can be controllably deposited onto substrates to create coatings between 1-30µm in thickness or drop cast to form free standing, smooth and transparent films ranging from 7-70µm in thickness. When HEC_MTP-coated substrates are exposed to physiologically relevant concentrations (40-80µM) of reactive oxygen species (ROS) <i>in vitro</i>, thioether moieties on the HEC_MTP are oxidized to sulfoxide groups, resulting in a significant increase in hydrophilicity and softening of the coating interface, as well as a &gt;92% decrease in cell biofouling <i>in vitro</i>. HEC_MTP coatings show a strong resistance to delamination, a capacity for oxidation-responsive and controlled release of small molecules and biomacromolecules, and exceptional optical transparency. Subcutaneous implantation of HEC_MTP resulted in a significant decrease in remodeled tissue thickness relative to similarly functionalized, non-oxidation responsive, HEC-derived materials. These results highlight the wide utility of HEC_MTP and support its use as a coating for implanted medical devices to enhance device efficacy and longevity.