(600e) Tunable Brush-like Polymers on Biomaterials for Controlled Drug Delivery

A drug release platform that can be placed in a desired pocket of tissue, remain fixed in place yet ultimately degrade, and release a therapeutic locally and controllably would be transformative for many disease states, but is of critical importance for therapeutics that have high systemic toxicity. This work seeks to address these needs by synthesizing new brush-like polymeric materials whose interactions at the molecular scale are designed to generate functional properties at the macroscale. Brush architectures contain polymers that are projected away from the main polymer backbone to resemble blades of grass on a lawn. Brushes are expected to be a powerful biomaterial tool, due to the potential to engineer composition, density, interconnectivity, porosity, and interactions with other materials, but they are seldom employed because achieving a high density of substitutions is challenging, yet necessary for the architecture.

We use a “grafting from” strategy to grow a dense layer of brush-like polymers on degradable biomaterial films, which generates much higher densities of polymer chains on a surface than attaching a pre-formed polymer to the film’s surface. Additionally, polymer chains prepared by “grafting from” feature extended backbones like the bristles of a toothbrush. In our work, these brushes have side groups to control polymer chain hydrophilicity, tune interactions between neighboring blades, and facilitate drug attachment via a hydrolyzable tether. This drug delivery surface has a distinct architecture that has the potential to increase the efficiency of delivery and permit more precise engineering of the delivery profile compared to drug encapsulation methods.

A variety of methacrylate monomers that possess different charges were selected to generate brush-like polymers on the surface of Bombyx mori silk fibroin films. Silk fibroin (SF) has been widely used for preparation of drug delivery systems due to its biocompatibility, controllable degradability, and tunable drug release properties. SF films were enriched with hydroxyl groups, immobilized with a suitable chain transfer agent (RAFT agent), and finally reacted with methacrylate monomers using reversible addition-fragmentation chain transfer polymerization (RAFT). A drug molecule was attached to these polymer grafts as a final synthetic step by swelling the brushes and linking using a hydrolyzable tether. ATR-FTIR spectra was used to characterize the films before and after grafting, and the formation of new peaks confirmed successful reaction. Water contact angle measurements showed that the contact angle varied with brush composition. In vitro drug release showed that different amounts of drug released into media based on the hydrophobicity of the brush-like polymer. In vitro cell compatibility showed no differences in fibroblast viability compared to silk films that were not functionalized with the brush-like polymers, and films degraded over a period of 12 weeks in vitro in the presence of collagenase Type IV. This new approach to modify silk fibroin surfaces is expected to enable tailoring of silk-drug interactions to achieve more controllable and continuous delivery of small bioactive molecules suitable for biomedical applications.

Figure 1. (a) Synthesis of brush-like polymers on silk with hydrophobic (Silk-MMA), hydrophilic (Silk-DMAPS), and hydrophobic followed by hydrophilic (Silk-MMA-DMAPS) Blocks. (b) ATR-FTIR shows successful polymerization of Blocks of varying hydrophilicity (order of hydrophilicity: DMAPS > AEMA > MMA) with vertical lines indicating stretching of ester (from repeat units) and sulfonate (from DMAPS). (c) Water contact angle shows silk film becomes more hydrophobic with MMA Blocks or more hydrophilic with DMAPS Blocks. Each Block contains at least 20% AEMA for drug linking. Brushes with two Blocks, MMA proximal and DMAPS distal to the film, are hydrophilic and demonstrate successful synthesis of vertical multi-Block polymers. *** denotes p< 0.001 for all pairwise comparisons. (d) In vitro degradation containing 1U/mL collagenase showed < 20% mass remaining at 12 weeks. If collagenase is not used, films retain >80% of original mass remaining over this period. (e) In vitro testing revealed no difference in fibroblast viability when cultured with medium incubated with silk and silk-brush films compared to control medium that was not incubated with films.