Approaches for extending insulin catheter longevity

Abstract

Implantable medical devices serve a wide range of therapeutic purposes; however, they are an alien material in the body and are subject to the effects of the body’s immune reaction—the foreign body response (FBR). For insulin catheters, a foreign body capsule occludes the catheter tip within 2-3 days, thereby eliminating any therapeutic effects. Here, a few approaches are proposed to reduce the extent of the FBR to lengthen the medical device lifetime and lessen the disease management burden. The first approach is to minimize initial protein adsorption on the device—a traditional method of improving biocompatibility. In this work, a nonfouling zwitterionic polymer, poly(sulfobetaine methacrylate) (pSBMA), was grafted to the surface as a polymer brush coating using an alternative polymerization initiator—a plasma-deposited bromoester. The plasma-deposited initiator robustly covers the entirety of the surface independently of device material or shape. To further-optimize these polymer brush coatings, the effects of polymer brush length and density were investigated utilizing self-assembled monolayers. Quartz crystal microbalance with dissipation was used to measure protein adsorption after in situ polymerization and sum frequency generation spectroscopy measured water structure at the interface. In a second approach to reduce the FBR, macrophages will be guided to an alternative, ‘pro-healing’, phenotype—M2. A de novo version of interleukin-4 (IL-4) was computationally designed with high stability, binding affinity, and an additional cysteine residue. In this work, an SN2 reaction was used to substitute the cysteine on a brominated surface, immobilizing the therapeutic. The reaction was confirmed by immobilizing cysteine-containing cell adhesion RGD peptides and culturing with fibroblasts to confirm bioactivity maintenance in preparation for the de novo IL-4. Finally, with the proposed increase in device lifetime there is an elevated infection risk. Therefore, a method for antibiotic incorporation was developed for the insulin catheter. The extended release of the drug was measured over time and a concentration model was developed to predict the antibiotic concentration around the catheter to ensure minimum inhibitory concentration (MIC) was maintained. The approaches investigated here may significantly reduce the effects of the FBR, aiming to extend insulin catheter longevity or other implantable medical devices.