Each year, nearly 6 million deaths worldwide are caused by lower respiratory tract infections, diarrhoeal diseases, and tuberculosis. These infectious diseases are leading causes of death worldwide. Currently, the pharmacological treatment of infection is encumbered by the presence of inaccessible intracellular pathogen reservoirs, and the need for prolonged treatment regimes. Drug delivery systems can be engineered to overcome these biological barriers for effective treatment by facilitating intracellular delivery and tailored release. Extended release of drugs alleviates the need for exhaustive treatment regimes and increases patient compliance. Furthermore, this can decrease treatment duration, reduce the cost of treatment, and improve access for disadvantaged populations. Our research utilizes modular polymeric prodrugs composed of molecular targeting agents, cleavable linkers, and antimicrobial drugs. This platform permits facile alteration of functional modalities, enabling custom tailored treatments for each disease setting. By utilizing tunable linkers, we can control the precise delivery mechanism and therefore direct the localized release of drugs. To characterize the controlled release of antimicrobial drugs from our polymeric prodrugs, we are designing high performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC-MS) assays. The developed assay will evaluate the release mechanism with stability and release studies. Furthermore, the robust methodology will enable the determination of the pharmacokinetics of the polymeric prodrug delivery system. The assay and results from this study will ultimately support the development of improved therapies.

In the Ratner Lab, our research focuses on engineered biomaterials and surface coatings for improving biocompatibility of implantable medical devices and tissue engineering. Currently, the long-term performance of implantable medical devices is limited by the body’s foreign body reaction (FBR). The body reacts to foreign materials in an inflammatory manner and ultimately encapsulate the device with a dense, avascular scar layer. The Ratner Lab has developed multiple strategies to reduce scarring and improve vascularization, including precision-engineered porous materials. The lab has discovered that materials with uniform 40 μm pores seamlessly heal within the body in a vascularized fashion. Previous research has mostly focused on biostable synthetic materials which remain stable in the body over the duration of implantation. My research will explore the potential of gelatin, a biodegradable, bioderived material, as a precision-engineered porous scaffold to promote healing. IL-4 is a cytokine that directs the inflammatory response towards a healing response. My research will also incorporate IL-4 into the biodegradable porous material to further enhance healing. Our long-term scientific goal is to enable complete regeneration of tissue by first promoting healthy blood vessels growth throughout the porous structure, then allowing the material to completely disappear (biodegrade) to make room for rest of the tissue to heal.

More than 442 million people worldwide have been diagnosed with diabetes, many of which regulate their glucose levels using the pump/catheter system. However, just 2-3 days after the catheter is inserted into the body, the tissue clogs due to the foreign body reaction (FBR), an immune reaction elicited by the body in response to any foreign material injected in the body. At this point, the patient must remove the catheter and insert a new device into fresh skin elsewhere, resulting in excess scar tissue. Our project focuses on preventing the FBR by reducing its triggering event--protein attachment--so that insulin catheters can last longer (2-3 weeks) and can reduce fibrotic accumulation in patients. To combat the frequency of delivery site changes, we have designed a nonfouling zwitterionic polymeric brush coating for the surface of the catheter to reduce protein attachment. For the coating, zwitterionic sulfobetaine methacrylate (SBMA) was surface-polymerized onto the catheter using atom transfer radical polymerization (ATRP). SBMA has been shown to resist protein adsorption down to less than 1ng/cm². The ATRP initiator was plasma-deposited to robustly adhere to the unique geometry of the catheter. In this work, we used a full factorial design of experiment (DOE) to determine significant experimental factors to the polymerization protocol to maximize the amount of SBMA on the surface. The coating was characterized using x-ray photoelectron spectroscopy (XPS) to confirm the presence of SBMA and the radiolabeled protein adsorption assay to measure the amount of protein adsorbed to the coating. We plan to use the results of the DOE screening to further optimize the nonfouling coating and ultimately plan to test this coating on insulin-delivering catheters in a diabetic mouse model to observe sustained lowered blood sugar levels and histologically review the extent of the FBR through collagen accrual.