In situ formed microneedle-like depots for spatiotemporally controlled drug delivery

PROJECT ABSTRACT Conventional systemic drug delivery methods suffer from non-specific distribution, which can lead to reduced efficacy, severe side effects, and the development of drug resistance. Drug-induced liver injury is the main cause of acute liver failure, while drug-induced renal injury is the cause of around 20% of acute renal failure. Antimicrobial resistance contributed to 4.95 million global deaths in 2019, while around 90% of metastatic cancer patients experience resistance to chemotherapy. Localized delivery approaches have been implemented to resolve these challenges. However, limited drug penetration, specifically for the treatment of biofilm infections, results in poor outcomes. In the United States, more than 5 million patients suffer from superficial infections, with an annual financial burden of ~$11-28 billion. Microneedle arrays (MNAs) can resolve the penetration issue in localized drug delivery by bypassing the barriers against drug exposure to the cells and microbes. However, “prefabricated” MNAs have limited translational capability due to poor tissue penetration, challenges associated with their adaption to irregularly shaped large wounds, and limited compatibility with controlled spatiotemporal distribution of different drugs. Furthermore, the limited number of needles in MNAs is insufficient to effectively disrupt the biofilm and expose the microorganisms. We have recently developed a novel drug delivery strategy based on intralesional printing of drug-eluting biomaterials depots to resolve these challenges of prefabricated MNAs for drug delivery applications, and here we propose its evaluation in the treatment of wound infections. Our hypothesis is that intralesional patterning of drug-eluting depots has a strong chance of treating various defects including infected wounds through disruption of the physical barriers such as biofilms and delivery of drugs with controlled spatiotemporal distribution. The ultimate goal of this proposal is to develop an intralesional drug delivery strategy that enables maximum drug exposure to the target cells or microorganisms and enable spatiotemporal control over drug distribution, with effectiveness in treatment of infected wounds. Our objective is to in situ fabricate defect-specific and biodegradable gelatin-based drug depots carrying antimicrobial and pro- regenerative drugs directly into the defect and compare their effectiveness with topical delivery for the treatment of infected wounds. We will test our hypothesis in vitro, ex vivo, and in vivo, and achieve our objective through the following specific aims: (1) characterization of the in situ formed microneedle-like drug depots and drug release kinetics in vitro; (2) development and evaluating the effectiveness of sustained drug delivery from in situ fabricated drug depots in the treatment of biofilms in an ex vivo porcine wound biofilm model; and (3) assessing the effects of in situ fabricated drug depots on the healing of biofilm-challenged diabetic wounds in vivo. Completion of this work will demonstrate the feasibility of the technology and enable us to evaluate its efficacy in patient-derived microorganisms and pre-clinical large animal models of infected wounds in an R01 application.