Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering (ENAS)
First Advisor
Kyriakides, Themis
Abstract
Cutaneous leishmaniasis (CL) is a debilitating and disfiguring parasitic disease that predominantly manifests clinically as ulcerative skin lesions. Despite extensive global transmission, frontline treatments for CL have remained unchanged for decades due to underfunding and being overlooked scientifically. Consequently, available treatment options for CL demonstrate toxicity and varied efficacy. There exists the possibility of improving CL treatment options by developing new topical therapeutics. However, development is impeded by limited physiological and pharmacological knowledge of the CL lesion site. This work provides an improved understanding of the altered skin structure and barrier function both during acute CL infection and as a consequence of the treatment-initiated healing process. These physiological and histological findings were then leveraged to (1) create a mechanistic, physiologically-based dermal Pharmacokinetic/Pharmacodynamic (PK/PD) model of CL and (2) develop a multi-compartment, topical nanofibrous scaffold for CL using electrospinning and electrospraying techniques. By employing a nested Human-Centered Design approach with this clinical and engineering work, multi-functional scaffolds based on polycaprolactone and hyaluronan for improved treatment of CL were designed, fabricated, and iteratively evaluated. The resulting design consisting of a core-shell nanofiber scaffold with enmeshed particles considers (1) key altered physiological and pharmacological properties of ulcerative CL lesions, (2) the therapeutic design preferences of CL patients, and (3) certain available infrastructure and local environmental constraints. Scaffolds were designed to release gentamicin, miltefosine, and allantoin over distinct time scales to optimize therapeutic effect and promote CL lesion healing. The incorporation and release of active compounds from the construct was confirmed in vitro and in vivo. This work has direct implications for CL control in rural endemic areas where existing CL treatments are otherwise of limited feasibility and acceptability. More broadly, this work indicates a preliminary topical drug delivery platform and approach for tackling global health challenges that can be applied to other neglected tropical skin diseases.
Recommended Citation
Byler, Rebecca, "Lesion-Informed Design and Characterization of a Multi-Drug Compartment, Topical Nanofibrous Scaffold for Treatment of Cutaneous Leishmaniasis" (2022). Yale Graduate School of Arts and Sciences Dissertations. 758.
https://elischolar.library.yale.edu/gsas_dissertations/758
