Year of Award

2023

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Pharmaceutical Sciences

Other Degree Name/Area of Focus

Drug Design

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Monica Serban

Commitee Members

Erica Woodahl, Philippe Diaz, Travis Hughes, Cole DeForest

Keywords

Anti-Inflammatory, Antioxidant, Hearing Loss, Hyaluronan, Silk Fibroin

Publisher

University of Montana

Abstract

We have developed four projects using biomaterials including hyaluronan (HA) and silk fibroin (SF) for biomedical applications. First, we investigated an HA-antioxidant conjugate for topical application in sensorineural hearing loss (SNHL). Drug delivery to the ear is very difficult. Systemic approaches usually result in low concentration to the ear and topical approaches are difficult with the two anatomical membranes of the ear: the tympanic membrane (TM) and the round window membrane (RWM). We have chosen an HA-based drug conjugate as HA has been shown to permeate through anatomical membranes like the skin. Our hypothesis was that an antioxidant like DMethionine will more readily travel across the TM and RWM when chemically conjugated to HA. After crossing these membranes, D-Met will then act as an antioxidant to protect against reactive oxygen species (ROS) prevalent in SNHL. We found that our HA-D-Methionine conjugate is cytocompatible, protects against oxidative stress and apoptosis as well as permeates through a RWM model, therefore showing promise as a topical prophylactic against hearing loss.

Second, we synthesized a series of HA-antioxidant and HA-anti-inflammatory drug conjugates for protection and treatment against noise- induced hearing loss (NIHL) a form of SNHL. The mechanism of damage in NIHL is well established and includes the recruitment of inflammatory signaling pathways and reactive oxygen species to the cochlea. As a result, we have developed HA-conjugates that would be able to suppress the inflammation and ROS formation.

Additionally, we standardized and optimized the testing and formulation of a thixotropic HA-TEOS hydrogel for the single application in treating otitis externa. We were able to standardize preparation for more consistent and reliable hydrogel formation. We also were able to standardize and streamline some of the characterization of mechanical properties. In addition, we saw no major effect on thixotropy or storage modulus when using HA of different manufacturers or scale of preparation.

Lastly, we explored the environmental sensing abilities of silk fibroin (SF). To increase sensitivity, SF was chemically modified to enrich the tryptophan concentration.

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© Copyright 2023 Elizabeth Marie Arrigali