Schilling, Andrea Leigh
(2021)
Engineering a Temperature-Responsive, Local and Sustained Release System for the Paranasal Sinuses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Controlled-release drug delivery is a valuable strategy for providing long-acting treatment, especially to anatomical regions with limited access, such as the paranasal sinuses. Chronic inflammation of the sinuses associated with the prevalent condition, chronic rhinosinusitis (CRS), is routinely treated with topical corticosteroids. While numerous methods for daily intranasal administration exist, the anatomy and physiology of the nasal cavity and sinuses, along with maintaining patient adherence, can limit their efficacy. Controlled-release sinus stents are also available; however, their degradation or uneven contact can cause local adverse tissue reactions. Instead, a reversibly conformable system could improve mucosal compatibility while achieving sustained drug release. Accordingly, a thermoresponsive poly(N-isopropylacrylamide)-based hydrogel with poly(lactic-co-glycolic acid) microspheres (PLGA MS) was developed. This delivery system, called “TEMPS” (Thermogel, Extended-release Microsphere-based delivery to the Paranasal Sinuses), undergoes a reversible sol-gel transition at approximately 33°C such that it can be applied as a liquid at ambient temperature, conform to the sinonasal epithelium as it gels at body temperature, and localize controlled-release MSs. Following application in rabbit sinuses for 30 days, TEMPS engineered to steadily release the corticosteroid mometasone furoate significantly reduced sinonasal inflammation, as characterized by micro-computed tomography and histopathology analysis. As TEMPS is intended for apposition with ciliated epithelium, thermogel compatibility was demonstrated by ex vivo incubation with human nasal epithelium for 24 hours and showed that cilia motility was maintained. In CRS patients, enhancing cilia regeneration would also help improve airway health. Thus, TEMPS was engineered to provide 30-day sustained release of retinoic acid, which promotes cilia differentiation. In terms of the formulation of TEMPS, the drug-loaded PLGA MSs are susceptible to hydrolysis, therefore the MSs and thermogel must be combined immediately prior to administration. Removing the water content of TEMPS through freeze drying resulted in a shelf-stable, ready-to-use form, mitigating aqueous instability. Freeze-dried TEMPS stored under ambient conditions for 6 weeks maintained its release kinetics and MS morphology. Additionally, when applied to a simulated mucosal surface, freeze-dried TEMPS rehydrated and gelled in situ without undergoing displacement. Ultimately, TEMPS is a versatile and clinically-translatable system that provides uniform distribution along the sinonasal epithelium for local drug delivery.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
6 May 2021 |
| Defense Date: |
16 September 2021 |
| Approval Date: |
16 January 2022 |
| Submission Date: |
24 August 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
184 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Chemical Engineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
drug delivery; paranasal sinuses; thermoresponsive; microspheres |
| Date Deposited: |
16 Jan 2023 06:00 |
| Last Modified: |
16 Jan 2023 06:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41835 |
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Engineering a Temperature-Responsive, Local and Sustained Release System for the Paranasal Sinuses. (deposited 16 Jan 2023 06:00)
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