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Valeria Cota Dissertation Final2.93 MB
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Dissertation
Assessment of micropore closure after microneedle application in diverse skin types
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007820
Abstract
Microneedles (MNs) Microneedles (MNs) are micron scale projections that allow for improved drug delivery through the skin via formation of transient micropores. For successful transdermal drug delivery, it is crucial that the micropores remain open as drug delivery ceases rapidly after micropore closure, usually within ~48-72 hrs. Delaying micropore closure would be advantageous by allowing a longer period of drug delivery from each MN treatment. Previous methods that have been explored for delaying micropore closure timeframes did not account for the biochemical differences seen in diverse skin types; further, previous studies did not address the physiological processes that impact micropore closure. We showed that darker skin types have longer micropore closure timeframes. This could result in altered therapeutic outcomes from unexpected drug delivery windows in diverse skin types, which may be especially problematic for drugs with narrow therapeutic windows.
Catecholamines such as dopamine play a role in cutaneous wound healing and may mediate micropore closure, but the direct role of dopamine in micropore closure has never been studied. Dopamine may alter wound healing through dopamine receptor binding and subsequent cAMP modulation. Interestingly, melanin production, the main pigment responsible for skin color, also relies on the same dopaminergic precursors and similarly alters intracellular cAMP production. Therefore, we hypothesize that drug delivery through micropores in darker skin types is dependent upon micropore closure times, and variability in micropore closure among skin types is influenced by dopamine secretion and receptor signaling.
Micropore formation was visualized using optical coherence tomography (OCT) at baseline, 24-, and 48-hrs post MN application. Micropore depth was measured at each timepoint, and closure was assessed as percentage of micropore closure and compared to electrical impedance measurements. Tristimulus colorimetry was used to objectively assess skin pigmentation and study participants were categorized as dark, medium, and light using individual typology angle (ITA°) values. We showed that there was lower percentage of micropore closure in darker skin despite no initial difference in micropore formation.
We assessed drug delivery through micropores in vivo using a crossover pharmacokinetic (PK) study, with a hydrophilic model drug (MTZ). We assessed the influence on formulation and micropore closure timeframes on total drug exposure (AUC), maximum drug delivered (Cmax), and time of maximum drug concentration (Tmax). We showed no difference in drug delivery across age groups, but did observe increased micropore closure timeframes and increased drug permeation in darker skin types. Additionally, we saw that there was more drug delivered in the gel formulation in comparison to the cream after MN pretreatment.
Lastly, we assessed dopamine and subsequent dopamine signaling in skin and primary cells from diverse skin types. We showed increased dopamine in darker skin and keratinocytes. We confirmed that both D1 and D2 receptor types are present in the skin and that D1 agonists and D2 antagonists delay cell migration. Initial assessment of cAMP levels indicates that treatment with D1 agonists increases cAMP production. These results initially show that the dopaminergic signaling pathway is a promising pathway for addressing pigment dependent variability in micropore closure timeframes.
Details
- Title: Subtitle
- Assessment of micropore closure after microneedle application in diverse skin types
- Creators
- Valeria Cota
- Contributors
- Nicole Brogden (Advisor)Martine Dunnwald (Committee Member)Ethan Anderson (Committee Member)Dave Roman (Committee Member)Jonathan Doorn (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007820
- Publisher
- University of Iowa
- Number of pages
- xx, 161 pages
- Copyright
- Copyright 2025 Valeria Cota
- Language
- English
- Date submitted
- 04/28/2025
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 151-161).
- Public Abstract (ETD)
- Microneedles (MNs) allow for improved drug delivery through the skin via formation of micropores. For successful transdermal drug delivery, it is crucial that the micropores remain open as drug delivery stops after micropores close. Delaying micropore closure allows for a longer period of drug delivery from each MN treatment. We showed that darker skin types have longer micropore closure timeframes, which may lead to increased drug dosages delivered. Therefore, this work aims to identify a pathway that delays micropore closure and addresses the extended micropore closure time observed in darker skin. Dopamine plays a role in wound healing but its direct role in micropore closure has never been studied. Dopamine shares overlapping pathways with melanin (responsible for skin color) and provides a possible connection between dark skin and delayed micropore healing. In this work micropore formation after microneedle application was assessed to determine if differences in micropore closure were a result of larger initial micropore depth. Next, the influence of micropores and formulation on total drug exposure was assessed in participants with delayed micropore closure timeframes. Lastly, we evaluated dopamine signaling to identify a pathway for delayed micropore closure timeframes in darker pigmented skin. We visualized micropores after microneedle application and showed delayed micropore closure in darker skin despite no difference in initial micropore depth. Our PK data show that drug delivery may differ in darker skin. Lastly, more dopamine was measured in darker skin and dopamine D1 receptor binding delayed cell migration, delaying wound healing in human skin cells.
- Academic Unit
- Craniofacial Anomalies Research Center; Interdisciplinary Graduate Program in Human Toxicology
- Record Identifier
- 9984830825002771
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