Mechanisms of micropore closure after microneedle application in diverse skin types

项目摘要 微针（MN）是微米级的突出物，其允许通过微针（MN）改善通过皮肤的药物递送。 瞬时微孔的形成。对于成功的透皮药物递送，至关重要的是微孔 保持开放（药物输送在血管闭合后迅速停止，通常在约48小时内）。延迟时间 通过允许每次MN治疗的较长时间的药物递送，封闭将是有利的。先前 已经探索的延迟关闭时间框架的方法没有考虑到 在不同皮肤类型中观察到的生物化学差异;此外，以前的研究没有解决生理学差异。 影响关闭的流程。我们已经证明，深色皮肤的人有更长的寿命。 关闭时限。这可能会导致意外的药物递送窗口改变治疗结果 在不同的皮肤类型中，这对于具有窄治疗窗的药物可能是特别成问题的。 多巴胺等儿茶酚胺类物质在皮肤伤口愈合中起作用，并可能介导炎症反应。 关闭，但多巴胺的直接作用，在脑白质关闭从来没有被研究过。多巴胺可能会改变 通过多巴胺受体结合和随后的cAMP调节的伤口愈合。有趣的是， 产生（负责皮肤颜色）也依赖于相同的多巴胺能前体， cAMP产生。因此，我们假设通过不同皮肤类型中的微孔的药物递送将 不同的方式取决于血管闭合时间，以及皮肤之间血管闭合的变异性 类型受多巴胺分泌和受体信号的影响。为了验证这一点，我们将建立一个 通过两个目标。在目标1中，我们将评估不同的关闭时间对 使用药代动力学研究模拟药物吸收。在目标2中，我们将研究多巴胺D1/D2 受体信号传导使用双重体外敲低方法改变微创伤恢复。总体目标是 确定一个可能的药物靶点，用于延迟腹膜后淋巴结闭合，最终改善MN辅助的 经皮给药和为不同人群开发更好的MN产品提供信息。

PROJECT ABSTRACT 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 (drug delivery ceases rapidly after micropore closure, usually within ~48 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 have shown 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 (responsible for skin color) also relies on the same dopaminergic precursors and alters intracellular cAMP production. Therefore, we hypothesize that drug delivery through micropores in diverse skin types will differ in a manner dependent upon micropore closure times, and variability in micropore closure among skin types is influenced by dopamine secretion and receptor signaling. To test this, we will establish a translational approach through two Aims. In Aim 1 we will assess the impact of differences in micropore closure times on model drug absorption using a pharmacokinetic study. In Aim 2 we will investigate how dopamine D1/D2 receptor signaling alters microwound recovery using a dual in-vitro knockdown approach. The overall goal is to identify a possible pharmaceutical target for delaying micropore closure, ultimately improving MN-assisted transdermal drug delivery and informing development of better MN products for diverse populations.