Mechanisms of micropore closure after microneedle application in diverse skin types

项目摘要 微针(MN)是微米级的突起，允许通过皮肤改善药物输送 瞬时微孔的形成。对于成功的经皮给药，微孔至关重要 保持开放(药物输送在微孔关闭后迅速停止，通常在约48小时内)。延缓微孔 关闭将是有利的，因为允许从每个MN治疗中给药更长的时间。上一首 已经探索的延迟微孔关闭时间的方法并没有考虑到 不同皮肤类型的生化差异；此外，以前的研究没有涉及生理上的 影响微孔闭合的过程。我们已经表明，深色皮肤类型有更长的微孔 关闭时间范围。这可能会导致意外给药窗口的治疗结果发生变化 在不同的皮肤类型中，这可能对治疗窗口较窄的药物尤其有问题。 儿茶酚胺，如多巴胺，在皮肤伤口愈合中发挥作用，并可能介导微孔 但多巴胺在微孔关闭中的直接作用从未被研究过。多巴胺可能会改变 伤口愈合通过多巴胺受体结合和随后的cAMP调节。有趣的是，黑色素 产生(负责肤色)也依赖于相同的多巴胺能前体，并改变细胞内 夏令营制作。因此，我们假设通过不同皮肤类型的微孔给药将 不同的方式取决于微孔闭合时间和皮肤间微孔闭合的变异性 类型受多巴胺分泌和受体信号的影响。为了测试这一点，我们将建立一个翻译 通过两个目标来接近。在目标1中，我们将评估微孔关闭时间的差异对 利用药代动力学研究建立药物吸收模型。在目标2中，我们将研究多巴胺D1/D2是如何 受体信号改变微创愈合使用双重体外基因敲除方法。总体目标是 确定一个可能的药物靶点，以延迟微孔关闭，最终改善MN辅助 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.