MICROFABRICATED MICRONEEDLES FOR DRUG DELIVERY

给药的最大挑战之一是大分子以治疗速率通过皮肤给药。这一提议描述了微型针头的使用，这种针头足够长，可以通过皮肤角质层的外层输送药物，但又足够短，可以避免触及神经，从而避免引起疼痛。初步研究表明，微针阵列可以用与制造集成电路相同的微加工技术从硅中蚀刻出来。这些阵列已被证明可以在体外将小分子（钙黄蛋白）、大分子（胰岛素、牛血清白蛋白）和纳米球（直径100纳米）的皮肤渗透性提高5个数量级。初步的人体研究表明，微针插入皮肤是无痛的。提出的工作的第一个具体目标是将微针-皮肤相互作用作为微针几何形状的函数进行量化。将通过体外和人体研究考虑六个几何特征的影响，以测量(1)微针插入的力，(2)微针引起的疼痛，(3)微针引起的皮肤刺激，(4)微针取出后的重新密封。研究强调定量测量和面向机制的分析。第二个具体目标是将透皮运输作为运输机制和微针几何形状的函数进行量化和建模。通过扩散、对流和电泳的转运将在体外进行研究，并以无毛大鼠为模型系统进行体内验证。透皮转运的速率和分布将通过输运、微观和电学测量进行实验量化，并将使用从第一原理发展而来的理论模型进行分析，不涉及拟合参数。通过提供(1)无痛注射和(2)一种用户友好的方法，可在数小时至数天内控制化合物（如常规药物和大分子（如蛋白质、DNA））的递送，用于经皮给药的微针可显著影响药物。

One of the greatest challenges in drug delivery is the administration of macromolecules across the skin at therapeutic rates. This proposal describes the use of microscopic needles which are long enough to deliver drugs across the skin's outer layer of stratum corneum, but are short enough to avoid hitting nerves and thereby avoid causing pain. Preliminary studies show that arrays of microneedles can be etched from silicon using the same microfabrication technology used to made integrated circuits. These arrays have been shown to increase skin permeability in vitro by up to five orders of magnitude for small molecules (calcein), macromolecules (insulin, bovine serum albumin) and nanospheres (100 nm diameter). Preliminary human studies indicate that microneedles inserted into the skin are reported as painless. The first specific aim of the proposed work addresses quantifying the microneedle-skin interaction as a function of microneedle geometry. The effects of six geometrical features will be considered through in vitro and human studies to measure the (1) force for microneedle insertion, (2) pain caused by microneedles, (3) skin irritation caused by microneedles and (4) resealing after microneedles are removed. Studies emphasize quantitative measurements and mechanism-oriented analysis. The second specific aim addresses quantifying and modeling transdermal transport as a function of transport mechanisms and microneedle geometry. Transport by diffusion, convection and electrophoresis will be studied in vitro, with in vivo validation using delivery of insulin to hairless rats as a model system. Rates and distribution of transdermal transport will be quantified experimentally using transport, microscopic and electrical measurements and will be analyzed using a theoretical model developed from first principles and involving no fitted parameters. Microneedles for transdermal drug delivery could significantly impact medicine by providing (1) painless injections and (2) a user-friendly method for controlled delivery of compounds such as conventional drugs and macromolecules (e.g., proteins, DNA) over hours to days.