NEONATAL SKIN--BARRIER FUNCTION AND DRUG DELIVERY

我们建议的研究的长期目标是：(1)确定如何 早产儿的屏障功能可能会受损 尽快达到完全成熟；以及(2)形成透皮 治疗婴幼儿戒断症状的药物释放系统 依赖药物的母亲和接受医源性手术的婴儿所生的 吸毒成瘾。经皮给药是一种给药策略 对这一受试者群体有明显的优势，但机制和因素 会影响早产儿和足月儿的皮肤运输 都没有被很好地理解。为了达到我们的目标，需要一个详细的 对新生儿皮肤屏障的认识及其作为一种 孕期和出生后年龄的作用。《公约》的具体目标 项目是：[1]利用红外(IR)光谱表征， 差示扫描量热法(DSC)和小角X射线衍射仪 (SAXD)在切除的新生儿组织上，地层中的生物物理变化 伴随皮肤成熟的角质(SC)脂类。[2]学习，使用 透射电子显微镜与激光扫描共聚焦 显微镜(LSCM)观察细胞的结构和超微结构特征 资深大律师。[3]测定新生儿SC皮脂成分。[4]至 激光共聚焦显微镜在体外和体内对屏障功能的评价 经皮失水(TEWL)测量。[5]关联输入 活体数据与生物物理、生化和形态 测量，并确定SC如何发展以控制经皮 运输。主要的试验性战略涉及：(A)使用 红外光谱、差示扫描量热法和小角X射线衍射法探索SC的生物物理基础 阻隔功能；(B)使用层析方法分析 新生儿SC的脂质；(C)用透射电子显微镜和激光共聚焦显微镜观察SC 探讨新生儿皮肤的结构标志。这项研究 建议的目的是回答以下问题：(1)什么是 功能屏障的化学和生物物理要求 新生儿？随着障碍的发展，这些成分发生了哪些变化？ (2)干细胞的结构如何取决于孕期和出生后 年龄？新生儿SC与成人SC的形态有何不同 SC？(3)TEWL和LSCM测量的渗透率是否可以关联 用生物物理和生化方法检测屏障功能？(4) 最终，基于我们对 新生儿皮肤屏障，我们能否加速早产儿皮肤 开发全功能并设计透皮制剂 安全有效地提供治疗性剂量的药物以治疗 新生儿有戒断症状吗？

The long-term objectives of our proposed research are: (1) to identify how the compromised barrier function of the premature neonate can be brought to full maturation as quickly as possible; and (2) to develop transdermal drug delivery systems for the treatment of withdrawal symptoms of infants born to drug-dependent mothers and of infants undergoing iatrogenic narcotic dependency. Transdermal delivery is an administrative strategy of clear advantage to this subject population, but the mechanisms and factors that affect transport through the skin of premature and full-term infants are not well understood. To attain our objectives requires a detailed understanding of the neonatal skin barrier and its development as a function of gestational and postnatal age. The specific aims of the project are: [1] To characterize, using infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and small-angle X-ray diffraction (SAXD) on excised neonatal tissue, the biophysical changes in the stratum corneum (SC) lipids which accompany skin maturation. [2] To study, using transmission electron microscopy (TEM) and laser-scanning confocal microscopy (LSCM), the structural and ultrastructural characteristics of the SC. [3] To determine the skin lipid composition of neonatal SC. [4] To evaluate barrier function in vitro with LSCM and in vivo using measurements of transepidermal water loss (TEWL). [5] To correlate the in vivo data with the biophysical, biochemical, and morphological measurements, and to determine how the SC develops to control percutaneous transport. The principal experimental strategies involve: (a) the use of IR spectroscopy, DSC, and SAXD to probe the biophysical bases of SC barrier function; (b) the use of chromatographic methods to analyze the lipids of neonatal SC; (c) the visualization of the SC with TEM and LSCM to investigate the structural landmarks of neonatal skin. The research proposed is intended to answer the following questions: (1) What are the chemical and biophysical requirements of a functional barrier in the neonate? What changes in these constituents accompany barrier development? (2) How does the structure of the SC depend on gestational and postnatal age? What are the morphological differences between neonatal SC and adult SC? (3) Can measurements of permeability from TEWL and LSCM be correlated with biophysical and biochemical measurements of barrier function? (4) Ultimately, based on the insight we gain into the development of the neonatal skin barrier, can we accelerate premature neonatal skin development to full functionality and design transdermal formulations which deliver, safely and effectively, therapeutic doses of drugs to treat withdrawal symptoms in the neonate?