NEONATAL SKIN--BARRIER FUNCTION AND DRUG DELIVERY

新生儿皮肤——屏障功能和药物输送

• 批准号: 2391026
• 负责人: RICHARD H GUY
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-15 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2391026
• 关键词: body water dehydration; gestational age; growth /development; histogenesis; human subject; human tissue; infrared spectrometry; lipids; low angle X ray diffraction analysis; microcalorimetry; newborn human (0-6 weeks); skin; skin absorption; transdermal drug delivery; transmission electron microscopy

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?

我们建议的研究的长期目标是：（1）确定如何 早产儿的屏障功能受损 尽快完全成熟;（2）开发透皮 用于治疗婴儿戒断症状的药物输送系统 药物依赖母亲所生婴儿和接受医源性 毒品依赖透皮给药是一种管理策略， 这对受试者群体有明显的优势，但机制和因素 影响早产儿和足月儿皮肤运输的 并没有得到很好的理解。为了实现我们的目标，需要一个详细的 了解新生儿皮肤屏障及其发展， 妊娠期和产后年龄的功能。的具体目标 项目是：[1]为了表征，使用红外（IR）光谱， 差示扫描量热法（DSC）和小角X射线衍射 （SAXD）在切除的新生儿组织上， 角质层（SC）脂质伴随皮肤成熟。[2]学习，使用 透射电子显微镜（TEM）和激光扫描共聚焦 显微镜（LSCM），结构和超微结构特征， [3]测定新生儿SC的皮肤脂质组成。[4] 用LSCM在体外和体内评价屏障功能， 测量经表皮水分损失（TEWL）。[5]为了将输入 生物物理学、生物化学和形态学的体内数据 测量，并确定SC如何发展以控制经皮 运输主要的实验策略包括：（a）使用 IR光谱、DSC和SAXD以探索SC的生物物理基础 屏障功能;（B）使用色谱方法分析 新生儿SC的脂质;（c）用TEM和LSCM显示SC 研究新生儿皮肤的结构标志。 研究 提出的目的是回答以下问题：（1）什么是 化学和生物物理要求的功能屏障， 新生儿？这些成分的变化伴随着屏障的发展？ (2)SC的结构如何依赖于妊娠期和出生后 年龄？新生儿SC与成人SC在形态学上有何不同 SC？(3)TEWL和LSCM的渗透率测量值是否相关 生物物理和生物化学的屏障功能的测量？（四） 最后，根据我们对发展的洞察， 新生儿皮肤屏障，我们可以加速早产儿皮肤 开发全功能和设计透皮制剂 其安全有效地递送治疗剂量的药物以治疗 新生儿的戒断症状