Tissue Engineering a Novel Alveolar-Capillary Interface Within Microchannels

描述（由申请人提供）：肺发育不全是新生儿的一种疾病，以肺组织发育不全为特征，据报道死亡率高达54-89%，病变肺的病理评估显示支气管和动脉结构发育不全，肺泡数量不成熟和减少。组织工程是一种方法，可以允许补充一个不发达的肺。许多成功的努力已经能够证明三维肺结构的水凝胶利用胎儿肺细胞的混合群体，产生类似肺泡的末端呼吸单位的结构。然而，构建临床上有用的三维肺结构的一个主要障碍是任何工程肺组织的血管化，以及提供气体可以直接进入肺泡并进行交换的界面。微机电系统（MEMS）是在半导体和微电子工业中发展起来的一项强大的技术，它可以控制长度范围从<1 |jm到| cm的特征。软光刻技术的出现使得生物相容性聚合物（如聚二甲基硅氧烷）（PDMS）的微尺度器件的发展成为可能。先前在PDMS微芯片上封闭通道内的研究表明，PDMS通道能够构建与内皮细胞融合的人工毛细血管网络，其他研究表明，PDMS通道可以用作气体管道。因此，本研究提出的具体假设是，在混合鼠胎肺细胞的双层PDMS微通道装置中，可以成功地建立毛细管-毛细管界面的三维模型。计划中的微型装置的一层将被设计用于提供连续的营养供应，而第二层将被用来使肺泡-毛细血管界面暴露于气体中。这些研究旨在为微通道内新型肺泡-毛细血管界面的发展奠定基础，这可能是迈向临床更有用的肺组织结构的第一步。此外，从微制造技术在组织血管化中的应用中获得的经验教训可能对肺以外的器官构建工作有用。

DESCRIPTION (provided by applicant): Pulmonary hypoplasia is a condition of the newborn characterized by the incomplete development of lung tissue whose mortality is reported as high as 54-89% Pathologic evaluation of diseased lungs reveals incomplete development of the bronchial and arterial structures as well as immaturity and a reduction of the numbers of alveoli. Tissue engineering is one method which may allow for supplementation of an underdeveloped lung. A number of successful efforts have been able to demonstrate three dimensional pulmonary constructs in hydrogels utilizing mixed populations of fetal pulmonary cells which produced structures similar to the terminal respiratory unit of the alveolus. However, a major obstacle in building a three dimensional lung construct that will be clinically useful is vascularization of any engineered pulmonary tissue as well as providing an interface through which gas can travel directly to the alveoli and be exchanged. Microelectromechanical systems (MEMS) is a powerful technology developed within the semiconductor and microelectronics industries which can control features at length scales from <1 |jm to >1 cm. The emergence of soft lithography techniques have allowed for the development of microscale devices in biocompatible polymers such as poly(dimethyl siloxane) (PDMS). Previous work within closed channels on PDMS microchips have shown the ability to construct artificial capillary networks confluent with endothelial cells and other studies have shown that PDMS channels can be utilized as conduits for gas. Thus, the specific hypothesis behind this proposed research is that a successful three dimensional model of the aveolar-capillary interface can be developed within a dual layer PDMS microchannel device populated with a mixed population of murine fetal pulmonary cells. One layer of the planned microdevice will be designed to provide a continuous nutrient supply while the second layer will be utilized to expose the alveolar-capillary interface to gas. These investigations seek to lay the foundation for the development of a novel alveolar-capillary interface within microchannels which may serve as the first step towards a more- clinically useful pulmonary tissue construct. Additionally, lessons learned from the application of microfabrication technology to tissue vascularization within this proposal may be useful for organ building efforts beyond the lung.