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，其特征是肺组织发育不完全，据报道死亡率高达54-89%。病变肺的病理学评价显示支气管和动脉结构发育不完全，以及肺泡不成熟和数量减少。组织工程是一种可以允许对发育不全的肺进行补充的方法。许多成功的努力已经能够证明利用胎儿肺细胞的混合群体在水凝胶中的三维肺构建体，其产生类似于肺泡的末端呼吸单元的结构。然而，构建临床上有用的三维肺构造的主要障碍是任何工程化肺组织的血管化以及提供气体可以通过其直接行进到肺泡并交换的界面。微机电系统（MEMS）是在半导体和微电子工业中开发的强大技术，其可以控制长度尺度从<1| jm至> lcm。软光刻技术的出现已经允许在生物相容性聚合物如聚二甲基硅氧烷（PDMS）中开发微尺度器件。先前在PDMS微芯片上的封闭通道内的工作已经显示了构建与内皮细胞汇合的人工毛细血管网络的能力，并且其他研究已经显示PDMS通道可以用作气体的导管。因此，该提议的研究背后的具体假设是，可以在填充有鼠胎儿肺细胞的混合群体的双层PDMS微通道装置内开发成功的肺泡-毛细血管界面的三维模型。计划的微型装置的一层将被设计为提供连续的营养供应，而第二层将被用来将肺泡-毛细血管界面暴露于气体。这些研究试图为开发微通道内的新型肺泡-毛细血管界面奠定基础，这可以作为迈向临床上更有用的肺组织构造的第一步。此外，从该提案中的组织血管化微制造技术的应用中吸取的经验教训可能对肺部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.