Tissue Engineering a Novel Alveolar-Capillary Interface Within Microchannels

描述(申请人提供)：肺发育不良是一种新生儿的情况，其特征是肺组织发育不全，据报道死亡率高达54-%。病变肺的病理评估显示，支气管和动脉结构发育不全，以及肺不成熟和肺泡数减少。组织工程学是一种可以补充不发达肺的方法。许多成功的努力已经能够利用混合的胎肺细胞群体在水凝胶中展示三维肺结构，这些细胞产生类似于肺泡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化的肺组织的血管化，以及提供一个界面，通过这个界面气体可以直接进入肺泡并进行交换。微电子机械系统(MEMS)是半导体和微电子行业中发展起来的一项强大的技术，它可以控制从&lt；1|jm到&gt；1厘米的长度特征。软光刻技术的出现使生物相容性聚合物如聚二甲基硅氧烷(PDMS)等微尺度器件的发展成为可能。之前在PDMS微芯片上的封闭通道内的研究表明，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通道可以用作气体的管道。因此，这项研究背后的具体假设是，可以在双层PDMS微通道设备中建立成功的肺泡-毛细血管界面三维模型，该设备填充了混合的小鼠胎肺细胞群。计划中的微设备的一层将被设计为提供持续的营养供应，而第二层将被用于将肺泡-毛细血管界面暴露在气体中。这些研究试图为微通道内新的肺泡-毛细血管界面的发展奠定基础，这可能是迈向更具临床用途的肺组织结构的第一步。此外，将微制造技术应用于组织血管化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.