Tissue-Engineered Skin with Built-in Capillary Flow Newtworks

组织工程(TE)产品有可能给医疗保健带来革命性的变化。人体内的许多组织和器官 人体，如软骨、骨骼、心脏瓣膜、血管、皮肤和肝脏正在被作为炎症性疾病的目标进行调查。 苏工程公司。然而，目前只有少数几种药物在临床上使用，如TE Skin。此外，几乎所有的 目前正在使用或正在进行临床试验的TE产品针对的是无血管组织(例如心脏瓣膜和心脏 LAGE)，或在临床使用之前未进行血管处理(例如皮肤替代品)。应用中的一个主要障碍 以高功能组织为靶点的TE工程缺乏一种通用的方法来开发具有集成功能的TE产品。 格栅微血管系统，用于对流输送营养物质和清除代谢废物。我们的战略- GIC的目标就是开发这样一种方法。在这项建议中，我们描述了一种建立‘血管化’的皮肤组织的方法。 结构。我们提出了四个具体目标，解决了从质量转移要求到质量转移要求的几个具体问题 利用内置的毛细管流动网络，从组织到制造，以及对组织进行体外测试。这些是：具体目标1。 使用微制造和微流控方法评估细胞的传质要求。这将是 从而合理地设计毛细管流网络，并更好地理解传质极限。 组织结构中的运动。具体目标2.设计和制造最佳的平面微血管模拟系统 生物聚合物基质。在这一特定目标下，为满足代谢需求而量身定做的最佳毛细血管网络设计 的靶组织将被包埋在胶原-糖胺多聚糖(胶原-GAG)中，形成微血管支架- 使用微细加工方法。具体目标3.通过内皮化使毛细血管网络“血管化” 和微流控技术，并在体外进行评估。这将导致胶原蛋白-GAG支架具有微血管 可以通过对流方式提供营养物质和清除废物的网络。具体目标4.发展 在灌流生物反应器中合成TE皮肤，并评估集成对流传输系统的效果。 透射电子显微镜对复合皮肤生长分化的影响。在这个特定的目标中，复合皮取代了 将在灌流生物反应器中开发集成的流动网络，以验证对流传输的假设 底物可提高分化的表皮的形成速度。这些目标的成功实现将导致 一种可扩展且易于在体内进行测试的产品。

Tissue engineered (TE) products have the potential to revolutionize health care. A number of tissues and organs in the human body such as cartilage, bones, heart valves, blood vessels, skin and liver are being investigated as targets for tis- sue engineering. However, only a handful of them such as TE skin are currently in clinical use. In addition, almost all TE products currently in use or undergoing clinical trials are targeted at avascular tissues (e.g. heart valves and carti- lage), or are not vascularized before their use in the clinics (e.g. skin substitutes). A major obstacle in the application of TE engineering to target tissues of higherfunction is the lack of a general approach to develop TEproducts with inte- grated microvascular systemfor convective delivery of nutrients and removal of metabolic waste products. Our strate- gic goal is to develop such an approach. In this proposal, we describe a method to build 'vascularized' TE skin con- structs. We propose four specific aims, which address several specific issues that range from mass transfer requirements of tissues to fabrication, and in vitro testing of tissues with built-in capillary flow networks. These are: Specific Aim 1. To assess mass transfer requirements of cells, using microfabrication and microfluidic methodologies. This will lead to subsequent rational design of the capillary flow networks and to better understanding of mass transfer limita- tions in tissue constructs. Specific Aim 2. To design and fabricate optimal planar microvascular analog systems in biopolymeric matrices. In this specific aim, optimal capillary networks designs tailored to meet the metabolic demand of target tissue will be embedded in collagen-glycosaminoglycans (collagen-GAG) to form scaffolds for microvascula- ture using microfabrication methodologies. Specific Aim 3. To 'vascularize' capillary networks by endothelializa- tion and by microfluidics, and to assess them in vitro. This will lead to collagen-GAG scaffolds with 'microvascular' networks that can supply nutrients and remove waste products via convective means. Specific Aim 4. To develop composite TE skin in a perfusion bioreactor and to assess the efficacy of an integrated convective transport sys- tem on the growth and differentiation of composite TE skin. In this specific aim, composite skin substitutes with integrated flow networks will be developed in a perfusion bioreactor to test the hypothesis that convective transport of substrate improves the rate of formation of a differentiated epidermis. Successful completion of these aims will result in a product that is scalable and that can readily be tested in vivo.