Intestinal Tissue Engineering

描述(申请人提供)：肠道组织工程学已经成为短肠综合征患者的一种潜在的治疗方法。目前，肠粘膜可以用上皮细胞团和聚合物支架来再生。虽然粘膜是肠道功能所必需的，但如果没有推动肠道内容物前进的小肠肌层，它是不够的。因此，肌层的再生是实现肠道组织工程临床潜力的关键一步。这项拟议研究的长期目标是设计肠道肌层形成的环境。三个具体目标将检查支架设计、信号提示和细胞相互作用，如下所示。具体目的1：研究支架设计对肌层形成的影响。在定向纤维上生长的排列整齐的平滑肌细胞将被生产出来。对制备取向纤维片材的材料选择进行了研究。碱性成纤维细胞生长因子的空间梯度将使用微球来促进正交层管中的血管生成。特异目的2：探讨丁酸对种植后平滑肌细胞表型的影响。在体内，丁酸的释放会对血管细胞的表型产生影响。标记的丁酸盐将被封装在可生物降解的微球中，该微球将在一段时间后释放内容物。丁酸盐输送的滞后时间的空间梯度将被创造出来，以匹配多层管中平滑肌细胞增殖的不同速率。具体目的3：研究起搏细胞对平滑肌细胞的作用。为了创造有节奏的收缩，我们将重建一个起搏细胞网络，毗邻处于收缩状态的平滑肌细胞的各层。一个多层管子，由卷曲的薄片中的平滑肌细胞和围绕管子的胶原凝胶中的起搏细胞组成，将形成运动单元的基础。将研究干细胞因子传递、胶原浓度、细胞密度和细胞类型排列的影响。 与公共卫生相关：小肠的大量丢失会导致短肠综合征。这些患者依赖静脉营养，这可能会导致肝功能衰竭。这项研究将为短肠综合征患者的小肠再生迈出关键的一步。

DESCRIPTION (provided by applicant): Tissue engineering of the intestine has emerged as a potential curative therapy for patients with short gut syndrome. Currently, the intestinal mucosa can be regenerated using epithelial cell clusters and polymeric scaffolds. Although the mucosa is necessary for intestinal function, it is insufficient without the muscularis of the small intestine that propels the enteric content forward. Therefore, the regeneration of the muscularis represents a critical step in realizing the clinical potential of intestinal tissue engineering. The long-term objective of the proposed research is to engineer the environment for the formation of the intestinal muscularis. Three specific aims will examine the scaffold design, signaling cues, and cellular interaction as follows. Specific Aim 1: Investigate the effects of scaffold design on muscularis formation. Sheets of aligned smooth muscle cells growing on oriented fibers will be produced. The choice of the material for the fabrication of the oriented-fiber sheets will be investigated. A spatial gradient of basic fibroblast growth factor will be created using microspheres to enhance angiogenesis in the orthogonal-layer tube. Specific Aim 2: Investigate the effect of butyrate on the phenotype of smooth muscle cells after implantation. The phenotype of the smooth muscle cells will be modulated by the delivery of butyrate in vivo. Labeled butyrate will be encapsulated in biodegradable microspheres that will release the content after a period of delay. A spatial gradient of lag time in butyrate delivery will be created to match the differential rates of smooth muscle cell proliferation in the multi- layer tube. Specific Aim 3: Investigate the effects of pacemaker cells on smooth muscle cells. To create the rhythmic contractions, we will reconstitute a network of pacemaker cells adjacent the layers of the smooth muscle cells in the contractile state. A multi-layer tube with smooth muscle cells in rolled sheets and the pacemaker cells in collagen gel surrounding the tube will form the basis of the motor unit. The effects of stem cell factor delivery, the collagen concentration, the cell density, and the arrangement of the cell types will be studied. PUBLIC HEALTH RELEVANCE: The massive loss of the small intestine results in short gut syndrome. These patients rely on intravenous nutrition that can lead to liver failure. This research will address a critical step toward the regeneration of the small intestine for patients with short gut syndrome.