Intestinal Tissue Engineering

描述（由申请人提供）：肠组织工程已成为短肠综合征患者的潜在治疗方法。目前，肠粘膜可以使用上皮细胞簇和聚合物支架再生。虽然粘膜是肠功能所必需的，但如果没有小肠的肌层推动肠内容物前进，粘膜是不够的。因此，肌层的再生是实现肠组织工程临床潜力的关键一步。这项研究的长期目标是为肠肌层的形成创造环境。三个具体的目标将检查支架设计，信号线索和细胞相互作用如下。具体目标1：研究支架设计对肌层形成的影响。将产生在定向纤维上生长的对齐的平滑肌细胞片。将研究用于制造定向纤维片材的材料的选择。将使用微球产生碱性成纤维细胞生长因子的空间梯度，以增强正交层管中的血管生成。具体目的2：研究丁酸盐对植入后平滑肌细胞表型的影响。平滑肌细胞的表型将通过丁酸盐的体内递送来调节。标记的丁酸盐将被封装在可生物降解的微球中，该微球将在延迟一段时间后释放内容物。将产生丁酸盐递送中的滞后时间的空间梯度以匹配多层管中平滑肌细胞增殖的差异速率。具体目标3：研究起搏细胞对平滑肌细胞的影响。为了产生有节奏的收缩，我们将在收缩状态下的平滑肌细胞层附近重建起搏细胞网络。一个多层的管与平滑肌细胞在卷片和起搏细胞在胶原凝胶管周围将形成运动单位的基础。将研究干细胞因子递送、胶原蛋白浓度、细胞密度和细胞类型排列的影响。 公共卫生相关性：小肠的大量损失导致短肠综合征。这些患者依赖静脉营养，可能导致肝功能衰竭。这项研究将解决短肠综合征患者小肠再生的关键一步。

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.