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，利用上皮细胞簇和聚合物支架可以实现肠黏膜的再生。虽然肠粘膜是肠功能所必需的，但没有小肠的肌层推动肠道内容物前进是不够的。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。拟议研究的长期目标是为肠肌层的形成设计环境。三个特定的目的将检查支架设计，信号信号和细胞相互作用如下。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片将产生。研究了取向纤维片材的材料选择。利用微球促进成纤维细胞生长因子的空间梯度，促进正交层管血管生成。目的2：探讨丁酸盐对移植后平滑肌细胞表型的影响。体内丁酸盐的递送可调节平滑肌细胞的表型。标记的丁酸盐将被封装在可生物降解的微球中，延迟一段时间后将释放内容物。在丁酸盐递送的滞后时间的空间梯度将被创建，以匹配平滑肌细胞增殖的不同速率在多层管。专项目的3：研究起搏器细胞对平滑肌细胞的影响。为了产生有节奏的收缩，我们将重建一个与处于收缩状态的平滑肌细胞层相邻的起搏器细胞网络。平滑肌细胞卷成薄片的多层管和胶原凝胶包裹的起搏器细胞将构成运动单元的基础。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。

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.