Intestinal Tissue Engineering

肠组织工程

• 批准号: 8290494
• 负责人: James C Dunn
• 金额: $ 33.16万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290494
• 关键词: Address; Biodegradable microsphere; Butyrates; Cell Communication; Cell Density; Cell Proliferation; Cells; Characteristics; Clinical; Collagen; Contracts; Cues; Encapsulated; Engineering; Enteral; Environment; Epithelial Cells; Exhibits; Fiber; Fibroblast Growth Factor 2; Gel; Implant; Interstitial Cell of Cajal; Intestinal Mucosa; Intestines; Intravenous; Label; Lead; Length; Liver Failure; Microspheres; Motion; Motor; Mucous Membrane; Muscle Contraction; Natural regeneration; Pacemakers; Patients; Phase; Phenotype; Polymers; Property; Research; Short Bowel Syndrome; Signal Transduction; Small Intestines; Smooth Muscle; Smooth Muscle Myocytes; Stem Cell Factor; Time; Tissue Engineering; Tissues; Tube; angiogenesis; base; cell type; density; design; implantation; in vivo; nodal myocyte; nutrition; public health relevance; reconstitution; response; scaffold

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.

描述（由申请人提供）：肠道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来再生。虽然粘膜对于肠道功能是必需的，但如果没有推动肠内容物前进的小肠肌层，粘膜是不够的。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。该研究的长期目标是设计肠肌层形成的环境。三个具体目标将检查支架设计、信号传导和细胞相互作用，如下所示。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。将使用微球创建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。具体目标 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体内丁酸盐的递送来调节。标记的丁酸盐将被封装在可生物降解的微球中，在一段时间的延迟后释放内容物。将产生丁酸盐递送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，我们将在收缩状态的平滑肌细胞层附近重建起搏细胞网络。多层管具有卷状片材中的平滑肌细胞和管周围胶原凝胶中的起搏器细胞，将构成运动单元的基础。将研究干细胞因子输送、胶原蛋白浓度、细胞密度和细胞类型排列的影响。 公众健康相关性：小肠的大量丧失会导致短肠综合症。这些患者依赖静脉营养，这可能导致肝衰竭。这项研究将为短肠综合征患者的小肠再生迈出关键一步。

项目成果

Collagen and heparan sulfate coatings differentially alter cell proliferation and attachment in vitro and in vivo.

胶原蛋白和硫酸乙酰肝素涂层在体外和体内不同地改变细胞增殖和附着。

• 发表时间: 2016-09
• 作者: Walthers, Christopher M;Lyall, Chase J;Nazemi, Alireza K;Rana, Puneet V;Dunn, James C Y
• 通讯作者: Dunn, James C Y

An Engineered Living Intestinal Muscle Patch Produces Macroscopic Contractions that can Mix and Break Down Artificial Intestinal Contents.

工程化活肠肌肉贴片可产生宏观收缩，从而混合和分解人工肠内容物。

• 发表时间: 2023-04
• 作者: Wang, Qianqian;Wang, Jiafang;Tokhtaeva, Elmira;Li, Zhen;Martín, Martín G;Ling, Xuefeng B;Dunn, James C Y
• 通讯作者: Dunn, James C Y

The effect of scaffold macroporosity on angiogenesis and cell survival in tissue-engineered smooth muscle.

支架大孔隙度对组织工程平滑肌血管生成和细胞存活的影响。

• DOI: 10.1016/j.biomaterials.2014.03.025
• 发表时间: 2014-06
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Walthers, Christopher M.;Nazemi, Alireza K.;Patel, Shilpy L.;Wu, Benjamin M.;Dunn, James C. Y.
• 通讯作者: Dunn, James C. Y.

Enhancing angiogenesis alleviates hypoxia and improves engraftment of enteric cells in polycaprolactone scaffolds.

增强血管生成可缓解缺氧并改善肠细胞在聚己内酯支架中的植入。

• 发表时间: 2012-04-18
• 作者: Singh, Shivani;Wu, Benjamin M;Dunn, James C Y
• 通讯作者: Dunn, James C Y

Accelerating vascularization in polycaprolactone scaffolds by endothelial progenitor cells.

内皮祖细胞加速聚己内酯支架中的血管化。

• DOI: 10.1089/ten.tea.2010.0708
• 发表时间: 2011-04-27
• 期刊: Tissue engineering. Part A
• 作者: Shivani Singh;Benjamin M. Wu;J. Dunn
• 通讯作者: J. Dunn