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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083319-03
Application #
8290494
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Carrington, Jill L
Project Start
2010-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$331,601
Indirect Cost
$116,276
Name
University of California Los Angeles
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wagner, Justin P; Sullins, Veronica F; Dunn, James C Y (2014) Skin-derived precursors generate enteric-type neurons in aganglionic jejunum. J Pediatr Surg 49:1809-14
Wagner, Justin P; Sullins, Veronica F; Dunn, James C Y (2014) Transplanted skin-derived precursor stem cells generate enteric ganglion-like structures in vivo. J Pediatr Surg 49:1319-24; discussion 1324-5
Jabaji, Ziyad; Brinkley, Garrett J; Khalil, Hassan A et al. (2014) Type I collagen as an extracellular matrix for the in vitro growth of human small intestinal epithelium. PLoS One 9:e107814
Wagner, Justin P; Sullins, Veronica F; Dunn, James C Y (2014) A novel in vivo model of permanent intestinal aganglionosis. J Surg Res 192:27-33
Wagner, Justin P; Sullins, Veronica F; Khalil, Hassan A et al. (2014) A durable model of Hirschsprung's colon. J Pediatr Surg 49:1804-8
Lei, Nan Ye; Jabaji, Ziyad; Wang, Jiafang et al. (2014) Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 9:e84651
Walthers, Christopher M; Nazemi, Alireza K; Patel, Shilpy L et al. (2014) The effect of scaffold macroporosity on angiogenesis and cell survival in tissue-engineered smooth muscle. Biomaterials 35:5129-37
Joshi, Vaidehi S; Lei, Nan Ye; Walthers, Christopher M et al. (2013) Macroporosity enhances vascularization of electrospun scaffolds. J Surg Res 183:18-26
Singh, Shivani; Wu, Benjamin M; Dunn, James C Y (2012) Delivery of VEGF using collagen-coated polycaprolactone scaffolds stimulates angiogenesis. J Biomed Mater Res A 100:720-7
Qin, Harry H; Dunn, James C Y (2011) Small intestinal submucosa seeded with intestinal smooth muscle cells in a rodent jejunal interposition model. J Surg Res 171:e21-6

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