Inflammatory bowel disease (IBD) is one of the most prevalent gastrointestinal disease burdens in the US, with an overall health care cost of more than $1.7 billion and affecting an estimate of 1.4 million patients in the US. Crohn's disease (CD) and ulcerative colitis (UC) are the two major types of inflammatory bowel disease (IBD), both characterized by chronic and relapsing inflammation in the intestinal tract which commonly requires a lifetime of care. Meanwhile, infants with microvillus inclusion disease (MVID) have severe malabsorption caused by hypoplasia and/or atrophy of the intestinal epithelium. These infants require total parental nutrition to survive but quickly develop liver failure and potential death within 2 years. The only effective therapeutic approach is small intestine transplantation that requires a donor and is logistically complicated and impractical. One potential long term treatment for IBD and MVID would be therapeutic intestinal stem cell (ISC) transplantation. The goal of this renewal grant is to use our biodegradable and biocompatible elastomers as a multifunctional delivery platform for drug and cell delivery to treat diseases affecting intestinal mucosa. Although ISCs could be delivered and engraft to intestinal epithelium, initial cell retention with high efficiency is not easily achieved owing to the harsh intestinal environment and the lack of supportive stem cell niche prior to engraftment. Through combining biodegradable elastomers with our high efficiency ISC expansion protocols, we can deliver stem cells under the protection of a defined synthetic niche. By maximizing rapid adhesion and engraftment, we aim to achieve high efficiency delivery of stem cells to diseased epithelium. We propose to utilize the delivery platform either as small cell/drug carriers, which can disperse quickly into the colon via enema for Ulcerative Colitis, or as larger patches that will be delivere via endoscope for Crohn's disease or intestinal anastomotic failure. These delivery vehicles will achieve 1. Efficient and selective adhesion to damaged or diseased intestinal epithelium; 2. Survival of delivered stem cells before and during engraftment, and 3. local delivery of anti-inflammatory agents such as IL-10, IL-22, or TNF-? neutralizing antibodies to facilitate and maximize the engraftment of stem cells and maintain remission.
We aim to 1. Develop biodegradable and biocompatible elastomer patch enabling efficient and selective mucosal adhesion via both endoscopic (Crohn's disease) and enema-based (ulcerative colitis) delivery in vivo. 2. Engineer elastomer patch to support intestinal stem cell growth while control- releasing anti-inflammatory agents in vitro. 3. Evaluate drug and cell therapeutic efficacy in vivo.

Public Health Relevance

The goal of this renewal grant is to use our biodegradable and biocompatible elastomers as a multifunctional delivery platform for drug and cell delivery to treat diseases affecting intestinal mucosa. We will utilize the delivery platform either as small micronized cell/drug carriers, which can disperse quickly into the colon via enema for Ulcerative Colitis, or as larger patches that will be delivered via endoscope for Crohn's disease or intestina anastomotic failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013023-17
Application #
9065550
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lumelsky, Nadya L
Project Start
1998-09-15
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
17
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
Tong, Zhixiang; Martyn, Keir; Yang, Andy et al. (2018) Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells. Biomaterials 154:60-73
Mead, Benjamin E; Ordovas-Montanes, Jose; Braun, Alexandra P et al. (2018) Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types. BMC Biol 16:62
McLean, Will J; Yin, Xiaolei; Lu, Lin et al. (2017) Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Rep 18:1917-1929
Doloff, Joshua C; Veiseh, Omid; Vegas, Arturo J et al. (2017) Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat Mater 16:671-680
Vegas, Arturo J; Veiseh, Omid; Gürtler, Mads et al. (2016) Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22:306-11
Vegas, Arturo J; Veiseh, Omid; Doloff, Joshua C et al. (2016) Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol 34:345-52
Langer, Robert; Vacanti, Joseph (2016) Advances in tissue engineering. J Pediatr Surg 51:8-12
Yin, Xiaolei; Mead, Benjamin E; Safaee, Helia et al. (2016) Engineering Stem Cell Organoids. Cell Stem Cell 18:25-38
Jhunjhunwala, Siddharth; Alvarez, David; Aresta-DaSilva, Stephanie et al. (2016) Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation. J Leukoc Biol 100:253-60
Lim, Dong-Kwon; Wylie, Ryan G; Langer, Robert et al. (2016) Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF(165). Biomaterials 77:130-138

Showing the most recent 10 out of 76 publications