Bioengineering A Bioartificial Pancreas

生物工程生物人工胰腺

• 批准号: 7925682
• 负责人: Emmanuel C. Opara
• 金额: $ 51.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925682
• 关键词: Acids; Address; Alginates; Allografting; Angiogenic Proteins; Animal Model; Animals; Biomedical Engineering; Blood Circulation; Blood Glucose; Blood capillaries; Blood flow; C-Peptide; Caliber; Cells; Chimera organism; Clinical; Control Animal; Control Groups; Data; Diffusion; Drug Formulations; Encapsulated; Endocrine; Evaluation; Exclusion; Experimental Models; Fibroblast Growth Factor 1; Gel; Glucocorticoids; Glucose; Graft Rejection; Greater sac of peritoneum; Growth Factor; Human; Imaging Techniques; Immunosuppression; Immunosuppressive Agents; In Vitro; Inbred Lew Rats; Inbred WF Rats; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Isogenic transplantation; Kinetics; Length; Liver; Longevity; Measurement; Measures; Metabolism; Methods; Microcapsules drug delivery system; Microencapsulations; Modeling; Monkeys; Nature; Nutrient; Nutritional; Omentum; Outcome; Oxygen; Oxygen measurement, partial pressure, arterial; Pancreas; Patients; Permeability; Pharmaceutical Preparations; Principal Investigator; Problem Solving; Procedures; Proteins; Protocols documentation; Rattus; Reaction; Regimen; Reporting; Resected; Resistance; Retrieval; Site; Source; Starvation; Steroids; Streptozocin; Structure; Surface; System; Techniques; Testing; Therapeutic; Three-Dimensional Imaging; Thrombin; Tissues; Toxic effect; Transplant Recipients; Transplantation; Vascular blood supply; Vascularization; Viscosity; Waste Products; Work; Xenograft procedure; angiogen; base; capillary; cohort; density; design; diabetic; diabetic patient; diabetic rat; fluorescence imaging; follow-up; graft failure; image processing; improved; improved functioning; in vitro Model; in vitro testing; in vivo; islet; islet xenograft; method development; mutant; neovascularization; novel; pleiotrophin; polyornithine; prevent; programs; public health relevance; research study; response; theories

DESCRIPTION (provided by applicant): Despite the promise of the Edmonton protocol, the need to use immunosuppressive drugs and the severe shortage of human islets remain major barriers to clinical islet transplantation. An attractive strategy to overcome these two barriers is the technique of microencapsulation of islets prior to transplantation. Still, there are a number of issues that need to be resolved before this approach can become a clinical reality. Microencapsulated islet transplantation is currently performed in the unmodified peritoneal cavity because of the need for a large space to accommodate the large graft volume for which conventional islet transplant sites, such as the liver, are not suitable. The relatively large surface-to-volume ratio of microcapsules and the absence of a blood supply in the peritoneal cavity pose challenges to adequate supply of oxygen and nutrients to the encapsulated islets as well as exchange of glucose and insulin between the encapsulated islets and the systemic circulation. We will test the hypothesis that neovascularization of encapsulated islet transplants would enhance the viability of the islets because of adequate supply of oxygen and nutrients. The specific aims of this proposal are: 1) To design an optimum delivery system for angiogenic proteins to induce neovascularization around alginate microcapsules. After encapsulating the novel HBGAM-R136K angiogen in either of the alginate layers of alginate-polyornithine- alginate microcapsules, we will first study its release kinetics in vitro and the nature and level of microvasculature in vitro using fluorescence and image processing techniques. We will then examine tissue angiogenic and fibrotic responses to the protein in in vivo studies. 2) To determine the function of islets encapsulated and transplanted with the angiogenic protein to induce neovascularization. Using an isograft model of normal Lewis rat islet donors and Streptozotocin-diabetic Lewis rat recipients, we will co- encapsulate islets with angiogenic protein, and will assess blood glucose and insulin levels for 90 days after transplantation in omentum pouches of recipients. 3) To determine the efficacy of the optimized model of this bioartificial pancreas in a rat allograft. We will isolate and encapsulate islets from normal Wistar-Furth rats and transplant them in diabetic Lewis rats. 4) To assess the bioartificial pancreas function in xenograft animal models - first, human islets transplanted in diabetic Lewis rats for 90 days; and second, human islet transplants in diabetic monkeys for 180 days. PUBLIC HEALTH RELEVANCE: It is now clear that islet transplantation provides the best treatment option for individuals afflicted with Type 1 diabetes. However, the shortage of human islets and the need to use risky drugs to prevent transplant rejection remain major obstacles to routine use of islet transplantation in diabetic patients. The purpose of this project is to develop a viable strategy to overcome these two barriers and make islet transplantation a more appealing and widely used treatment option for diabetic patients.

描述（由申请人提供）：尽管埃德蒙顿方案有希望，但需要使用免疫抑制药物和人类胰岛的严重短缺仍然是临床胰岛移植的主要障碍。克服这两个障碍的一个有吸引力的策略是在移植前微囊化胰岛的技术。尽管如此，在这种方法成为临床现实之前，还有一些问题需要解决。微囊化胰岛移植目前是在未经修饰的腹膜腔中进行的，因为需要大的空间来容纳大的移植物体积，而传统的胰岛移植部位（例如肝脏）不适合于该大的移植物体积。微胶囊的相对大的表面积与体积比和腹膜腔中缺乏血液供应对向包封的胰岛充分供应氧气和营养物以及包封的胰岛和体循环之间的葡萄糖和胰岛素交换提出了挑战。我们将检验这一假设，即由于有足够的氧气和营养供应，包封胰岛移植物的新血管形成将增强胰岛的活力。本研究的具体目标是：1）设计一种最佳的血管生成蛋白递送系统，以诱导藻酸盐微囊周围的新血管形成。在将新的HBGAM-R136 K血管生成剂包封在藻酸盐-聚鸟氨酸-藻酸盐微胶囊的藻酸盐层中的任一个中之后，我们将首先使用荧光和图像处理技术研究其体外释放动力学以及体外微血管的性质和水平。然后，我们将在体内研究中检查组织血管生成和纤维化对蛋白质的反应。2)探讨血管生成蛋白包埋胰岛移植诱导新生血管形成的作用。使用正常刘易斯大鼠胰岛供体和链脲佐菌素-糖尿病刘易斯大鼠受体的同种移植物模型，我们将用血管生成蛋白共包封胰岛，并将在受体网膜袋中移植后90天评估血糖和胰岛素水平。3)确定优化的生物人工胰腺模型在大鼠同种异体移植中的有效性。我们将从正常的Wistar-Furth大鼠中分离和封装胰岛，并将其移植到糖尿病刘易斯大鼠中。4)评估异种移植动物模型中的生物人工胰腺功能-第一，将人胰岛移植到糖尿病刘易斯大鼠中90天;第二，将人胰岛移植到糖尿病猴中180天。公共卫生相关性：现在很明显，胰岛移植为1型糖尿病患者提供了最佳治疗选择。然而，人类胰岛的短缺和需要使用高风险的药物来防止移植排斥反应仍然是糖尿病患者常规使用胰岛移植的主要障碍。本项目的目的是开发一种可行的策略来克服这两个障碍，使胰岛移植成为糖尿病患者更有吸引力和广泛使用的治疗选择。

项目成果

Engineered multilayer ovarian tissue that secretes sex steroids and peptide hormones in response to gonadotropins.

响应促性腺激素的工程多层卵巢组织，分泌性类固醇和肽激素。

• DOI: 10.1016/j.biomaterials.2012.11.059
• 发表时间: 2013-03
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Sittadjody, Sivanandane;Saul, Justin M.;Joo, Sunyoung;Yoo, James J.;Atala, Anthony;Opara, Emmanuel C.
• 通讯作者: Opara, Emmanuel C.

New alginate microcapsule system for angiogenic protein delivery and immunoisolation of islets for transplantation in the rat omentum pouch.

• DOI: 10.1016/j.transproceed.2011.10.030
• 发表时间: 2011-11
• 期刊: TRANSPLANTATION PROCEEDINGS
• 影响因子: 0.9
• 作者: McQuilling, J. P.;Arenas-Herrera, J.;Childers, C.;Pareta, R. A.;Khanna, O.;Jiang, B.;Brey, E. M.;Farney, A. C.;Opara, E. C.
• 通讯作者: Opara, E. C.

In vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure.

• DOI: 10.1038/s41467-017-01851-3
• 发表时间: 2017-12-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Sittadjody S;Saul JM;McQuilling JP;Joo S;Register TC;Yoo JJ;Atala A;Opara EC
• 通讯作者: Opara EC

Synthesis of multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1.

• DOI: 10.1002/jbm.a.32883
• 发表时间: 2010-11
• 期刊: JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
• 影响因子: 4.9
• 作者: Khanna, Omaditya;Moya, Monica L.;Opara, Emmanuel C.;Brey, Eric M.
• 通讯作者: Brey, Eric M.

Long-term function of islets encapsulated in a redesigned alginate microcapsule construct in omentum pouches of immune-competent diabetic rats.

• DOI: 10.1097/mpa.0000000000000107
• 发表时间: 2014-05
• 期刊: Pancreas
• 影响因子: 2.9
• 作者: Pareta R;McQuilling JP;Sittadjody S;Jenkins R;Bowden S;Orlando G;Farney AC;Brey EM;Opara EC
• 通讯作者: Opara EC