Optimizing Therapeutic Revascularization by Endothelial Cell Transplantation

通过内皮细胞移植优化治疗性血运重建

• 批准号: 9516109
• 负责人: JORDAN S POBER
• 金额: $ 37.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-26 至 2019-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9516109
• 关键词: 3D Print; Address; Adult; Allogenic; Animal Sources; Animals; Apligraf; Attention; Autologous; Basement membrane; Beds; Biological; Blood Vessels; Cattle; Cell Line; Cell Transplantation; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Collagen; Collagen Type I; Collagen Type IV; Culture Media; Cutaneous; Dermal; Dermis; Development; Elastin; Elderly; Eligibility Determination; Endothelial Cells; Engineering; Engraftment; Epidermis; Evaluation; Exposure to; Extracellular Matrix; FDA approved; Failure; Fibroblasts; Fibronectins; Funding; Generations; Goals; Grant; Harvest; Histology; Human; Human Engineering; Hyaluronic Acid; Immune system; Immunodeficient Mouse; Impaired wound healing; Impairment; Implant; In Vitro; Individual; Infection; Ink; Institutes; Jordan; Karyotype; Laminin; Medical; Membrane Proteins; Morbidity - disease rate; Morphology; Mus; Muscle Cells; Natural Products; Neonatal; Newborn Infant; Papillary; Parents; Perfusion; Pericytes; Preparation; Primary Lesion; Printing; Production; Proteins; Recombinants; Regenerative Medicine; Research Project Grants; Rheology; Risk; Sirolimus; Site; Skin; Skin Substitutes; Skin Ulcer; Skin graft; Source; System; Therapeutic; Thick; Tissue Engineering; Tissues; Transmission Electron Microscopy; Ulcer; Umbilical Cord Blood; Vascular Smooth Muscle; Vascular blood supply; Work; adult stem cell; angiogenesis; biophysical techniques; bioprinting; cell type; clinical development; clinical practice; curative treatments; diabetic; experimental study; fetal bovine serum; healing; human tissue; immunocytochemistry; innovation; interstitial; keratinocyte; macromolecule; method development; novel strategies; paracrine; parent grant; peripheral blood; pre-clinical; response; self assembly; senescence; success; vascular tissue engineering

7. PROJECT SUMMARY/ABSTRACT The overall goal of this research project is to develop a vascularized full thickness skin substitute, engraftment of which can provide a definitive clinical cure of chronic cutaneous ulcers, an unmet medical need. This application is a competitive Revision to add a specific aim to a funded R01 grant (HL-085416 “Optimizing Therapeutic Revascularization by Endothelial Cell Transplantation”) submitted in response to RFA-HL-17-029 (Revision Applications for Regenerative Medicine Innovation Projects). The parent R01 grant is focused on establishing perfusion of tissue engineered grafts through the self-assembly of incorporated human endothelial cells (EC) into microvessels. We have found that the best source of EC for this purpose is the differentiated progeny of human endothelial colony forming cells (HECFC), an “adult” stem cell type isolated from neonatal cord or adult peripheral blood as defined by the terms of this RFA. Over the past six months, Drs. W. Mark Saltzman and Jordan S. Pober, co-PIs of the parent grant, have established a collaboration with Dr. Pankaj Karande to apply their approach for microvessel generation to his approach for 3D printing to create a full thickness human skin substitute. Current FDA-approved skin substitutes have all had only limited clinical success because they fail to vascularize, and consequently slough over the course of a few weeks. The vascularized skin substitute produced through this collaboration can potentially address this problem. However, the skin substitutes that we have generated to date employ bio-inks containing human cells that have been cultured in fetal bovine serum and use extracellular matrix molecules derived from animal sources. Similar exposures to animal proteins used in the production of currently approved skin substitutes have further limited their approved use. The goal of our new specific aim is to develop a vascularized full thickness human skin substitute through 3D printing made with bio-inks that are composed of human cells that have not been exposed to animal proteins and extracellular matrix molecules that are either derived from human tissues or made by recombinant approaches that do not involve exposure to animal proteins. Subaims a and b describe our approaches to achieve this. Subaim c will involve evaluation of perfusion of the resultant 3D bioprinted skin graft compared to natural skin and to Apligraf, a currently approved full thickness skin substitute, after engraftment on immunodeficient mouse hosts. The development of methods for creating a fully humanized and vascularized full thickness skin equivalent will provide the information needed to develop Good Manufacturing Practice (GMP) conditions for preparing clinical grade skin substitutes.

7. 项目总结/文摘