A major hindrance for the successful transplantation of tissue-engineered constructs is proper oxygenation in the early period post-transplantation prior to the establishment of a functioning vascular bed. Thus, this proposal is concerned with the development of oxygen-generating biomaterials to enhance nutrient delivery in tissue-engineered constructs upon implantation. Our working hypothesis is that by introducing an oxygen generating biomaterial, in conjunction with the sustained and local delivery of pro-angiogenic factors, we can prevent hypoxia-induced cellular death during the early engraftment period. In this proposal we seek to overcome hypoxia-induced cellular death by delivering localized supplemental oxygen to our cell-based constructs, and, at the same time, decreasing the time for revascularization via the introduction of pro- angiogenic matrices.
The specific aims of this proposal are: 1) to develop and characterize a prototype of an oxygen generating biomaterial that has the capacity to provide a sufficient amount of oxygen to beta cells and prevents hypoxia-induced cellular death;and 2) to introduce a pro-angiogenic releasing hydrogel that, in the presence of the oxygen generating biomaterial, enhances the formation of a vascular network for long-term graft function. The oxygen production from the biomaterial will be assessed via non-invasive oxygen monitoring. The viability, functionality, protein and gene expressions of the cell-based constructs will be assessed both in vitro, with beta cells and islets and in vivo in a chemically induced diabetic rodent model. It is our belief that by improving the overall oxygen delivery to the implant, both through oxygen generating material and promotion of vascularization, we have the potential to substantially improve construct engraftment and long term success of cellular based therapies for the treatment of type I diabetes mellitus (TIDM).
The incidence of type I diabetes mellitus (TIDM) among the US population has increased steadily in recent years. Current treatment is unable to provide a physiological regulation of blood glucose levels, leading to patient's poor quality of life and lowr life expectancies. Within this proposal we seek to fabricate oxygen- generating biomaterials that, in conjunction with pro-angiogenic matrices, have the capability of preventing hypoxia-induced cellular death, thus increasing the viability and function of cellular based constructs. This approach is not only applicable for the treatment of TIDM, but is a universal challenge for cell-based implants. We believe these studies are highly relevant to the mission of the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), as well as the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and are design to result in a significant impact on public health.
|Coronel, Maria M; Geusz, Ryan; Stabler, Cherie L (2017) Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial. Biomaterials 129:139-151|
|Coronel, Maria M; Stabler, Cherie L (2013) Engineering a local microenvironment for pancreatic islet replacement. Curr Opin Biotechnol 24:900-8|