A three dimensional perfusion device for building networks of blood vessels for exploring the limits of vascular tissue engineering, chemotaxis, and stem cell homing.
Tools and Technologies I
Surgeons perform more than 8 million surgical procedures in the United States each year to treat patients experiencing organ failure or tissue loss. These patients are treated by transplanting organs from one individual to another, performing reconstructive surgery, or by using mechanical devices such as kidney dialysis, prosthetic hips, or mechanical heart valves. However, the transplantation of organs such as the heart, liver, and kidney is limited by the declining availability of donor organs. For example, only about 3,000 donor livers are available for the roughly 30,000 people who may die from liver failure each year. The field of tissue engineering has the potential to create tissues to use as model systems in fundamental studies, and eventually, as replacement tissues for damaged or diseased body parts. One of the major challenges in tissue engineering is the mass transfer limitation in tissues thicker than a few cell layers (like skin). The aims of the work presented in this proposal will explore key signals for enhancing the stabilization and strength of new blood vessels grown in vitro. We expect that this work will bring the field of tissue engineering closer to building larger tissues in vitro. The ex vivo model will also be a novel system for studying stem cell homing.
Statement of Benefit to California:
The research proposed is expected to result in new techniques and methodology for the developing three-dimensional tissues with living blood vessels from stem cells for therapeutic repair of scarred heart tissue after a heart attack, and towards the engineering of many other tissues. The citizens of California could benefit from this research in three ways. The most significant impact would be in the potential for new medical therapies to treat a large medical problem. The second benefit is in the potentil for these technologies to bring new business ventures to the state of California. The third benefit is the stem cell training of the students and postdocs involved in this study, especially in [REDACTED].
This application focuses on the development of a new scaffolding system for in vitro, three-dimensional vasculature that could be used for a variety of applications in regenerative medicine. First, the applicants propose to embed a tubing system within a 3-D matrix that enables sprouting and neovessel formation from endothelial progenitor cells. Next, a perfusion system will be incorporated that exerts fluid mechanical forces on the tissues, permits cell migration, and should ultimately result in a stable endothelial structure. Finally, this in vitro system will be used to investigate stem cell homing behavior in response to tissue damage. The reviewers were unenthusiastic about the proposed technology due to concerns over the feasibility of the research design, and consequently, the low likelihood of impact. While the applicants are qualified in the area, the research plan was lacking in details and testable hypotheses. Finally, a convincing case was not presented showing how the proposed methods would offer significant improvements over existing methodologies. The impact that the proposed technology would have on the field was thought to be somewhat limited, given the weakness of the research design. While addressing a key roadblock in regenerative medicine, the proposed approaches are out of touch with the ongoing shift towards minimally invasive translational techniques. Moreover, the use of mouse embryonic stem cells rather than human cells decreased the overall enthusiasm of the reviewers. Despite these concerns, a successful implementation could prove useful, especially in terms of general impact on other tissue systems, since all regeneration requires revascularization. It was unclear to the reviewers that this technology could be easily translated, however, without addressing additional challenges that were beyond the scope of a two-year funding period. Reviewers were not presented with an example of how the proposed technology would integrate with a plan for regeneration of a particular organ, and such a presentation would have helped reviewers envision a specific application for which the technology would be useful. The applicants failed to provide a compelling case for how the proposed technology represents improvement over alternative approaches. In fact, the reviewers commented that the proposed system would offer less control over experimental parameters than do other in vitro methods. Of greater concern, the proposal was lacking in details, comprised no testable hypotheses, and did not adequately specify the criteria by which success would be judged. Omission of certain key references was of concern to a reviewer. The principal investigator has appropriate experience with stem cell biology, and the overall team is well trained in the biomechanics of endothelial cells and materials engineering. The team included a mathematician, but the reviewers were uncertain how mathematical modeling was integrated into the experimental design. The budget was considered to be slightly excessive. One reviewer commented that the travel requests and a postdoctoral salary were inadequately justified. Overall, the proposed technologies could prove useful, but the work was judged to have potential for only limited impact because of research feasibility issues, and lack of convincing reasons why the technology has merit compared to other approaches.