Endomyocardial Catheter Delivery of Artificial Biopolymer Matrices for Enhanced Cell Retention in Cardiovascular Cell Based Therapy.
Tools and Technologies I
Novel therapeutic approaches using cell therapy that may contribute to grow new vessels and repair the cardiac tissue have shown great promise. However, successful retention of therapeutic cells in the target tissue after delivery is an important challenge that remains in that up to 98% of the cells delivered are lost very soon after delivery. The proposal here seeks to improve and study cell retention by incorporating biopolymer tissue matrix strategies with catheter delivery technologies appropriate for routine clinical use. The results of this work may prove critical to enabling cardiovascular tissue engineering strategies broadly, and should also have important implications for other local tissue engineering therapies including spinal cord repair. This study will lead to the development of new delivery system including a new tri-lumen catheter, a biopolymer and cells with regenerative capabilities. Validation of its interest in cardiac pathology will be followed with other fields where regenerative capabilities are required.
Statement of Benefit to California:
Disease: Heart failure affects 5 million Americans according the AHA, and approximately 90 thousand Californians. The California Healthcare Foundation estimated in 2002 that the cost to California institutions was $13 thousand per patient per year, or $65 thousand over the expected 5-year survival of a heart failure patient. Current Treatments: Heart failure is currently treated with drugs aimed at slowing down the effects of the heart dysfunction, and devices that can provide structural support for the progressively weakening heart muscle, rather than actually treating the disease. Solution/Research Our research focuses on the use of biopolymers combined with therapeutic agents to increase retention of the agents in the myocardium. Novel therapeutic approaches using cell therapy that may contribute to regeneration of the heart through growth of new vessels and repair the cardiac tissue have shown great promise. However, retention of therapeutic agents and cells in the target tissue after delivery remain quite low, with up to 98% of the cells delivered being lost through venous or lymphatic drainage, or leakage through the access site for intramyocardial delivery. Benefits to California: 1. Potential to create an improved therapeutic approach that maximizes the therapeutic benefit of regenerative therapies by improving retention in the target treatment area. This would help to change the treatment of Heart Failure from slowing deterioration, to stopping or reversing the disease. This has two primary benefits; 1) it limits California’s expense of managing patient care by creating a single treatment versus chronic care, and 2) it improves the quality of life of those patients. 2. Potential to create a research and corporate development reputation for California that attracts scientists and researchers to California public and private institutions, and attracts entrepreneurs and investment that help to create jobs and a higher standard of living.
This proposal focuses on the development of technology for delivery and retention of therapeutic cells at a desired location. Specifically, the applicants propose to create biopolymer matrices incorporated with bone marrow cells that will be delivered to the heart using a tri-luminal catheter, and the biopolymer formulations will be evaluated for their capacity to improve cell retention at the site of injection. The applicants will first assess the properties of several biopolymer formulations, and those with the most desirable features will evaluated for their capacity to safely improve cell retention using an in vivo heart model. Finally, the applicants propose to optimize this technology and provide biological proof of concept for safety and efficacy. The reviewers felt that this technology addressed an important problem in the use of stem cells for therapy. The proposal was well written and conceived. However, while technically feasible, the reviewers questioned its potential to advance the field due to its lack of novelty and uncertain clinical benefits. In theory, the impact of the proposed technology could be high, particularly in the area of cardiovascular research. Injection of therapeutic cells represents a promising route for treating heart disease, but current delivery methods are extremely inefficient due to poor cell retention at the treatment site. If the proposed technology improves this retention sufficiently, it may be possible to produce better therapies for heart disease or injury. In addition, the technology would be widely applicable for retaining cells in other injected tissues such as pancreas, liver or spinal cord. In practicality, however, the reviewers questioned the extent to which retention must be improved in order to have clinical benefits. Furthermore, a reviewer noted the commercial availability of a similar biopolymer/injection device that the applicants failed to consider when discussing the advantages of their approach. These factors served to substantially diminish the reviewers’ confidence that the proposed technology would significantly impact the field. In terms of feasibility, the reviewers were confident that the research team could accomplish the work described. The proposal was well written, and the applicants provided excellent discussion of the criteria for success, the anticipated timelines, and potential difficulties that might be encountered. One reviewer questioned, however, whether the proposed criterion for retention improvement was sufficient for clinical benefit. Reviewers also expressed some concern that excess biopolymer gel might alter the regenerative capabilities of the injected cells. In addition, it was unclear if the applicants would test whether the cell/biopolymer matrices induce myocardial damage directly, as this could pose a clinical risk. A reviewer noted that the proposed safety experiments were too narrowly focused on the distribution of cells and not accounting for the combined effect of the cells with the biopolymer. Finally, the strategy to assess retention by fluorescence was also criticized, as this method would be neither quantitative nor robust. The applicants were described as well qualified to perform the proposed experiments. The principal investigator has experience with catheters and cell delivery, and collaborators are in place to provide expertise with the bioengineering aspects of this proposal. Overall, while the proposed technology is technically feasible, the reviewers were not convinced of its potential to significantly advance the field.