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Tunable hydrogels for therapeutic delivery of multipotent stem cells.

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06460
Principle Investigator: 
Funds requested: 
$2 964 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Rationale: Skin ulcers represent the largest economic burden of all skin diseases. Human adult stem cell therapies for the treatment of chronic wounds have shown considerable promise. However, a delivery system is needed before they can be used clinically. Hydrogels have emerged as a promising vehicle for stem cell delivery because their 3-D structure and high water content mimic the natural environment of the stem cell. However, the surface of some hydrogels cannot interact well with stem cells. Our objective is to develop hydrogels with small adhesion contact sites for stem cells to allow the stem cells to interact better with the hydrogels. We will also make hydrogels with other biomolecules to better promote wound healing. If successful this research will lead to new therapies for chronic wounds.
Statement of Benefit to California: 
Diseases of the skin are among the medical conditions in which spending has increased the most. Within this group, skin ulcers represent the largest economic burden. In 2004, the prevalence of skin ulcers was 4.8 million, far below the prevalence of other common skin diseases. However, the total healthcare cost for these patients, not including intangible cost due to quality of life impact, was $11.951 billion. This is five times higher than the economic burden of non-melanoma skin cancer, the most prevalent cancer in the U.S.. Current treatment options for patients with ulcers are limited and often ineffective. Even with the best care, the healing rate is only between 30-70% at 6 months and the recurrence rate is >70%. Ulcers are also a major risk factor for amputation, especially in patients with diabetes. This is true for people of any state, including California. Human adult stem cell therapies for the treatment of chronic wounds have shown considerable promise. However, their clinical application is predicated on developing an appropriate delivery platform, and relatively little research has been conducted in this area with respect to cutaneous wound healing. This proposal outlines an approach to develop novel stem cell delivery platforms. If successful this will lead to new treatments for chronic wounds.
Review Summary: 
Executive Summary The goal of this application is to develop a synthetic biomaterial to support viability and facilitate delivery of stem cells to skin ulcer wounds. The biomaterial, termed a “tunable hydrogel”, will incorporate specific stem cell ligands to yield a customized scaffold that will enhance cell-matrix interactions. These interactions will provide better adhesion and thereby improved incorporation of the cells into the hydrogel, and ultimately, into the wound bed. To achieve this goal, the Principal Investigator (PI) proposes first to screen for novel stem cell-specific small molecules that bind to specific adhesion proteins (Aim 1). Next, the PI will immobilize these small molecules onto the hydrogel to create a three-dimensional matrix capable of sustaining the stem cell population of interest (Aim 2). Finally, the PI will assess the efficacy of the hydrogels with wound healing models, including an in vitro human skin model and an in vivo preclinical model (Aim 3). Research Plan - Overall, reviewers found this to be a well-written proposal with a logical experimental design and well-developed project milestones. In particular, the reviewers praised the PI’s presentation of the biomaterials design and chemistry components. - Although the proposed materials for the hydrogel are used widely in the field, reviewers acknowledged that the approach using a tunable hydrogel was a strength because it permitted the inclusion of biomimetic small molecules, which would improve cell adhesion. - The proposed work could have a substantial potential impact on treatment for chronic skin wounds, which represent a significant medical problem. Additionally, the research could be applicable to other medical problems beyond a dermatological scope. - The preliminary data demonstrated the PI’s expertise with each of the experimental systems, including a clear strength with the use of the proposed wound healing models. - Reviewers expressed some reservation regarding the rationale for the type of multipotent stem cells proposed for the study; the role of these cells in wound healing remains unclear. Without adequately elucidating the role of these cells, the design of potential therapeutic strategies may be impeded. - Reviewers cited concerns about some aspects of the experimental design including a lack of clarity regarding which hydrogels would be tested in the wound healing models, deficient details of how cell fate will be tracked at the wound site, and concern that the cells might alter the chemical and mechanical properties of the hydrogel. - Reviewers suggested that more characterization be performed on the small molecules identified in Aim 1 to ensure that the most efficacious candidates are selected for further work. Principal Investigator - The PI has a strong track record and has already won several career development awards; these provide evidence of his/her potential as a clinician-scientist. - The PI has expertise in immunology, and reviewers were excited about PI’s entry into the stem cell/regenerative medicine field. - The proposed set of mentors is excellent. - The career development plan is well presented and shows appropriate training in statistics, ethics, and stem cell biology. Institutional Commitment - The institution is committed to the PI and has provided appropriate laboratory space and access to core facilities and institutional infrastructure. - The institution has a solid track record of developing clinical and translational investigators in the stem cell field. The institution also has a well-developed mentoring program for new clinician-scientists. Responsiveness - The application is responsive to the RFA as it includes a proof-of-concept development of a potential stem cell-based therapy.
Conflicts: 

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