Diabetic foot ulcers (DFU), chronic, non-healing wounds on the feet of diabetic patients, present a serious challenge to global health. These ulcers affect between 15-25% of the 18-21 million Americans who have diabetes (world-wide incidence of diabetes: 366 million people). DFUs have a huge impact on our health care system, not only in terms of economic cost, but also from a psychosocial perspective, associated with significant morbidities, decrease in quality of life, prolonged hospitalization and importantly, often result in the amputation loss of lower extremity. In the United States, persons with diabetes are at twice the risk for amputation compared to non-diabetic individuals. According to recent census, DFU is the leading cause of lower limb amputation and greater than 85% of amputations are preceded by an active foot ulcer.
Treatments for curing DFU are very far from optimal. Current standard of care can cure only about 30% of DFU and even the most advanced therapies, cell-based devices containing skin-derived keratinocytes and fibroblasts, boost the cure rate only to about 50%, leaving a tremendous unmet need for new effective cures for DFU.
The research that we propose with our collaborative partners in Germany is directed specifically at this problem. The candidate device is a combination of mesenchymal stem cells that have curative powers, and secrete potent stimulatory molecules, coupled with a collagen scaffolding creating a template upon which new tissue can be rebuilt and regenerated. The combined mesenchymal stem cell- scaffold device will be pre-conditioned so that its reparative properties are maximized. Testing of the material will occur in animal models that closely mimic the human DFU condition, so that the results can be reliably translated to a human curative product. The product will come to the clinic as living mesenchymal stem cells embedded in the pre-optimized scaffolding. All the treating physician will need to do is rinse the bandage-like material and apply it to the wound. Based on our preliminary studies that have examined the potent healing and revascularizing effects of MSC on damaged tissues, we anticipate that rapid healing will ensue.
While the number of individuals with all forms of chronic wounds is increasing in the general population, particularly with the rise of diabetes and aging of the population, the number of individuals affected by diabetic foot ulcers (DFU), the target disease for the development candidate in this proposal, is increasing in California at an alarming rate. That is because the prevalence of type 2 diabetes is now increasing within the state of California to epidemic proportions. In 2002, over one million California adults age 45 and older were diagnosed with diabetes, and by 2005 that number had risen to 1.5 million: 5.9% of the California population. For reasons that are not all that clear, there are marked differences in the prevalence of diabetes in different Californian ethnic and racial groups. Among Californians 65 and older, diabetes is significantly more common in African Americans (25.6%) , and Latinos ( 24.4%) as compared to caucasians (12.2%). (1) The diabetes brings with it devastating health impacts: it is the sixth most common cause of death in the United States. Among the morbidities associated with diabetes, DFU is one of the most debilitating. Approximately 15-25 percent of patients with diabetes will develop DFU, and of those, six percent will be hospitalized due to infection or other ulcer-related complication. According to a recent census, DFU is the leading cause of lower limb amputation and greater than 85% of amputations are preceded by an active foot ulcer.
Sadly for our state, we lead others in the US in the prevalence of DFU: "Of the 45 areas (44 states and DC) that reported information from the BRFSS diabetes module, Indiana (16.3%), California (16.2%), and Nevada (16.2%) had the highest age-adjusted prevalence of a history of foot ulcer among persons with diabetes, and Colorado (7.4%), Wisconsin (8.8%), and Hawaii (8.9%) had the lowest " (2).
Treatments for curing DFU are very far from optimal. Current standard of care can cure only about 30% of DFU and even the most advanced therapies, cell-based devices containing skin derived keratinocytes and fibroblasts, boosts the cure rate only to about 50%, leaving a tremendous unmet need for new effective cures for DFU, particularly in California. We anticipate that the development candidate that we propose, a stem cell-based “biological bandage”, will bring such a new and effective cure to our citizens who are suffering from diabetic foot ulcers.
Sources: 1) California Health Care Survey, UCLA, http://www.chis.ucla.edu/
2) CDC reports Morbidity and Mortality Weekly Report (MMWR), http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5245a3.htm
This application for a Development Candidate Award focuses on an allogeneic off-the-shelf mesenchymal stem cell (MSC)-seeded scaffold to treat diabetic foot ulcers. Dermal regeneration scaffolds containing other cell types are currently in clinical use but only provide modest benefit. The applicant proposes that MSCs derived from bone marrow or adipose tissue, pre-conditioned to optimize reparative properties, will promote vascularization of the wound and improve healing. There are three Specific Aims: (1) to optimize the expansion, survival and differentiation of MSCs on an FDA-approved dermal regeneration scaffold; (2) to optimize the pre-conditioning of MSCs by two specific methods in the scaffold and test for efficacy in a rodent model; and (3) to validate efficacy in a large animal model.
Reviewers agreed that this proposal addresses a major unmet medical need and could have a significant impact if successful. Diabetic foot ulcers are the leading cause of lower limb amputation in diabetics and current treatment options are only partially successful. Reviewers agreed that MSCs have trophic effects that may lead to enhanced healing and that pre-conditioning could improve these effects. They did note that the rationale for pharmacological pre-conditioning of the MSC-scaffold is not as strong as the rationale for the other proposed method, but they found the overall approach to be well justified.
The reviewers described the research plans as focused, well designed and eminently feasible. Potential pitfalls are acknowledged and alternative plans are proposed. Research milestones are clearly described, address all key activities and provide clear, quantifiable endpoints for measuring the project’s progress. Reviewers found the preliminary data compelling, demonstrating that MSCs populate and interact with the scaffold. Reviewers appreciated that the proposed scaffold is well characterized and already marketed and in widespread clinical use. However, one reviewer was concerned about the implications of seeding MSCs onto an FDA-approved medical device. This reviewer noted that the resulting product would likely be regulated as a biologic rather than a device, which could create corporate and regulatory complexities. The reviewer suggested pursuing an alternative scaffold in parallel to avoid these issues. The applicant mentions a comparable matrix that is currently under development at the applicant institution, but testing of this matrix is not described in the research plan.
Reviewers described the Principal Investigator (PI), co-PI and Collaborative Funding Partner PI as well suited to carry out the proposed research. The PI and Partner PI have strong track records in wound healing research. The co-PI has valuable experience with clinical translation of MSC research. Reviewers were particularly impressed by the commitment of the California and international teams to work together. They have an existing track record of collaboration and have proposed a post-doctoral fellow exchange, ensuring a connected research program and strong communication between the two groups. Reviewers described the research environments at both institutions as excellent.
Overall, the reviewers were strongly supportive of this proposal to develop an allogeneic off-the-shelf MSC-scaffold to treat diabetic foot ulcers. They praised the outstanding, collaborative research team and felt that this proposal has an excellent chance of advancing to IND-enabling studies at the end of three years.