Human adult stem cell therapies for the treatment of chronic wounds have shown considerable promise. However, appropriate delivery systems are needed to apply these therapies in the clinic. This award funds the development of stem cell delivery systems for the treatment of chronic wounds. We envisioned that tunable hydrogels can be used to deliver stem cells to wounds. Over the past year we have been engineering hydrogels for this application. First, we screened large libraries of small molecules and identified a variety of stem cell-specific small molecules. These molecules have the ability to bind to stem cells. So far we have demonstrated that the small molecules can capture stem cells on 2-D surfaces. In the upcoming years we will determine their ability to hold stem cells within hydrogels. We expect that the different small molecules will have different effects on the stem cells. So we will also test for this. In addition, we have developed a variety of hydrogels that degrade at different rates. We have demonstrated that these hydrogels can polymerize within a living organism and that their degredation rate can be set by their building blocks. In the upcoming year(s) we will attach our stem cell-specific small molecules to our hydrogels and then use these hydrogels to treat chronic wounds.
Reporting Period:
Year 2
Integrins are cell surface receptors that allow cells, including stem cells, to interact with their environment. One of their functions is to transmit signals about the environment to stem cells. There are many types of integrins, which bind to extracellular proteins found in a cell's environment. Our group has been using chemistry to isolate different novel small molecules that can bind specifically to the different integrins. Our goal is to incorporate these novel small molecules into hydrogels, which we are using as 3 dimensional homes to grow stem cells within the incubator. The ultimate plan is to use these same hydrogels to transfer the stem cells to patients with a variety of ailments, such as chronic ulcers.
Over the past year we have helped to develop a variety of hydrogels that can grow stem cells. We have also isolated a variety of novel small molecules specific to different integrin molecules.
Reporting Period:
Year 3
During this funding period we have identified many molecules that can bind to stem cells. When stem cells are cultured with these cells, we have found that some of the molecules induce the stem cells to differentiate while others induce them to proliferate but not differentiate. We will continue to characterize these ligands. We have also dramatically improved our methodologies to identify new stem cell-binding molecules. We are now incorporating stem cell-binding small molecules into hydrogels to characterize the effects of these ligands on stem cells in a 3D culture system.
We have also demonstrated that several parameters of the 3D hydrogel cultures can be “tuned” to achieve optimal results, i.e. controlled stem cell differentiation. In addition, to our extensive experimentation with cultured stem cells, we have started to characterize the properties of our hydrogels when implanted into an animal model, and have been able to control the degradation rates within the animals. Those results demonstrated that we can “tune” hydrogels to degrade at different rates. This technology can be incorporated into a variety of Stem Cell applications. We have also started to incorporating stem cell-binding molecules into hydrogels and have tested their ability to increase the rate of wound healing. From these experiments, it appears that our functionalized hydrogels containing our synthetic molecules are able to increase the rate of wound healing. Another fascinating finding is that our stem cell-binding small molecules appear to be able to alter the differentiation of mesenchymal stem cells when they are incorporated into 3D cultures.
Reporting Period:
Year 5
Skin diseases are among the cohort of medical conditions in which spending has increased the most. Within this group, skin ulcers represent the largest economic burden and current treatment options for patients are often ineffective. Mesenchymal stem cells (MSCs) have been reported by many groups to aid wound healing. Therapeutic applications for mesenchymal stem cellsare growing; however, the successful implementation of these therapies requires the development of appropriate MSC delivery systems. This CIRM award has yielded novel hydrogel delivery systems for mesenchymal stem cells that we wish to work towards commercialization. We have demonstrated that the hydrogel-encapsulated stem cells remain viable and that when delivered to wounds they aid in wound healing. We have also characterized the ability of our different hydrogel MSC delivery systems to induce gene transcription. Each hydrogel delivery system was designed to incorporate different small molecule attachment sites to allow MSC adherence to the 3D matrix. These MSC-binding interactions altered MSC gene expression in a reproducible fashion. We are hopeful that this research will lead to a product for delivering MSCs to patients for a variety of applications.
Reporting Period:
Year 5/NCE
Skin diseases are among the cohort of medical conditions in which spending has increased the most. Within this group, skin ulcers represent the largest economic burden and current treatment options for patients are often ineffective. Mesenchymal stem cells (MSCs) have been reported by many groups to aid wound healing. Therapeutic applications for mesenchymal stem cellsare growing; however, the successful implementation of these therapies requires the development of appropriate MSC delivery systems. This CIRM award has yielded novel hydrogel delivery systems for mesenchymal stem cells that we wish to work towards commercialization. We have demonstrated that the hydrogel-encapsulated stem cells remain viable and when delivered to wounds, they aid in wound healing. We have also characterized the ability of our different hydrogel MSC delivery systems to induce gene transcription and protein expression. Each hydrogel delivery system was designed to incorporate different small molecule attachment sites to allow MSC adherence to the 3D matrix. These MSC-binding interactions altered MSC gene expression in a reproducible fashion. We are hopeful that this research will lead to a product for delivering MSCs to patients for a variety of applications.
Grant Application Details
Application Title:
Tunable hydrogels for therapeutic delivery of multipotent stem cells.
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.
