Researchers have been working for more than 20 years to develop regenerative medicine therapies which will repair or replace tissue or organ function that does not heal or repair on its own.  This field, still in its infancy, holds great promise.  To date, however, there’s been a fair share of disappointment surrounding regenerative medicine, since after all these years it hasn’t  delivered cures for diseases like Parkinson’s or type 1 diabetes.  That said, regenerative medicine has had its successes, and one of them is in the treatment of diabetic foot ulcers.  Dean Tozer, Senior Vice President of Advanced BioHealing, Inc. answered questions for us about diabetic foot ulcers, Dermagraft, a therapy used to treat them, and a new community health education program called Heal2gether.

What are diabetic foot ulcers?

Diabetic foot ulcers (DFUs) are chronic sores or wounds that can develop on the feet or lower extremities of people with diabetes. About 15% of people with diabetes will develop DFUs in their lifetime, and approximately 2.5% develop a DFU each year. If not treated properly, DFUs can result in serious complications, including amputation. In fact, of those patients who do develop a DFU, 14% to 24% will require an amputation. However, DFUs can often be more easily treated if caught early.

What causes them?

For people with diabetes, prolonged high blood sugar levels can lead to damaged nerves in their feet. This condition, called peripheral neuropathy, can cause diabetics to lose sensation in their feet and may prevent them from noticing injuries, including sores caused by repetitive minor trauma (such as long walks); wounds caused by a single major trauma (like scraping the foot, stepping on rocks, putting the feet in hot water, cutting toenails incorrectly, wearing shoes that don’t fit properly); or foot problems such as calluses and hammertoes.

If left untreated, these injuries can turn into DFUs. Additionally, people with diabetes may have poor blood flow to the feet, which slows the wound healing process and increases risk of infection and amputation.

Heal2gether

Recently, a community health education program, Heal2gether, supported by Advanced BioHealing, was created to increase awareness of diabetic foot ulcers.  Heal2gether encourages patients to seek treatment from a wound care specialist, and provides resources and guidance to help patients adhere to their treatment plans, with the ultimate focus on driving better clinical outcomes.

Who can benefit from Heal2gether?

Patients with diabetes and their caregivers can visit www.heal2gether.org to find resources on DFUs, including: what DFUs are, the advanced treatment plans available to treat them, and how to find a wound care specialist.

The Heal2gether phone support program emphasizes relationship-building with the goal of providing support to both patients and physicians in the healing process. Patients who are interested should ask their wound care specialist for more information.

Who funds it?

The Heal2gether Partnership Program is supported by Advanced BioHealing, a leader in commercializing the promise of regenerative medicine and the maker of Dermagraft, a bio-engineered skin substitute that is FDA approved to treat diabetic foot ulcers (more on Dermagraft below).

How many patients have been treated through Heal2gether?

As of September 2010, more than 100 patients have completed the Heal2gether Partnership Program. More than twenty patients are currently enrolled in the program.

One Patient’s Story

Meet Lisa Summers of Conyers, Georgia, 47, a single mom and a first grade school teacher.  Lisa first developed a diabetic foot sore through a simple blister.  “I had joined a gym (to get healthy and fit) and was using a stationary bike,” she said. “Apparently, my foot was slipping in my shoe, as well as on the pedal, and since I have neuropathy in my feet I didn’t feel the blister developing. Once I discovered the blister (about the size of a dime) I went to my physician. They immediately placed me on antibiotics and scheduled me to go to a wound care center. By the time I arrived at the center (about 10 days later) the wound had gotten much worse and was now about the size of a 50 cent piece and was so deep that I could actually see the bone! I had contracted a bacterial infection called Methicillin-resistant Staphylococcus aureus, or MRSA.

The process of healing was very slow, somewhat painful (remember, I have neuropathy so I feel very little to no pain in my feet), and it required a great deal of patience and faith. I lived in fear of amputation the first 4 weeks of treatment. I was going to the hospital daily (at first twice a day) for outpatient IV therapy, along with visits to the wound care center twice a week. I had to offload (stay off my foot) which landed me in a wheelchair for 5 months. We tried various treatments which did not work and often brought temporary frustration. I think the worst part was having to keep my foot dry at all times.  That meant no bubble baths and no showers.   I went for months without stepping into a tub! I found some waterless soap and did the best I could. When I needed my hair washed, I had to ask someone (my daughter) to help me. When I needed groceries or medications I had to ask my kids. I virtually had no life outside of work and home.  Yes, I worked every day, teaching my 1st graders from a wheelchair! I only missed 2 1/2 days throughout this 5 month ordeal, so it shows that with determination anything is possible.

After trying various strategies in my healing process, the doctor recommended Dermagraft. He explained what it was and how it could help the healing process. The first application didn’t appear to work and once again I felt some temporary frustration. We waited a couple of weeks to let my wound become more healthy (it needed to show some granulation which causes the grafting process to adhere). We then tried the second application and within a week we began to see substantial improvement. Every week after that I felt the same anticipation the contestants on The Biggest Loser felt at each weigh in. How much did my foot heal? Did I keep to the doctor’s orders? Did I keep my blood sugars low enough to continue the healing process? Each week was an adventure. Some weeks were just like baby steps in healing, but then some weeks were jaw-dropping, dramatic improvements. I think what was so amazing is that I figured I’d have a dip in the bottom of my foot where the hole was, but it is smooth across like I never had a wound at all.”

How did you hear about Heal2gether? How did Heal2gether help you in terms of support and follow-up care?

The Heal2gether program, which was included in conjunction with the Dermagraft procedure, was a huge blessing. I connected immediately with my social worker, Phoebie. She was so informative and uplifting, especially on the weeks when I saw very little improvement. She offered to help find me help if I couldn’t get meds or food into the house and was calling every week to see how the visit went. It felt like someone really cared about me. I’m doing wonderfully now. I am back to walking and going to the store for myself. Life has become much more normal.

Was the Dermagraft procedure painful?

No, it was absolutely painless.  I have neuropathy in my feet, but even if I’d had feeling I think it would have been painless. All they did was place the cells (Dermagraft) on top of the wound and then they wrapped it.  Of course, it’s a little bit more detailed, but for a basic layperson they just laid the cells on the wound, packed it in, bandaged it up and we waited until my visit the next week to see my progress.

What is the success rate of Heal2gether?

Success rate of a program like Heal2gether is difficult to define, however there have been more than 100 patients to complete the Heal2gether Phone Support Program. Based on preliminary web metrics, more than 5000 unique visitors have visited Heal2gether.org since its launch to find resources on what DFUs are, the advanced treatment plans available to treat them, and how to find a wound care specialist.

Dermagraft Explained

Dermagraft is an advanced wound care product that contains living human skin cells. It is a skin substitute that is placed on the patient’s wound to cover it and to help it heal. Dermagraft is used to treat foot ulcers that have been present for more than 6 weeks in patients with diabetes. It is used together with standard methods of treating foot ulcers, including cleaning and preparing the wound, applying cover dressings to hold it in place, and wearing special shoes, casts, or other methods or devices to take the pressure off the sore, called “offloading.”

In order to give us a more thorough understanding of Dermagraft, Charles E. Hart, Ph.D., Vice President and Chief Scientific Officer for Advanced BioHealing answered some scientific questions about Dermagraft, its origin, the technology behind it, and its long-term safety.

Dermagraft tissue is assembled from fibroblasts.  What are fibroblasts and how are they assembled into Dermagraft tissue?

A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen (the structural framework) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.

During the manufacturing process of Dermagraft, which is a cryopreserved human fibroblast-derived dermal substitute, living neonatal fibroblasts are seeded onto a bioabsorbable scaffold. The fibroblasts migrate throughout the scaffold, proliferate to fill the interstices of this scaffold and secrete human dermal collagen, matrix proteins, growth factors, and cytokines, or proteins associated with wound healing.  The product is then stored frozen in a special buffer that allows the cells to retain their viability when the product is thawed at the time of use, yielding a three-dimensional human dermal substitute containing living fibroblast cells with the proven ability to stimulate tissue repair.

The fibroblasts come from newborn foreskin tissue; where do you get this tissue, and how reliable is that supply? Are there any plans to add alternate sources of the cells?

Newborn foreskin tissue is a good source of fibroblasts for use in the generation of an advanced wound therapy like Dermagraft. When you look at the biology of fibroblasts, fibroblast cells derived from tissues collected from younger donors (i.e. newborns) have a greater capacity to proliferate than cells from older donors (i.e. adults), and appear to make a number of factors thought to be critical to the wound healing process.

The fibroblast cell line used in the manufacture of Dermagraft was derived from a discarded foreskin donated by the consenting parents of a single individual almost 20 years ago.  The tissue was used as the source material for the collection of fibroblast cells that are present within the tissue. The isolated fibroblasts were then used to create a Master Cell Bank. The cells within the Master Cell Bank have been extensively tested for safety, demonstrating the absence of any infectious agent. To produce Dermagraft, individual vials of the fibroblast cells that were frozen down as part of the cell bank are thawed, expanded in culture, then seeded onto the bioabsorable scaffold used in the production of Dermagraft.

Currently, all of the Dermagraft that has been used in clinical trials and subsequent commercial distribution has been made from the fibroblasts isolated from the single donor tissue. It is anticipated that ABH will establish a new fibroblast cell line at some future date, though the current stock of fibroblast cells are sufficient to meet the company’s needs for several years to come.  Any new fibroblast cell line developed would also be derived from the donated foreskin tissue (upon parental consent) of a single individual.

Are there other potential uses of the Dermagraft technology?

In May 2009, ABH began patient recruitment for the largest venous leg ulcer (VLU) clinical trial ever conducted. The pivotal trial, which will be run in eight countries with more than 400 patients, will test the efficacy of Dermagraft for treatment of VLUs.  At the same time, based on the proven clinical efficacy of Dermagraft to heal chronic diabetic foot ulcers, ABH is exploring additional applications for the technology.

What parts of the Dermagraft technology does Advanced BioHealing own intellectual property for?

When Advanced BioHealing acquired Dermagraft from Smith & Nephew in 2006, the Company acquired all of the assets and rights associated with the product, including all patents and trademarks. ABH manufactures the product using proprietary cell-based techniques and expertise that were developed over a 20-year period. ABH has sole ownership of the product as well as the right to explore its use in all applications and treatments.

Are there any concerns about adverse effects of the foreign cells releasing cytokines and other immune signaling proteins?

The cells that are used in the production of Dermagraft are normal human fibroblasts. Cells of this type are a normal part of the skin and are known to play a key role in wound healing.  To date all of the Dermagraft that has been used in clinical studies and is being supplied for commercial use has been produced using fibroblast cells derived from a single donor.  This fact ensures consistency within the product, unlike many other cell-based products that have to routinely obtain new cells from different donors.  While the cells we use may be considered foreign to the patient being treated with Dermagraft, there has been no evidence that the cells themselves, or the Dermagraft product in total, stimulate an immune response, leading to rejection of the product.  The proteins (growth factors and cytokines) that are produced by the cells are made naturally by the cells and at physiologically relevant levels that are consistent with what would be expected to be made by cells naturally in the wound environment. The fibroblasts in Dermagraft have not been modified in any way so as to express high (supraphysiologic) levels of secreted cytokines and growth factors where there might be some concern of an impact of those proteins at sites distant from where the cells are placed within the body.

What about adverse oncogenic (that is, cancer cell forming) effects?  Should we be concerned?

The cells used in the production of Dermagraft have been extensively tested for a multitude of safety parameters, demonstrating that they are free of viruses and other potential infectious agents.  Safety testing has also been conducted to demonstrate that the product is non-tumorigenic, including studies that have evaluated the final product and the fibroblast cells directly. The fact that we use fully differentiated cells obtained from a single donor further provides an elevated safety profile for the product.  It should also be noted that published data highlight that primary fibroblast isolates (such as the fibroblasts use in the production of Dermagraft) rarely spontaneously transform into tumour forming cells.  Based upon all of the above data, we believe that the cells used in the production of Dermagraft have a very favorable safety profile. With approximately 10 years of use of Dermagraft, there have been no reported incidences of any oncologic adverse events related to treatment with Dermagraft.

Karmel Allison contributed to this story.