БиоПро Выбор потребителя 2018 #01

Stem cells in combination with glaucoma medication promote diabetic wound healing

A new study has demonstrated the promise of a revolutionary approach in the treatment of trophic foot ulcers associated with diabetes. Scientists have shown for the first time that a bioengineered scaffold composed of human mesenchymal stem cells (MSCs) combined with a drug commonly used to treat glaucoma improved healing and reduced wound inflammation in diabetic mice by as much as 75% compared to controls.

Trophic foot ulcers are one of the most dangerous and common complications of diabetes. In the United States alone, it affects about a quarter of the 25 million people living with diabetes, according to the American Diabetes Association. The association also predicts that 30% of these cases will eventually lead to amputation. Even more alarming is the predicted five-year mortality rate for those who have undergone an amputation of 48%, a rate equal to that of colon cancer deaths.

“U.S. healthcare expenditures for diabetes foot ulcers (DFUs) is over $43 billion a year. Yet, these expenditures for good standard of care – which includes such things as following a strict diet, off-loading pressure from the foot to allow wounds to heal, antibiotics or surgery — result in healing in only 30 percent of patients”, – said Roslyn Rivkah Isseroff, M.D., professor of dermatology at University of California (UC) Davis. “Treating these patients and trying to get them to heal is what propelled me to work on this problem”.

“This rather dismal cure rate has prompted vigorous research for therapeutic alternatives”, – Dr. Nolta said. “Several cellular therapies for treating DFU have already been approved by the Food and Drug Administration (FDA), but the healing rates show only modest improvement when compared to the DFU standard of care. None of these products, however, are composed primarily of MSCs. MSC-based therapies may offer advantages over the currently available cellular therapies by regulating the abnormal immune and inflammatory response typical of DFU”.

Earlier studies by the UC Davis team showed that 85% of MSCs applied to scaffolds are localized on the seeding side and remain viable in culture for 15 days. Previous work also demonstrated that preliminary hypoxic exposure, that is, depriving MSCs of oxygen, increased their survival and improved cell retention in the wound area.

“Hypoxic preconditioning decreases glucose consumption by the cells, resulting in longer survival in a nutrient-deficient environment”, – Dr. Nolta explained.

The idea of ​​adding timolol, commonly used to treat glaucoma, emerged in a new study as a result of another experiment conducted by scientists at the UC Davis. Then it was shown that the tissue of the wound surface generates the stress hormone catecholamine, which impairs healing.

Catecholamine plays an important role in the body’s response to stress by raising blood pressure and blood glucose levels. Timolol is known to reverse the negative effects of catecholamines and thus improve healing.

In a new study, the team cultivated human MSCs from the bone marrow of healthy donors onto circular matrix scaffolds. Several concentrations of MSCs have been tested in an attempt to determine their optimal MSC dosing. The scaffolds were then incubated in timolol at a 1% oxygen level (hypoxia) in a mesenchymal stem cells growth media.

Next, scaffolds were applied to the wounds of a group of diabetic mice. Two small circular wounds were made opposite each other along the animal’s spine and fixed in such a way that the edges of the skin did not tighten as it healed. The frame was inserted into the wound with the side with MSCs down. In the control group of mice, only the matrix scaffold was used (without MSC and timolol). The idea was to see how effective the animals’ own cells were in repairing the damaged tissue, compared to wounds treated with a matrix of MSCs and timolol.

In addition, the wounds of some mice treated with MSC scaffolds were treated daily with timolol (various doses were tested) to assess the effect of the drug on the healing process.

The results were analyzed after seven days. The researchers found that in all cases of using matrix scaffolds and a combination of MSCs, hypoxia and preconditioning with timolol, significantly improved wound epithelialization (tissue repair) was observed – by more than 70% compared to the group where only the matrix was used. Additional treatment with timolol, used in the combination of matrix and MSC, also increased re-epithelialization by almost 75% compared to the control that did not receive timolol.

“Overall, the combination of MSCs and timolol successfully improved wound healing and reduced inflammatory response in the mice”, – Dr. Nolta said. “This suggests that this unique approach could potentially provide superior healing responses in humans with diabetic wounds”.

“For this work, scientists have combined adult stem cells with a repurposed drug that improves healing to create a novel bioengineered scaffold that could someday lead to a new treatment for chronic diabetic ulcers”, – said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine, where the article was published, and director of the Wake Forest Institute for Regenerative Medicine. “The outcomes from this study are promising and offer therapy not just for diabetic ulcers, but also for other types of wounds”.