Live Cell Therapy Triggers Genomic Changes for Wound Healing

A wound before and after treatment with Apligraf.

A team of University of Miami Miller School of Medicine researchers has uncovered the secret behind a type of skin made from live human cells that stimulates healing of venous leg and diabetic foot ulcers.

The FDA-approved Apligraf, which is marketed by Organogenesis, Inc., does not take to the wound as a graft would. Instead, it disappears from the wound within a week or two, yet it still triggers healing.

Precisely how this bioengineered living cell therapy works has been a mystery, but the Miller School researchers, conducting the first clinical trial of Apligraf, have demonstrated that changes in the genome of the wound orchestrate a series of events that kick-start the healing process.

Their study, “A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers,” was published recently in the journal Science Translational Medicine.

“The public may not be fully aware of this, but chronic, non-healing wounds are the ‘cancer’ of the 21st century,” said researcher Marjana Tomic-Canic, Ph.D., professor of dermatology and director of the Wound Healing and Regenerative Medicine Research Program. “The high mortality and major morbidities pose a huge burden on patients, families, and health systems. Effective therapies are rare, and the last approval from the FDA for efficacy happened more than 15 years ago. This is why this is a true landmark paper in the field of wound healing.”

The article explains how the Apligraf activates a set of gene “responders” to shift non-healing venous leg ulcers into wounds that more closely resemble acute wounds, with the aim of healing over time.

Tomic-Canic, along with lead authors Rivka Stone, M.D., Ph.D., a research resident, and Olivera Stojadinovic, M.D., a graduate student, and co-workers, studied 24 patients. Some were treated with the Apligraf living skin substitute combined with standard of care (compression wound dressings); a control group received standard of care alone.

Comparative microarray analysis of tissue biopsies at baseline and one week post-treatment revealed distinct transcriptome patterns in the Apligraf-treated group that modulate inflammation and growth factor signaling, activation of keratinocytes and other pro-healing activities. Simply put, it transformed a non-healing venous leg ulcer into healing that resembled an acute wound.

The research offers hope for patients living with these debilitating ulcers because it provides insights into how this therapy works and gives guidance on how to change a non-healing wound environment into a wound that can be healed, tracing the roadmap for future targeted therapies

Tags: Apligraf, living cell therapy, wound healing