Thomas Morrow, MD

Traditional therapies predominate in wound care, but for those patients with chronic conditions, engineered skin may be a welcome relief from pain and infection.

Thomas Morrow, MD

Little time is spent by most of us thinking about the largest organ of the human body — our skin. Other than the recent biologic advances in treatment of psoriasis and the cosmetic application of the biologic Botox, the skin has remained pretty much ignored by managed care decision makers. But the skin has been a fruitful area of research for scientists who seek to produce treatments, both biologic and nonbiologic, to aid in those injuries caused by burns and vascular insults such as diabetic foot ulcers and venous stasis ulcers.

The need for skin repair products is great as there are approximately 75,000 burn victims each year in the United States. Although most of these patients are treated with traditional therapy, a few with major burns are candidates for engineered skin. In addition, there are literally millions of people who suffer from chronic skin wounds — defined as wounds that do not heal within six weeks. These chronic wounds often take years to heal and require costly outpatient as well as inpatient care.

This column will focus on the engineered skin products as well as future innovations.


For decades, surgical grafting of split thickness autologous skin has been the standard therapy for prompt closure of full thickness burns. But this care is only available for moderate-sized burns because of the lack of available donor sites on the individual's body. With large surface area burns, physicians must turn to alternative skin replacement products. Cadaver skin is one option but has a number of limitations.

As an alternative, scientists have developed grafts using sheets of fibroblasts embedded in a biodegradable matrix, sheets of cultured keratinocytes, as well as dual-layered dermal/epidermal engineered skin. Many products are already approved by the FDA and available to clinicians. In fact, there are approximately two dozen products available in the U.S. and Europe. The first generation products were intended for the treatment of severe full thickness burns. These products are used in a very small number of patients who require large quantities of skin replacement, typically those with burns on large surface areas. The three dominant products are Integra DRT (synthetic material), TransCyte (engineered tissue with no living cells), and a living murine/human cell product called Epicel.

Integra Dermal Regeneration Template (Integra LifeSciences Corp.) is a noncellular product comprised of a collagen and chondroitin-6 sulphate matrix overlaid with a thin silastic sheet. Integra DRT is indicated for the postexcisional treatment of life-threatening full-thickness, or deep partial-thickness thermal injuries where sufficient autograft is not available or not desirable due to the physiological condition of the patient. This template acts as a framework for dermal regeneration that inhibits scar-forming granulation and promotes healing. The patient's own epidermal cells will quickly engraft onto the dermal matrix seven to fourteen days after the application of Integra DRT. The advantages of Integra DRT are the reliability of its use, the immediate availability of large quantities, and its cosmetic properties.

TransCyte Human Fibroblast Derived Temporary Skin Substitute (Smith & Nephew) consists of a polymer membrane and newborn human fibroblast cells originating from infant human foreskin, which is removed during circumcision. As the fibroblasts proliferate during the manufacturing process, they secrete human dermal collagen, growth factors, and matrix proteins. The cells are killed during freezing, leaving behind the tissue matrix and growth factors.

Epicel (Genzyme Biosurgery), an actual living-skin substitute, uses the patient's own cells to create a permanent skin replacement. Epicel is grown from a postage stamp-size biopsy. In addition to using the patient's own cells, Epicel is comprised of mouse cells to form the cultured epidermal autografts. This growth takes as few as 16 days. The murine cells eventually die, leaving the patient's cells to form the skin layers.

Chronic wounds

Chronic wound treatment for pressure ulcers, chronic venous stasis ulcers, and diabetic foot ulcers is a much larger market for engineered skin due to the sheer number of patients and the increasing prevalence. Although exact numbers are not reported, this market is measured in millions of patients per year. It is estimated that 15 percent of people with diabetes will eventually develop a diabetic foot ulcer. There are now more than 100,000 lower extremity amputations in the United States each year attributed to diabetes. Because of the increasing prevalence of diabetes and the aging population the number of these wounds will increase dramatically in the coming decades.

Approximately 80 percent of these wounds are treated in the traditional manner using dressings and ointments. The rest are subject to split thickness skin grafts and tissue engineered skin. The most common living engineered skin products include Dermagraf (Smith & Nephew) and Apligraf (Organogenesis).

Both Apligraf and Dermagraf are derived from infant circumcisions. The manufacturing processes differ, however. Apligraf is developed using a process that separates the cells into two types, the dermal fibroblasts and epidermal cells. The dermal layer of human fibroblast cells, which produce additional matrix proteins, grows on a matrix or scaffold of bovine collagen and is topped by the epidermal cell layer. Dermagraf is a cyropreserved human fibroblast-derived dermal substitute.

The human fibroblasts are seeded onto a bioabsorbable polyglactin mesh scaffold and proliferate to fill the interstices of the scaffold. In the process, the fibroblasts secrete human dermal collagen, growth factors, and cytokines to create a three dimensional dermal substrate. Over time, the donor cells from infant foreskins disappear and are replaced by the patient's own cells, according to one study. Researchers found that after a period of several months, none of the graft DNA was present. Unlike human skin, neither Apligraf nor Dermagraf contain melanocytes, Langerhans' cells, macrophages, lymphocytes, or other structures.

These products are to be used on noninfected, chronic (>6 week) wounds with no exposure of bone, tendon, muscle, or joint capsule. Potential candidates are those who have failed to respond satisfactorily to traditional therapy including Unna boot care, have adequate arterial supply, and no history of allergy to the components. Studies of both products have resulted in significantly improved wound healing rates.

Future engineered skin will include recombinant growth hormones and cytokines to improve the ultimate outcome. And that is just the start. The entire industry has been learning from the developments in engineered skin. The future of tissue engineering is broad. The products of tomorrow will include cartilage, bone, heart muscle, blood vessels, and even organs. But those will be the developments of Tomorrow's Medicine!

Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.

Managed Care’s Top Ten Articles of 2016

There’s a lot more going on in health care than mergers (Aetna-Humana, Anthem-Cigna) creating huge players. Hundreds of insurers operate in 50 different states. Self-insured employers, ACA public exchanges, Medicare Advantage, and Medicaid managed care plans crowd an increasingly complex market.

Major health care players are determined to make health information exchanges (HIEs) work. The push toward value-based payment alone almost guarantees that HIEs will be tweaked, poked, prodded, and overhauled until they deliver on their promise. The goal: straight talk from and among tech systems.

They bring a different mindset. They’re willing to work in teams and focus on the sort of evidence-based medicine that can guide health care’s transformation into a system based on value. One question: How well will this new generation of data-driven MDs deal with patients?

The surge of new MS treatments have been for the relapsing-remitting form of the disease. There’s hope for sufferers of a different form of MS. By homing in on CD20-positive B cells, ocrelizumab is able to knock them out and other aberrant B cells circulating in the bloodstream.

A flood of tests have insurers ramping up prior authorization and utilization review. Information overload is a problem. As doctors struggle to keep up, health plans need to get ahead of the development of the technology in order to successfully manage genetic testing appropriately.

Having the data is one thing. Knowing how to use it is another. Applying its computational power to the data, a company called RowdMap puts providers into high-, medium-, and low-value buckets compared with peers in their markets, using specific benchmarks to show why outliers differ from the norm.
Competition among manufacturers, industry consolidation, and capitalization on me-too drugs are cranking up generic and branded drug prices. This increase has compelled PBMs, health plan sponsors, and retail pharmacies to find novel ways to turn a profit, often at the expense of the consumer.
The development of recombinant DNA and other technologies has added a new dimension to care. These medications have revolutionized the treatment of rheumatoid arthritis and many of the other 80 or so autoimmune diseases. But they can be budget busters and have a tricky side effect profile.

Shelley Slade
Vogel, Slade & Goldstein

Hub programs have emerged as a profitable new line of business in the sales and distribution side of the pharmaceutical industry that has got more than its fair share of wheeling and dealing. But they spell trouble if they spark collusion, threaten patients, or waste federal dollars.

More companies are self-insuring—and it’s not just large employers that are striking out on their own. The percentage of employers who fully self-insure increased by 44% in 1999 to 63% in 2015. Self-insurance may give employers more control over benefit packages, and stop-loss protects them against uncapped liability.