BOSTON-More than a decade after artificial skin seemed to be in the bag, researchers are still hard at it.
In the 12 years since rival teams here created intense excitement with the promise of cheap replacement skin by the bolt, skin’s fine tissue has turned out to be much tougher than joints or valves to duplicate.
A skin facsimile is needed to cover some 15,000 debrided burns a year and an estimated four million other wounds and ulcers. Though cadaver skin can serve as a temporary replacement, it’s in short supply, costs about $800 a square foot, and may transmit HIV or other organisms.
Dermal and epidermal substitutes have been made separately, but a biotextile that mimics the full skin’s structure, function, appearance, and comfort has proved elusive.
The ideal replica would be able to replace normal dermis and epidermis, be immediately available, have a prolonged shelf life, and look, act, feel, and grow like the real thing, says Mass General surgeon John Burke.
This year the FDA approved Integra Artificial Skin for post-excisional therapy of life-threatening burns. It’s a 4- by 10-inch bilayer membrane consisting of a lattice of bovine collagen and glycosaminoglycan fibers and a silicone epidermis. Though not Dr. Burke’s exemplar, it provides immediate wound closure, creates a template for dermal regeneration, and allows use of thin epidermal autografts. The silicone can stay until sufficient autograft is available.
Dr. Burke, who developed this skin surrogate with MIT chemist Ioannis Yannas, has used it on more than 120 patients, 2 to 90 years old, with burns on 1% to 98% of body surface. During the first six months postgraft, 78% of recipients reported it felt and functioned more like normal skin than areas with autografts.
There’s been no rejection or toxicity, but complications include subgraft hematoma, serous collections requiring drainage, graft wrinkling, and separation of the silicone layer.
The other rival artificial skin of the mid-1980s, cultured epidermal autografts made from the patient’s biopsied epidermal cells, was pioneered by Harvard physiologist Howard Green. Boston Shriners plastic surgeon G. Gregory Gallico, who did early clinical work, says some CEAs are still intact after a decade.
CEAs (Epicel, Genzyme) are produced by culturing cells to confluence and mounting them on fine mesh. Cells can be expanded 10,000-fold in culture, but it may take three to four weeks to turn out a graft. CEAs have been given to 800 patients in 105 hospitals in the U.S and Europe. Depending on wound severity and extent, CEAs cost $10,000 to $100,000, plus surgical and hospital fees.
It’s expensive technology and not yet that dependable, the University of Florida’s Dr. David Mozingo told the Wound Healing Society meeting here. CEAs made of keratinocytes work initially, but they’re fragile and thin, and their long-range performance is poor, especially in areas of great friction, says Dr. Keith Rose of Galveston Shriners Hospital.
CEAs are usually made by attaching cells to gauze manually. But Dr. Howard Clarke of Toronto’s Hospital for Sick Children is looking at a shortcut to the process by spraying cells as an aerosol on the wound.
Now genes are getting under the skin. The latest path to a complete skin equivalent is the gene for human platelet-derived growth factor-A, which Dr. Jeffrey Morgan’s Mass General team uses to stimulate growth of keratinocytes from human foreskins. The souped-up keratinocytes are seeded on a dermis that’s prepared by soaking cadaver skin until it’s an acellular combination of collagen, elastin, remnants of capillaries, and bits of basement membrane.
When cultured for a week, the dermis and keratinocytes formed bioartificial skin that’s been grafted on full-thickness wounds of athymic mice. In two weeks there were significantly more fibroblasts, mononuclear cells, and blood vessels under the genetically modified keratinocytes than under unmodified grafts.
Within four weeks the modified grafts contracted 50% less than the controls, Dr. Morgan told the Wound Healing Society meeting. But he sees a long lag between mice and men.
Keratinocytes transfected with the gene for human epidermal growth factor were transplanted on porcine partial-thickness wounds and cultured in vivo in a fluid-filled chamber by researchers at Brigham and Women’s. The treated wounds healed 2.1 days sooner than in controls (20%), says Dr. Elof Eriksson.
He also used a transparent vinyl chamber to promote the growth of a patient’s skin cells in vivo. This healed a seven-year-old wound from infected synthetic mesh in a woman’s abdomen. Antibiotics were injected every 48 hours into the sealed chamber that was glued to the skin and replaced every few days. After 10 weeks of therapy the wound healed.
One approach to full-thickness grafts, though still in early stages, is to co-culture autologous keratinocytes and a commercially available acellular dermal matrix, says Sacramento’s Dr. Debra Reilly, a surgeon.
She has morselized neonatal foreskin, incubated it in serum-free media, and used trypsin to separate the epidermis. The keratinocytes and melanocytes are cultured independently and trypsinized before they’re combined and seeded on pieces of processed cadaver dermis.
Dr. Reilly thinks such grafts, which are cultured for three weeks, may be more suitable for reconstructive procedures than for burns. Patients could have a biopsy and return after the cells are cultured. -Elsie Rosner
BOSTON-More than a decade after artificial skin seemed to be in the bag, researchers are still hard at it.
In the 12 years since rival teams here created intense excitement with the promise of cheap replacement skin by the bolt, skin’s fine tissue has turned out to be much tougher than joints or valves to duplicate.
