Skin Substitutes for Diabetic Foot Ulcers: What the Trials Show

If a foot ulcer has been open for weeks, you may have been offered a skin substitute: a thin sheet of bioengineered or donated tissue laid over the wound. Here is what the randomized trials found, what they leave out, and where these products sit next to offloading and surgery. For how we use them, see skin substitutes and placental tissue grafts.

Why a stalled ulcer may need more than dressings

Good standard care is the foundation, but alone it closes fewer ulcers than people expect. Pooling the standard-care groups from trials of nerve-related (neuropathic) diabetic foot ulcers, researchers found about 24% healed after 12 weeks of good wound care and about 31% after 20 weeks.⁠^[4]

The first month tells you a lot. In a trial of 203 people seen weekly, ulcers that shrank by more than the median amount in four weeks healed within 12 weeks 58% of the time; those that shrank less healed only 9% of the time.⁠^[5] For an uninfected ulcer that hasn’t healed after 4–6 weeks of optimal care, the International Working Group on the Diabetic Foot (IWGDF) suggests considering an added treatment, and a placental membrane graft is one of the options it lists.⁠^[6] See also why early wound care matters.

What counts as a skin substitute

Skin substitutes may be bioengineered, taken from another person (an allograft) or taken from an animal (a xenograft); a graft of your own skin is an autograft.⁠^[1] The IWGDF sorts them by whether they contain cells. Cellular products hold living human cells such as fibroblasts; acellular products are a framework, such as a collagen dermal matrix, with the cells removed. Products from placental membranes (the amnion and chorion) or umbilical cord form their own group.⁠^[3]

The choice is wide: a 2020 report for the federal Agency for Healthcare Research and Quality (AHRQ) counted 76 skin substitutes sold in the United States, and 89% were acellular, most made from human placental membrane or animal tissue.⁠^[7] Grafts of your own skin are covered under skin grafts and flaps.

What the main trials found

In each of the five trials below, both groups received standard wound care that included offloading, and one group also received the product. Each time, more wounds closed in the product group.⁠^{[8,9,10,11,12]}

Pooled results point the same way:

• All products. The Cochrane review (17 trials, 1,655 people) found healing about 1.55 times as likely, on low-quality evidence. The benefit varied by product, and in four trials comparing two products directly, neither came out ahead.⁠^[1]
• Placental products. A 2026 meta-analysis of nine comparisons with 944 people rated the certainty moderate, but cautioned that the average benefit may not be repeated with every product, patient group or setting.⁠^[2]
• Longer trials. A 2025 meta-analysis for the Italian diabetic foot guidelines, covering 27 skin substitute trials of at least 12 weeks, found more ulcers healed and faster healing, but no significant drop in major amputations.⁠^[13]

What the trials leave out

• Carefully chosen wounds. In the dermal template trial, people were randomized only if less than 30% of the ulcer had new skin after a 14-day run-in of standard care.⁠^[11] The placental membrane trial excluded infected wounds, wounds with exposed bone, tendon, muscle or joint capsule, and people whose circulation tests fell below set limits.⁠^[10]
• Many real patients wouldn’t qualify. An analysis of 17 trials of high-technology wound products estimated that 15 of them would have excluded more than half of a typical wound-care population.⁠^[14]
• Industry involvement. In the Cochrane review, 15 of the 17 trials reported industry involvement, and small trials with negative results appeared less likely to be published.⁠^[1]
• Missing outcomes. The AHRQ report found that studies rarely reported amputation, whether the ulcer came back, or how people functioned afterward.⁠^[7] Only two Cochrane trials counted amputations; together they showed slightly fewer, on very low-quality evidence.⁠^[1]

What the guidelines recommend

The IWGDF’s 2023 healing guideline gives placental-derived products a conditional recommendation as an add-on when standard care alone has failed, based on low-certainty evidence.⁠^[3] It suggests not using cellular and acellular products routinely, because the trials were at high risk of bias and the products are costly.⁠^[3] Each added treatment it supports is for wounds that standard care hasn’t healed.⁠^[3]

Where surgery fits

A skin substitute works on the surface of the wound. Guidelines stress that even excellent local wound care can’t make up for an untreated infection, poor circulation or pressure that keeps landing on the same spot.⁠^[6] Those causes are where surgery does its work.

• Pressure from a deformity or a tight calf. For an ulcer under a metatarsal head (the ball of the foot) that won’t heal with offloading, the IWGDF suggests considering Achilles tendon lengthening or removing that metatarsal head.⁠^[6] In a randomized trial, about two years after healing, ulcers had come back in 38% of people who had Achilles lengthening with a total contact cast, against 81% with the cast alone.⁠^[15] Dr. Ozturk performs these operations for the ulcers that need them; see surgery that takes pressure off ulcers and Achilles lengthening for forefoot ulcers.
• Deep wounds and infected bone. One trial took the kind of ulcer trials often exclude: 220 people with exposed bone, tendon, muscle or joint capsule and bone infection under control. Both groups had debridement, removal of infected bone, offloading and six weeks of antibiotics. By 26 weeks, 66.1% had healed with an added umbilical cord membrane and 59.8% without it, a difference that was not statistically significant.⁠^[16] See surgery for bone infection.
• Covering a surgical wound. After surgery for infection, bone or tendon may be left showing. A systematic review, drawn mostly from case series, found that the limited data appear to support acellular dermal matrices for such wounds.⁠^[17] Dr. Ozturk uses amniotic and placental tissue in the operating room and closes wounds with skin grafts or local flaps when they need it.

If blood flow is the problem, a vascular specialist restores it. We start with noninvasive circulation testing at our practice and refer you when needed; see circulation tests for foot wounds and why toe pressures matter.

How we decide at our practice

Dr. Efe Ozturk, a Foot and Ankle Surgeon who is board certified in wound care (FAPWH), starts with the foundation: debridement, offloading, antibiotics chosen from culture results when there is infection, and circulation testing. For an ulcer on the sole, that usually means a knee-high device you can’t take off; we fit it and show you how to get around safely (see total contact casting). Visits are usually every week or two, and we measure the wound each time.

In the trial of 203 people above, ulcers that went on to heal had shrunk by 82% on average at four weeks, against 25% for those that didn’t.⁠^[5] So if a wound has shrunk by less than about half after four weeks, we look again at pressure, infection and blood flow. If those are handled and the wound is clean, we may apply a skin substitute in the office; many ulcers never need one. If a deformity, a tight tendon or infected bone is holding the wound open, surgery is usually the more direct fix. If hyperbaric oxygen suits your wound better, we refer you; see who benefits from hyperbaric oxygen.

Cost, coverage and risks

In the Cochrane review, no trial found a significant difference in side effects between people who received a product and those who didn’t.⁠^[1] Cost is the bigger question: it is one reason the IWGDF gives for not using these products routinely,⁠^[3] and the Cochrane review found their cost-effectiveness uncertain.⁠^[1] Coverage depends on your plan and the product, and some plans need prior authorization. Call 908-215-5953 to inquire about your insurance.

Surgery has its own risks, such as infection and a longer recovery, and we talk them through before any operation. Neither a product nor an operation can promise a wound will close; the aim is to treat what keeps it open.

Common questions

Will a skin substitute heal my ulcer when nothing else has?

Not by itself. In the trials, the products were added to debridement, dressings and offloading, and many wounds still stayed open: with placental products, 59.0% had closed at 12 weeks.⁠^[2] If infection, poor circulation or pressure is still at work, that cause needs treating first.⁠^[6]

Is one brand more effective than the rest?

The evidence can’t say. In the Cochrane review, the four trials that compared two products directly found no clear winner.⁠^[1]

How many applications will I need?

It depends on the product and the wound. In one trial, the living skin equivalent was applied weekly, up to five times;⁠^[8] in another, the amnion-chorion membrane went on weekly for up to 12 weeks.⁠^[12] In the trial of deep ulcers, where reapplication was at least four weeks apart, wounds that closed needed 1.67 applications on average.⁠^[16]

Can a skin substitute prevent an amputation?

That hasn’t been shown. The IWGDF found no evidence that placental products lower amputation rates, and the Italian meta-analysis found no significant drop in major amputations with skin substitutes.⁠^[3,13]

The bottom line

For a clean ulcer with good blood flow that stalls after about four weeks of good care, a skin substitute is a reasonable next step, and trials show more of those wounds close. They don’t fix pressure, infection or poor circulation, and they haven’t been shown to prevent amputation. When a deformity, a tight tendon or infected bone keeps a wound open, the operation that removes that cause is usually the step that saves the foot.