Acellular Orthobiologics: Can They Improve Wound Healing?

The Centers for Disease Control and Prevention recently announced that diabetes now affects nearly 24 million people in the United States. Foot ulcers will affect up to 25 percent of people with diabetes during their lifetime.1 People with diabetes have a 30-fold higher lifetime risk of undergoing a lower extremity amputation in comparison to those without diabetes.2 A foot ulcer precedes a lower extremity amputation 85 percent of the time.3
Diabetic foot problems are a major burden to society and come at great costs to the healthcare system. Prevention of foot ulcers is key. However, when a patient presents with an open wound, appropriate management is necessary to prevent lower extremity amputation.

The foundation of treatment includes the “VIPs” of diabetic wound healing. The VIPs stand for Vascular (ensuring adequate limb perfusion), Infection (controlling infection) and Pressure (mitigation of plantar pressures through proper offloading). Until one addresses all three of these factors, the wound will persist.
The treatment plan should progress through three key phases. The first of these phases is debridement, the second is promotion of granulation tissue and third is wound closure. Accordingly, let us take a closer look at the use of orthobiologic scaffolds in attaining wound closure.
Sheehan, et al., conducted a prospective, controlled trial of diabetic foot ulcers that were not complicated by ischemia or infection. After providing good clinical care, the researchers found that wound area changes over a four-week period can strongly predict complete wound healing over a 12-week period.4 Therefore, when patients receive good fundamental wound care and the ulcer size fails to reduce by half over the first four weeks of treatment, they are unlikely to achieve wound healing over a reasonable period, and require more aggressive and “advanced” therapies.4
There have been some exciting advances in wound healing and orthobiologics specifically. If the wound remains stagnant after addressing the VIPs, then one should consider more advanced therapy.

A Primer On Adjunctive Advances In Wound Care
Over the past decade, many new treatment technologies have emerged and researchers have shown that they increase the probability of wound closure in difficult-to-heal foot ulcerations in patients with diabetes. The use of negative pressure wound therapy (NPWT) via VAC therapy (KCI) helps promote granulation tissue formation so the wound size becomes more manageable.5

Negative pressure wound therapy facilitates an optimal healing environment inside the wound and in essence, provides a wound simplification device. However, the physician can best achieve ultimate wound closure by combining NPWT with an adjunctive advanced technology. These include bioengineered tissue alternatives and acellular matrix–based materials.
Bioengineered tissue alternatives are cell-based technologies that help deliver exogenous growth factors to the wound bed. These include products such as Apligraf® (Organogenesis) and Dermagraft® (Advanced Biohealing). Acellular-matrix-based materials are extracellular matrix scaffolds that help organize the healing process and provide scaffolding for the host cells to grow. These include GraftJacket® (Wright Medical), Integra® Bilayer Matrix Wound Dressing (Integra Life Sciences), Oasis® (Healthpoint) and Unite® Biomatrix (Pegasus).
Tissue matrices act as scaffolding to allow the migration of host tissue across the wound surface. Matrix proteins become incorporated and utilized as the scaffold remodels the host. Let us take a closer look at the aforementioned acellular orthobiologic scaffolds.

What The Literature Reveals About GraftJacket
GraftJacket is a regenerative tissue matrix derived from cadaveric skin that is supplied from tissue banks within the United States. GraftJacket is cryogenically preserved and has a two-year shelf life. Processing removes the epidermal and dermal cells while preserving bioactive components and the structure of dermis. GraftJacket is an allogenic, acellular matrix that supports regeneration of dermal tissue and the patient’s cells grow into the matrix to form the patient’s own skin.
It is available in 0.4- to 0.8-mm thickness and is pre-meshed for passage of wound exudates. The application of the graft requires a thawing and rehydration process, and one must use it within four hours of rehydration.6 Physicians must secure the product in place with sutures or staples.
GraftJacket is indicated for a variety of wound types including deep or superficial wounds. In deeper wounds, Beniker and his colleagues showed preliminary evidence that one may utilize the dermal membrane material as a scaffold for periosteum regeneration that allows for cellular repopulation, revascularization and bone defect restoration.7 When the graft covers lower extremity wounds, research has shown it to be significantly superior to offloading and standard dressing changes when it comes to the percentage of wound closure, the percentage of complete closure and time to closure.8-10

Martin and colleagues evaluated the use of GraftJacket in neuropathic diabetic foot wounds. Seventeen consecutive patients received surgical debridement and a single application of a GraftJacket.10 Eighty-two percent of the wounds healed in an average of nine weeks. The authors concluded that a regimen consisting of moist wound healing and an acellular matrix provide a useful adjunct to appropriate care of diabetic foot ulcers.
One may also use GraftJacket to repair or replace damaged or inadequate soft tissue including tendon and ligament repair and augmentation, periosteal patching, and interposition arthroplasty.6,8-14 Recent articles have detailed the use of GraftJacket in Achilles tendon repair. In two different retrospective studies, Lee found that in both neglected and acute Achilles tendon ruptures, augmentation with GraftJacket offered excellent outcomes.13,14
The product’s absence of cells reduces the risk of graft rejection. GraftJacket is contraindicated in patients with diagnosed autoimmune connective tissue disease, infection, inadequate vascular supply, and sensitivity to gentamycin, vancomycin, lincomycin, cefoxitin and polymyxin B.6

What You Should Know About Unite Biomatrix
Unite Biomatrix is a regenerated acellular matrix comprised of equine pericardium. Similar to GraftJacket, the processing of Unite Biomatrix removes all epidermal and dermal cells, leaving only bioactive components and a collagen matrix. The xenograft then undergoes a unique step in the processing: stabilization with water-soluble carbodiimide.15 This step creates a very stable and resistant product but retains bioavailability unlike more traditional chemical stabilizers. The product again undergoes chemical sterilization, which carefully protects the bioavailability of the graft. However, it is thorough enough to eliminate traditionally resistant bacteria and viruses such as Mycobacterium and Parvovirus.15
One major advantage of the stabilization and sterilization process is the ability to store Unite at room temperature.15 One should still soak the graft for one to two minutes in sterile saline to ensure the rinsing of all foreign material and to maintain the pliability of the graft. It is available in multiple sizes, thicknesses and with or without fenestration within foil peel pouches. Secure the graft with suture or staples, and apply appropriate dressings.
The indications are for repair or replacement of damaged or inadequate soft tissue including diabetic foot ulceration, and tendon and ligament repair and augmentation.16 Equine pericardium has been a dermal substitute to augment and/or bridge rotator cuff surgery, and for abdominal/thoracic wall defects.17 One can also theoretically use the graft for periosteal patching and interpositional arthroplasty.

Bear in mind that Unite Biomatrix is a newer product and there is a lack of high-level evidence. However, anecdotal and basic science evidence leads one to believe the graft will improve outcomes. It is extremely tough and resistant to breakdown since the processing does not destroy the cross-linking of collagen. Druecke and colleagues reported advantages with using a collagen matrix stabilized with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) to facilitate wound healing.18
Researchers have shown that Unite Biomatrix is equal in pullout strength to other grafts on the market.17 It is a newer product so independent research on its efficacy is limited and we look forward to future studies. The contraindications for this graft are patients with diagnosed autoimmune connective tissue disease, infection, inadequate vascular supply and allergic reaction to equine products.

Can Oasis Have An Impact?
Oasis is an acellular dermal regeneration matrix comprised of small intestine submucosa. The grafts are manufactured from the porcine jejunum. During processing, all cellular components are removed. The remaining scaffold structure includes glycosaminoglycans, fibronectin, proteoglycans and growth factors.
In the clinical setting, one can easily incorporate Oasis into a wound treatment plan. The product does not require refrigeration, storage or handling. One can store Oasis at room temperatures and it has a 24-month shelf life. It comes in sterile, sealed, peel-open packages containing fenestrated or non-fenestrated wound dressing.
The indications for Oasis include the treatment of partial and full thickness skin injuries (either chronic or acute in nature), pressure ulcers, vascular ulcers, diabetic ulcers, second-degree burns, wounds secondary to trauma and autograft donor sites.

In a prospective, randomized, controlled, multicenter trial, Mostow, et al., compared the effectiveness of Oasis wound matrix with compression versus compression therapy alone in healing chronic leg ulcers.19 After 12 weeks of treatment, 55 percent of the Oasis group healed in comparison to 34 percent of the control group.
In a separate prospective, randomized, controlled, multicenter trial, Niezgoda, et al., compared Oasis wound matrix to becaplermin (Regranex Gel, Johnson and Johnson) for diabetic foot ulcers. They found that treatment with Oasis is as effective as Regranex in healing full thickness diabetic foot ulcers.20
One should not use Oasis on third-degree burns, individuals with known sensitivity to porcine products or wounds with excessive drainage or uncontrolled infection. This graft may lead to increased inflammation. In cases of extreme reaction with blistering, pain and swelling, one should discontinue use of the product.21

What Are The Benefits Of A Bilayer Matrix Wound Dressing?
Integra Bilayer Matrix Wound Dressing is comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan obtained from shark cartilage, and a semi-permeable polysiloxane (silicone) layer. The semi-permeable silicone layer controls water vapor loss, provides a flexible covering for the wound surface and adds increased strength to the device.
One would store the graft flat at room temperature and it has a 24-month shelf life.
The indications for Integra include the management of deep and superficial wounds including: partial and full-thickness ulcers, surgical wounds (wound dehiscence, donor sites/grafts) and traumatic wounds (second-degree burns). Integra works especially well in deep wounds that require regeneration of the deeper soft tissue layers and one may place it over bone.22
Before application, one should rinse the graft in a basin of sterile saline for one to two minutes. Secure the graft in place with either sutures or staples. The collagen matrix allows for the migration of host tissue and once it becomes colonized with fibroblasts, the silicone layer will begin to separate. One would typically remove the silicone layer after 14 to 28 days.

Do not use the grafts in patients with known sensitivity to bovine collagen or chondroitin materials. It is also not indicated for use in third-degree burns. Most of the research on Integra has been in the treatment of burns. While there is minimal data available on this modality for the treatment of diabetic foot ulcers, there is great promise.23

In Conclusion
Clearly, physicians need to emphasize the fundamentals of sound wound care. Often, when it comes to achieving wound closure in recalcitrant wounds, one must combine the use of advanced therapies with sound medical and surgical management.
Indeed, there have been a variety of exciting advances that have emerged for possible treatment of diabetic foot ulcers. Orthobiologic scaffolds help organize the healing process and provide scaffolding for the host cells to grow. Negative pressure wound therapy provides an optimal healing environment inside the wound and at times one can best achieve wound closure by combining NPWT with an orthobiologic scaffold.
There are many new products on the horizon and the clinician must be aware of the strengths and shortcomings of each. One must rely on clinical experience and scientific data to decide which products will best suit the individual patient’s needs.

Dr. Bevilacqua is an attending surgeon at the Foot and Ankle Clinics and Amputation Prevention Center at Broadlawns Medical Center in Des Moines, Iowa.

Dr. Greenhagen is a first-year resident within the University of Pittsburgh Medical Center (UPMC) Southside Podiatric Residency Program.

For further reading, see “Point-Counterpoint: Extracellular Matrices: Are They Worth It?” in the July 2008 issue of Podiatry Today. Also check out the archives at www.podiatrytoday.com.

References:

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