Can An Emerging Extracellular Matrix Help Treat Acute And Chronic Diabetic Wounds?

A myriad of products exists for the treatment of acute and chronic wounds. The primary goal with any of these products is rapid wound closure. Studies have shown that a lack of reduction in wound size at four weeks of treatment should prompt the provider to engage in advanced wound care modalities to accelerate the wound toward closure.1,2

   Several advanced wound care products have established their efficacy through both scientific and anecdotal evidence.3 One of the newer products in the wound care arena is a naturally occurring, non-crosslinked, resorbable, acellular extracellular matrix derived from the lamina propria of porcine urinary bladder (MatriStem, ACell). One of the primary advantages of this product is its ability to generate “site specific” tissue instead of scar tissue to heal a wound. Unlike other wound care products, clinical indications for application include: partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, surgical wounds and traumatic wounds. It has a two-year shelf life and is currently reimbursable in the surgical setting and certain federal facilities.

   This product goes through a process of decellularization, lyophilisation, disinfection and terminal sterilization. It is available in both powder and sheet forms. The wound care sheets range in thickness from one to six layers. Both the powder and sheet forms contain: vascular endothelial growth factor; keratinocyte growth factor; transforming growth factor alpha and beta; bone morphogenetic protein 4; basic fibroblast growth factor; platelet-derived growth factor; insulin-like growth factor; epidermal growth factor; collagen type I, II, III and IV; lamin and elastin.4 Research has shown these growth factors possess antibacterial properties against Staphylococcus aureus and Escherichia coli via the release of antimicrobial peptides as the product degrades.5

   The wound care sheets have two sides: an intact basement membrane that faces away from the wound bed and the opposite side, which one places in contact with the wound bed to promote integration of the product. The basement membrane side encourages epithelial and endothelial cell attachment, proliferation and differentiation. The side that comes in contact with the wound bed supports angiogenesis and integration of connective tissue.6 The powder form and single layer sheet do not require hydration. The thicker wound care sheets should be rehydrated for five to 10 minutes in normal saline or lactated Ringer’s solution depending on the amount of exudate from the wound.

   Application to the wound bed requires proper wound bed preparation to form a healthy, bleeding, granular base. Apply the powder first and subsequently apply a wound care sheet. The thicker sheets are best for application in the operating room while single sheets are more conducive to application in a clinical setting. There is no proper orientation for application of a single layer wound care sheet on the wound bed. The thicker wound care sheets have a notch that needs to be in the upper right-hand corner to ensure proper application with the basement membrane facing away from the wound bed. Then cover the product with a non-adherent layer like Vaseline impregnated gauze.

   The wound care sheets take four to 10 days for incorporation with the rate of resorption being dependent upon the thickness of wound care sheet. As the sheets resorb, they create a green to yellow or tan-colored film, and an odor. Do not remove this film as this is the normal course of resorption of the product. One should consider other secondary clinical signs of infection apart from appearance and odor of the wound to assess for the potential for infection. These signs include increased drainage, increased pain, induration, fluctuance or creptius about the periwound tissue. Another application of the product should occur when there is no more of the product or film from product resorption visible in the wound bed.

   One can use the product with and without antibiotic therapy, and in conjunction with other advanced wound care modalities such as non-contact low frequency ultrasound and negative pressure wound therapy.4,7

What A Recent Study Revealed

LeCheminant and colleagues published a retrospective review of the use of this extracellular matrix product on wounds on the lower extremity treated in an outpatient wound care center.4 The study consisted of a 12-month follow-up of 34 patients (26 male, eight female) with a mean age of 62.4 ± 13.4 years. Nineteen patients had diabetes. The types of ulcerations treated were plantar foot (10), anterior lower leg (six), venous leg (six), ischemic (three), decubitus (three), surgical wound dehiscence (six), amputation dehiscence (six), traumatic (one), traumatic laceration (one) and acute open fracture (one). All patients received the extracellular matrix product as either the initial treatment or after use of other advanced wound care modalities. The modalities included Prisma (Systagenix), Aquacel Ag (ConvaTec), Oasis Wound Matrix (Healthpoint Biotherapeutics), Dermagraft (Shire Regenerative Medicine), Apligraf (Organogenesis), Regranex (Healthpoint Biotherapeutics), Medihoney (Derma Sciences) and Integra (Integra LifeSciences).

   Clinicians applied the extracellular matrix product to wounds that had previous treatment with other products when they felt that wound healing had stalled for four weeks despite these treatments.4 The decision to use the extracellular matrix product as the initial treatment was arbitrary. All 34 patients achieved full wound healing at an average of 35.3 ± 47.7 weeks. Patients who received the extracellular matrix product as an initial treatment healed at an average of 6.3 ± 3.7 weeks in comparison to 11.7 ± 10.8 weeks in those who received prior advanced wound care treatments. The mean duration of wounds previously treated with other advanced wound care treatments was 25.5 ± 43.5 weeks.

   This study shows the capability of this extracellular matrix product to enhance wound closure both as an initial treatment and in wounds that have stalled in the face of other advanced wound care therapies.4

Case Study: When A Patient Presented With A Plantar Heel Ulceration And A Necrotizing Gas Gangrene Infection

A 56-year-old female with congestive heart failure, diabetes, atrial fibrillation, hypertension, chronic renal disease, a previous history of cerebrovascular accident, retinopathy and hyperlipidemia presented to the emergency room for chronic heart failure exacerbation. Doctors subsequently found the patient had a necrotizing gas gangrene infection related to a plantar heel pressure ulceration of the left foot.

   She went to the operating room for multiple serial debridements, which resulted in the loss of the entire plantar heel fat pad to the level of the calcaneus with skin loss extending to the medial and lateral aspects of the heel. Despite the location and depth of the wound, she received no treatment apart from topical gel thrombin and dry dressings for 10 days.

   The patient’s care then transferred to the Limb Preservation Service. At this time, she received negative pressure wound therapy (NPWT). The wound was 10 cm x 6 cm x 1.5 cm with the calcaneus exposed at the plantar aspect of the wound. There was also a full thickness wound at the medial calcaneus that was 4 cm x 2 cm x 0.4 cm. A magnetic resonance image (MRI) at that time showed no evidence of calcaneal osteomyelitis. The NPWT continued and physicians applied a “kickstand” Delta frame external fixator to help offload the wound. Clinicians performed weekly dressing changes, utilizing NPWT as well as adjunctive application of Graftjacket (Kinetic Concepts Inc.) twice and Apligraf once prior to the utilization of the extracellular matrix product MatriStem.

   Once clinicians began to use the extracellular matrix product, the wound reduced in size to 3.9 cm x 4.4 cm x 0 cm. There was also an increase in the thickness of the plantar tissue covering the heel. Due to the concern of potential calcaneal osteomyelitis, physicians expedited final wound closure with a partial calcanectomy and closure with a unilobar flap. Application of the extracellular matrix product led to a rapid decrease in wound size and increased plantar tissue thickness, making expedited surgical wound closure possible 16 weeks after the initial presentation and 14 weeks after the initiation of NPWT.

   Dr. Schade is Chief of the Limb Preservation Service and Director of the Complex Lower Extremity Surgery and Research Fellowship at the Madigan Healthcare System in Tacoma, Wash. She is an Associate of the American College of Foot and Ankle Surgeons.

References
1. Sheehan P. Early change in wound area as a predictor of healing in diabetic foot ulcers: knowing “when to say when.” Plast Reconstr Surg. 2006; 117(7 Suppl):245S-247S.
2. Sheehan P, Jones P, Giurini JM, Caselli A, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Plast Reconstr Surg. 2006; 117(7 Suppl):239S-244S.
3. Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res. 2009; 9:115.
4. Lecheminant J, Field C. Porcine urinary bladder matrix: a retrospective study and establishment of protocol. J Wound Care. 2012; 21(10):476, 478-80, 482.
5. Brennan EP, Reing J, Chew D, et al. Antibacterial activity within degradation products of biological scaffolds composed of extracellular matrix. Tissue Eng. 2006; 12(10):2949-2955.
6. Mitchell KB, Gallagher JJ. Porcine bladder extracellular matrix for closure of a large defect in a burn contracture release. J Wound Care. 2012; 21(9):454-6.
7. Gonzalez J. Regenerative Medicine: Urinary Bladder Matrix Assistance with High Risk Diabetic Limb Salvage. Poster Presentation. https://www.acell.com/files/Gonzalez_Diabetic_Ulcer.pdf . Last Accessed 29 Dec 2012.