A Closer Look At The Role Of Collagen In Healing Complex Diabetic Foot Ulcerations

By Ann Zmuda, DPM

Currently, in the United States, the Centers for Disease Control and Prevention (CDC) reports there are approximately 25.8 million people with diabetes mellitus, which is 8.3 percent of the population.1 This number is estimated to grow to 44 million by the year 2034.

   One of the most feared complications for the patient with diabetes is amputation. More than 60 percent of non-traumatic lower limb amputations occur in people with diabetes and these are preceded by diabetic foot ulcerations about 85 percent of the time.2 To complicate things further, approximately 15 percent of people with diabetes will develop foot ulceration in their lifetime.3 Patients with diabetes have multi-organ comorbidities that contribute to further complications, delayed healing and an increased risk of infection. Accordingly, it is imperative that we prevent diabetic foot wounds from occurring and heal the wounds we cannot prevent as expeditiously as possible.

   It is important to understand the wound healing process so we can fully understand the optimal ways to heal these complex diabetic foot ulcerations. The wound healing process occurs in three phases. The initial inflammatory phase lasts about three to four days from the onset of injury. In this phase, platelets begin to form a clot and produce thrombin, which subsequently initiates the formation of fibrin. The platelets also release growth factors, which are essential for wound healing. White blood cells (neutrophils and macrophages) enter the wound to eliminate bacteria and necrotic tissue, and provide defense against infection.

   The wound then moves into the proliferative phase, which begins approximately four days after injury and usually lasts three weeks. Growth factors stimulate the mitosis of fibroblasts and other cells (i.e. epithelial). Wound contraction and building of the collagen framework takes place as well as neovascularization and epithelialization.

   The remodeling phase is the last stage of the wound healing process and can take up to two years to complete. This phase involves collagen synthesis and breakdown. The ultimate goal of wound healing is to restore the functional barrior of skin and increase the tensile strength of the scar.

How Collagen Can Speed Wound Healing

Collagen plays an important role in the wound healing process. Originally thought to be the framework of wound healing and the provider of structural support for all other processes to take place, collagen controls many other cellular functions necessary to heal a wound. These functions include cell shape and differentiation as well as migration and synthesis of a number of proteins.4

   Patients with diabetes stall in the first stage of wound healing and cannot lay down collagen. Collagen affects every phase of wound healing. The hyperglycemia caused by decreased insulin availability and increased resistance to insulin can affect the cellular response to tissue injury.5 In diabetes mellitus, insulin is not in adequate supply, energy from carbohydrates cannot enter cells, the body cannot synthesize protein and lipolysis occurs.6

   It is no surprise that wound care companies are focusing a lot of attention on collagen-based wound dressings. Currently, there are numerous types of collagen dressings available. These vary in the type of collagen as well as the concentration of collagen in the dressing. The collagen can come from a variety of sources such as bovine, equine and porcine. Many of the current collagen dressings also contain antimicrobial agents. These dressings are designed to increase fibroblast production. Several of the collagen dressings can also inhibit excess matrix metalloproteinases (MMPs). This is especially important in chronic wounds as the elevated levels of MMPs in these wounds degrade collagen.

Case Study: When A Patient Presents With A Chronic Open Sore Of Eight Months’ Duration On His Left Foot

The photo on page 1 shows a wound in a 46-year-old male patient who presented with a wound infection in the left foot. He had incision and drainage on the dorsal and plantar aspects of his left foot. He did not follow up with his previous physicians and presented eight months later complaining of a non-healing open sore on the bottom of his left foot.

   The patient’s past medical history included poorly controlled diabetes diagnosed at the age of 20, hypertension, dyslipidemia, chronic renal insufficiency, anemia, cataracts and a traumatic right leg disarticulation at the age of 9. He ambulates with a right prosthesis. The patient worked as a full-time janitor and had to walk five blocks to and from work. He adamantly refused any surgery as he could not miss work and was afraid of losing the only leg he had.

   The wound was initially 4.5 x 3.0 cm with a 0.4 cm depth. Over a two-month time period, his treatment consisted of several various regimens, including an offloading wedge shoe, oral antibiotics, sharp debridement, topical enzymatic debriding agents, silver dressings and total contact casting. Despite these efforts, the wound had increased in size to 5.5 x 4.7 cm with a depth of 0.4 cm and signs of infection. Lab values included C-reactive protein of 44 mg/L, an erythrocyte sedimentation rate of 108 mm/hr, a white blood cell count of 7.7 K/μL, mg/dL and HbA1c of 10.1%.

   At this point, magnetic resonance imaging (MRI) revealed fat between the ulcer and the first metatarsal head with intermediate signal intensity on T1 and T2 weighted images. There was abnormal signal intensity on T1 and T2 weighted images in regard to the marrow of the medial sesamoid bone that was compatible with osteomyelitis. There were also an increased T2 signal and a normal T1 signal within the lateral sesamoid and proximal phalanx of the great toe.

Keys To Treatment

I recommended surgical intervention as well as intravenous antibiotic therapy to try to save the limb. The procedure consisted of medial and lateral sesamoid removal, first metatarsal head resection through a dorsal incision, incision and drainage of the plantar ulceration with the use of Versajet (Smith and Nephew), and the subsequent application of the Integra Bilayer Matrix Wound Dressing (Integra LifeSciences).

   Integra is an advanced wound care dressing comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan, and a semi-permeable polysiloxane (silicone layer). The semi-permeable silicone membrane controls water vapor loss, provides a flexible adherent covering for the wound surface and adds increased tear strength to the device. The collagen-glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth.7 I chose this product to provide wound coverage and the structural support needed to complete the wound healing process.

   The patient tolerated the anesthesia and procedures well, and wore a wedge shoe for offloading. At the first postoperative visit, there was healthy granulation tissue through the intact silicone layer of the Integra graft. At three weeks, I removed the staples and silicone layer, and there was a healthy, healing wound bed. Approximately six weeks later, the wound was healed and the patient was able to return to work in protective shoe gear.

In Conclusion

This is just one example of the many collagen products available for use in the treatment of complex diabetic foot ulcerations. It also illustrates the use of surgical as well as advanced wound technology methods to salvage these high-risk limbs. Belatti and colleagues recently published a study showing a marked decline in the use of lower extremity amputations in the Medicare population over the last decade as well as an increase in distal, limb-conserving amputation locations, and a sharp increase in orthopedic/surgical treatments for diabetic foot ulcerations.8 However, one must never neglect the basic fundamentals of wound care including debridement of non-viable tissue, offloading, resolution of infection and adequate perfusion.

   Dr. Zmuda is an Assistant Professor in the Section of Endocrinology in the Department of Orthopedic Surgery at the University of Chicago.

1. Centers for Disease Control. 2011 National Diabetes Fact Sheet. Available at www.cdc.gov/diabetes/pubs/estimates11.htm .
2. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Harris MI, Cowie CC, Stern MP, Boydo EJ, Reiber GE, Bennett PH (eds). Diabetes in America, second edition. U.S. Government Printing Office, Washington, DC, 1995, pp. 409-428.
3. Reiber GE, Ledous WE. Epidemiology of diabetic foot ulcerations and amputations: evidence for prevention. In: Williams R, Herman W, Kinmonth AL, et al (eds). The Evidence for Diabetes Care. John Wiley & Sons, London, 2002, pp. 641-665.
4. Brett D, A review of collagen and collagen-based wound dressings. Wounds. 2008;20(12):347-53.
5. Meyer JS. Diabetes and wound healing. Crit Care Nurs Clin N Am. 1996; 8(2):195-201.
6. Terranova A. The effects of diabetes mellitus on wound healing. Plast Surg Nurs. 1991;11(1):20-25.
7. Integra Life Sciences Corporation. Available at www.ilstraining.com .
8. Belatti DA, Phisitkul P, Declines in lower extremity amputation in the US Medicare population, 2000-2010. Foot Ankle Int. 2013; 34(9):923-931.

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