Assessing The Evolution Of Advanced Products For Diabetic Foot Ulcers

Over the last 20 years, the treatment of diabetic foot ulcers has advanced beyond our greatest expectations. The amount of technology that has been dedicated to closing ulcers and saving feet and legs is staggering. Every few years, we have a major breakthrough that advances the field of limb salvage.  

In my time, we have learned about the importance of offloading of neuropathic ulcerations. Total contact casts were inconvenient but became the gold standard of treatment because they offered the best protection and produced outstanding results that were obvious to both doctor and patient.

Growth factors ushered in the age of advanced biologics. Initially, we sourced them from our patients’ concentrated blood but eventually, you could write a prescription for recombinant platelet-derived growth factors (PDGF) and suddenly exogenous growth factors were available. Doctors could see the progression of angiogenesis and difficult wounds were closing.

Negative pressure wound therapy (NPWT) provided a way for us to close our most difficult wounds. Even though there were wounds with deep fascia, joints, tendons and bone exposed, the NPWT devices provided a straightforward mechanism for us to manage these difficult wounds. Within a short period of time, we prepared the wound bed and readied it for skin grafting. In other cases, the wound went on to close on its own.

Decellularized collagen provided another critical building block for the treatment of diabetic foot ulcers. Collagen was the “yin” that was intertwined with the growth factor “yang.” Growth factors stimulated angiogenesis, mitogenesis and chemotaxis while decellularized collagen was useful for stabilizing granulation tissue found in the well-perfused wound. Decellularized collagen acted as a scaffold for migration and attachment for all of those newly arriving cells. Collagen also provided the essential building block necessary to guide a wound toward closure.

Wound debridement has also played a critical role in coaxing a wound to heal. Debridement rids the wound of necrotic and otherwise unhealthy tissue. It breaks up biofilms and causes wounds to bleed, which in turn results in coagulation, delivery of platelets and ultimately degranulation and the release of growth factors. Although one has to weigh the benefits of debridement against the inevitable disruption of the newly formed neodermal structures, most would agree that regular debridement is an important part of any treatment plan.

Sheehan and colleagues taught us that we needed to be vigilant in our treatment plan.¹ When wounds failed to progress, a new plan was essential. The authors reminded us that when a wound becomes stagnant, physicians have to reassess all aspects of that patient. Their work set the benchmark and a call to arms. They taught us that most properly managed wounds should show a steady advancement toward closure and when that does not occur, one must re-examine the wound to determine why. Oftentimes, it was unclear why a wound was not closing so the solution was to consider the use of new, better and commonly more complex treatment tools.

Reconciling The Use Of Advanced Therapies With The Advent Of ACOs
Although split thickness skin grafts offer the most comprehensive and complete treatment option — the patient’s own living cells and mature collagen — use of the grafts is often not feasible due to a variety of barriers including appropriate harvest sites, multiple trips to the operating room and donor site issues.

As an alternative, bioengineers brought us biologic skin substitutes and a new opportunity to introduce living cells to the wound bed. Although allograft living cells cannot survive for long in the hostile wound environment, there is a real benefit to their use as part of the treatment regimen. These living cells produce growth factors, cytokines and collagen, which help the wound to heal. The availability of cryopreserved, living, donated skin moves us even closer to the split thickness skin graft option by providing even more living cells and collagen for our most difficult wounds.

The literature supporting the use of bioengineered skin substitutes and cryopreserved donated human living skin is immense. The use of mesenchymal stem cells is also just around the corner. Our understanding of the impact of biofilms and circulatory issues has grown as well. We are now at the point where we can easily pick off the “low hanging fruit.” Most podiatric physicians can make minor adjustments in offloading, perform debridement or utilize wet-to-dry dressings to easily manage and close wounds. The more difficult wounds (inevitably associated with the least adherent patients) are really where the challenges lie.

Accountable care organizations (ACOs) are clearly the wave of the future and the outcomes we achieve per dollar spent will ultimately determine what treatments we provide. In the case of the advanced biologics podiatrists use for the treatment of the diabetic foot ulcer, the amount of bang you get for your buck matters. More collagen, more living cells and more growth factors will ultimately lead to a better chance of healing.

Take, for example, the two biologic skin substitutes, Apligraf (Organogenesis) and Dermagraft (Organogenesis). Both contain living cells but Apligraf contains significantly more living cells as well as fibroblasts and keratinocytes. Dermagraft only has fibroblasts. Apligraf has a lot of type 1 collagen, due to its bovine collagen matrix, while Dermagraft has relatively little collagen.

Recently, Organogenesis, the manufacturer of Apligraf, acquired Dermagraft. It appears that wound specialists won out. More cells and more collagen are better. I predict that this will further highlight the benefits of the cryopreserved human living skin allografts, such as TheraSkin (Soluble Systems). TheraSkin contains even more viable human cells (fibroblasts and keratinocytes), more growth factors and even more collagen, including type 1 and type 3. TheraSkin is also robust enough to use over exposed tendon and even bone. As we strive to get difficult wounds to close, we want to use the products that provide as much biologic material as possible at a reasonable price and I believe we are down to Apligraf and TheraSkin as our advanced therapy options.

In Conclusion
As we move forward with the ACO model of reimbursement, there are a lot of looming dangers. The new era of medicine factors in cost at every step. New technologies that do not actually offer something new are going to be hard to support. When we pick a biologic, it should be the one that offers the most bang for our patient’s buck. Products like TheraSkin provide the most comprehensive array of biologic materials. Essentially, it contains everything natural skin contains because it is living human skin.

So science marches on and we have these fantastic new but expensive tools at our disposal. Amputation is no longer the initial treatment option and we spend a lot of time and energy to get those wounds closed and keep them that way. Here is where reality sets in, where we come to the understanding that in some cases, we should not save the limb “at any cost.” In fact, our new health plans clearly dictate that cost can limit the effort that we may put into saving a limb.

Ultimately, I anticipate that a lot of the more expensive therapies will fall by the wayside as more comprehensive and complete products become more widely available. A new wave of placental collagen products is now available at six times the cost of existing collagen materials. Is there really a place for these in today’s healthcare reimbursement climate? Instead, I anticipate that we will place a premium on those products that are durable, versatile, readily available and have a proven record of success.

Dr. Landsman is an Assistant Professor of Surgery at Harvard Medical School. He is the Chief of the Division of Podiatric Surgery at Cambridge Health Alliance. Dr. Landsman is a Fellow of the American College of Foot and Ankle Surgeons.

Dr. Landsman has disclosed that he is on the Scientific Advisory Board of Soluble Systems.

Reference

1. Sheehan P, Jones P, Giurini JM, et al. Percent change in wound area of diabetic foot ulcers over a four-week period is a robust predictor of complete healing in a 12-week prospective trial. Plast Reconstr Surg. 2006; 117(7 Suppl):239S-244S.

For further reading, see “Exploring The Potential Of Advanced Wound Care Products For Diabetic Wounds” in the December 2013 issue of Podiatry Today or “A Closer Look At The Role Of Collagen In Healing Complex Diabetic Foot Ulcerations” in the November 2013 issue. To access the archives, visit www.podiatrytoday.com.