Citing the availability, growth factor content and reduced risks in high-risk patients, this author says bioengineered alternative tissues are his first-line treatment for advanced wounds.
Diabetic foot ulcers (DFU) are a marker of diabetes severity. Patients with diabetic foot ulcers have mobility difficulties and perceive their disability similar to a person with a below-knee amputation.1 Additionally, the mortality rate of these patients is in the 40 to 50 percent range for five-year survival.2 While foot ulcers are the most common diabetes pathology leading to hospital admission, the patients’ cardiovascular problems are what ultimately take their lives.
My own research experience on ulcerations and mortality in patients with Charcot arthropathy helped me understand that these mortality numbers are accurate.3,4
Margolis, Sheehan and Snyder helped us recognize the one-month marker in diabetic foot ulcer healing.5-7 Patients who have healed more than 50 percent continue their current therapy while those who have healed less than 50 percent may benefit from an advanced therapy. Lavery and Armstrong helped us understand the physical risk associated with an open ulceration.8 The patient with an open ulcer has a 2,000 times greater risk of infection versus the patient without a wound. Additionally, a foot wound present for greater than 30 days has a significant risk of becoming infected.
We must manage our patients in a way to speed ulcer closure and in a manner that provides the lowest cardiovascular risk.
Emphasizing The Importance Of Basic Wound Care
Our ulcerated patients must have a thorough workup. This will ensure adequate vasculature, adequate tissue nutrition, treatment of any infected tissues, possible biopsy of soft tissue/bone and appropriate wound protection and/or offloading of the ulceration.
Total contact casts and cast boots are the most effective offloading tools available but not all patients are safe wearing such devices. Adherence rates with removable devices are slightly over 25 percent.9 Gait assistive devices may help patients with their mobility and help them “feel the ground” by giving them an additional point of reference and stability. Wheelchairs and rolling leg walkers may be invaluable for some patients to utilize for extra protection.
A family member or caregiver is crucial for helping the patient remain on course for wound healing. Frequently, patients think of their residence as a “safe zone” where they do not need to wear or utilize their offloading device. Caregivers can provide ongoing reminders to the patient as well as feedback to the physician and staff on adherence. Patients who fail to become participants in offloading their wounds are probably not candidates for advanced or alternative tissue therapies.
Why BATs Are Effective For Diabetic Foot Ulcers
I feel that bioengineered alternative tissues (BATs) are a valuable treatment for our ulcerated wounds that fail to heal 50 percent in the first four weeks when we treat them as outlined above. These products have several benefits when one considers how sick this patient population is. The alternative tissues are readily available and one can apply them in a clinical situation. They rarely require a trip to the operating room for application and anesthetic need is infrequent because of the patient’s polyneuropathy. Without anesthetic, the cardiovascular risk to this sick patient population is minimal. Additionally, there is no donor site that requires postoperative care. Health risk reduction is my main reason for BATs being my first line of advanced therapy for these patients.
Cost also factors into this as a single surgical experience may cost well over $4,000 for a split-thickness graft. Depending on the type and size of the BAT applied, one could perform three to five BAT applications for the same cost. No one has done a cost analysis to compare these types of treatments head-to-head nor has there been a randomized trial comparing BATs with split thickness skin grafting (STSG). Authors have pointed out that skin grafting can be an effective therapy and that donor site morbidity is not significant.10 However, due to the cardiovascular risk associated with any surgical procedure, skin graft therapies may be better to reserve for the patient who fails to improve with the use of BAT therapy.
That said, there is a point in wound size that may make STSG application more economical. One needs to weigh the cost versus patient cardiovascular risk with larger wounds as the cost of clinical application of a more expensive BAT may not be covered under current payer rules in the ambulatory clinical setting. My clinical intuition is that 80 to 90 percent of the wounds we treat are small enough to be covered by BATs that will be reimbursed using 2015 guidelines for clinical care (depending on the product applied to the ulceration).
Significant data exists on the growth factor content of BATs and there seems to be reasonable equality of growth factors graft to graft (when evaluating the same product).11 I am uncertain that this is true with skin grafts and I could not find research evidence of this. Intuitively, I am concerned that we are harvesting graft tissue from an individual who has not been able to heal his own wound, creating a new donor site and expecting that the tissue that we harvest will stimulate and heal their diabetic foot ulceration. I feel that the high content of growth factors in the bioengineered tissues may be a more consistent treatment for these difficult wounds. Bioengineered alternative tissues will not heal all wounds. There are clinical study reports with healing rates of greater than 90 percent.12 Anecdotally, I believe the real-life healing rate with BATs is closer to 80 percent.
The evolution of BATs is still in its infancy. We don’t know if living cells survive or become a part of the new tissue, or if their presence is necessary rather than simply supplying growth factors alone to the wound.11 I look forward to seeing the results of more head-to-head research of the BATs as well as BAT versus STSG tissues so we can further improve the quality care for our patients as we move forward.
Am I against anesthesia and surgical care for our patients with diabetic ulcers? Absolutely not. Too many of our patients require bone biopsy, muscle balancing and other reconstructions to better solve their ulcer problem and limit their risk of relapse. Ulcer remission is our goal and ensuring long-term care to limit the risk of recurrence is our duty. However, we need to look realistically at how sick this patient population is and to limit anesthetic exposure when we can by using BAT therapy as our first advanced therapy when indicated.
Dr. Stuck is a Professor and Division Director for the Section of Podiatry Department of Orthopaedic Surgery and Rehabilitation at Loyola University Stritch School of Medicine in Maywood, Ill.
1. Willrich A, Pinzur M, McNeil M, Juknelis D, Lavery L. Health related quality of life cognitive function, and depression in diabetic patients with foot ulcer or amputation. A preliminary study. Foot Ankle Int. 2005;26(2):128-34
2. Iverson MM, Tell GS, Riise T, et al. History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trondelag Health Study. Diabetes Care. 2009;32(12):2193-2199.
3. Sohn MW, Budiman-Mak E, Stuck RM, Siddiqui F, Lee TA. Diagnostic accuracy of existing methods for identifying diabetic foot ulcers from inpatient and outpatient datasets. J Foot Ankle Res. 2010 Nov 24;3:27.
4. Sohn MW, Lee TA, Stuck RM, Frykberg RG, Budiman-Mak E. Mortality risk of Charcot arthropathy compared with that of diabetic foot ulcer and diabetes alone. Diabetes Care. 2009;32(5):816-21.
5. Margolis DJ, Allen-Taylor L, Hoffstad O, et al. Diabetic neuropathic foot ulcers; the association of wound size, wound duration, and wound grade on healing. Diabetes Care. 2002;25(10):1835-9.
6. Sheehan P, Jones P, Caselli A, et al. 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. Diabetes Care. 2003;26(6):1879-1882
7. Synder R, Cardinal M, Dauphinee D, et al. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage. 2010:56(3):44-50.
8. Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: a randomized controlled trial. Diabetes Care. 2005;28(3):551-4.
9. Donegan RJ, Schmidt BM, Blume PA. An overview of factors maximizing successful split-thickness grafting in diabetic wounds. Diabet Foot Ankle. 2014; 5(10):3402.
10. Buchberger B, Follmann M, Freyer D, et al. The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers. GMS Health Technol Assess. 2010; 6:Doc12.
11. Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29(6):1288-1293.
12. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014 Apr;11(2):122-8.
With no risk of rejection or interference with host immunity, split thickness skin grafts can facilitate rapid wound healing for acute and chronic diabetic foot ulcerations.
Healing diabetic foot ulcerations involves a multifactorial process. It should always include infection eradication, offloading, adequate vascularity and increased patient adherence. Some newer and advanced technologies have helped the practitioner achieve wound closure. A greater understanding of two of these methods, bioengineered alternative tissues (BATs) and split thickness skin grafting (STSG), will aid the physician in closure of diabetic foot ulcerations.
Split thickness skin grafts differ from BATs in that a STSG is an autograft and in most cases is readily available from the patient with a delayed healing or non-healing wound. Since they are autografts, STSGs do not interfere with host immunity and there is no risk of rejection. Bioengineered alternative tissues derive from a variety of sources. As a result, patients may not tolerate BATs and physicians need to consider this possibility when assessing treatment options for diabetic foot ulcerations.
For both acute and chronic diabetic foot ulcerations, STSG offer a rapid and effective way to provide closure and healing. Understanding that optimization of the wound bed (including tissue management, infection and inflammation control, and various types of debridement) and adjunctively using BAT to aid in facilitating appropriate granulation tissue can lead to a successful outcome.
Ideal conditions for successful STSG include red granulation tissue dominating the wound bed, no visible tendon or bone, no discernible sloughing or exudate in wound, no residual necrotic tissue, no local signs of soft-tissue infection, no systemic signs of infection, and no severe peripheral arterial disease (ankle-brachial index < 0.9 or distal pulses present).1
Ramanujam and colleagues showed that patients with diabetes without comorbidities had no significant difference in healing times in comparison to non-diabetic patients when it came to the use of STSG.2 However, the study authors found a significant difference for STSG in patients with diabetic comorbidities. Overall, the healing time is 1.99 weeks longer for patients with diabetic comorbidities than for those without diabetes. In comparison to patients without diabetes mellitus, patients with diabetic comorbidities experience a 5.15 times higher risk of postoperative complications after the use of STSG. These complications include wound dehiscence, infection and the need for revisional surgery. Patients with diabetic comorbidities are at a significantly higher risk for delayed healing from STSG in comparison to patients with diabetes without comorbidities and non-diabetic patients.
Again, optimization of each of the patient’s comorbidities and achieving an ideal wound bed for the STSG will maximize a successful outcome for those with diabetic foot ulcerations.
Can We Combine STSG With BAT?
Rather than viewing BATs as the alternative to STSG, we should view them as an adjunctive therapy and not as a monotherapy. One can utilize BATs to prepare and optimize the wound bed prior to STSG placement. In general, BATs are products deriving from human, animal and synthetic tissues that have been manufactured, cleaned or otherwise altered.
We can categorize BATs as dermoinductive or dermoconductive. Dermoinductive products deliver viable cells, including fibroblasts and keratinocytes, to the non-healing wound site with the goal of activating senescent cells in the chronic diabetic wound by releasing cytokines and growth factors the grafted cells produce. One should reserve dermoinductive products for more superficial wounds. This includes products such as Apligraf (Organogenesis) and Dermagraft (Organogenesis), which have both demonstrated clinical efficacy.3-5
In contrast, dermoconductive products provide an organized scaffold to facilitate cell migration of fibroblasts and serve as a template for the formation of neodermis, which is histologically similar in appearance and structure to normal dermis. This provides a durable dermal layer necessary for granulation tissue formation, allowing one to place a skin graft over the neodermis for definitive wound closure. Examples of this type of tissue include Integra Bilayer Wound Matrix (Integra LifeSciences) and hMatrix (Bacterin International).
Thorough debridement must occur before application of dermoconductive products to remove biofilm and necrotic tissue. Reserve this category of products for deeper wounds with exposed fascia, tendon or bone.6 As with STSG, BATs are subject to similar complications. These include seroma/hematoma formation secondary to shearing forces, leading to the disruption of the artificial dermis. Therefore, when it comes to deeper wounds, utilizing BATs with subsequent STSG can lead to a successful outcome.
In fact, the Integra Bilayer Matrix Wound Dressing demonstrates this principle well. Shores and coworkers placed this modality directly over exposed tendons with a subsequent STSG several weeks later in 42 patients.7 Physicians applied STSG after the generation of highly vascularized neodermis, which occurred on average 35.3 days after the initial placement of Integra. The size of the tissue defect including the area of tendon exposure ranged from 4 cm2 to 336 cm2 with an average of 65.1 cm2. The average STSG thickness was 0.011 inches. There was 92.5 percent take in all skin grafts with all patients exhibiting durable skin coverage at the end of their follow-up period.
Maximizing Graft Survival
Graft survival is predicated on several factors. Historically, graft failure rates were high and primarily attributed to infection.8 This highlights the importance of biofilm management and eradication as well preventing shearing, seroma and hematoma formation beneath the graft with immobilization. This allows for the initial take or incorporation, which occurs by diffusion of nutrition from the recipient site. This is called “plasmatic imbibition.” One must place STSGs on a well-vascularized wound bed with low bacterial counts to prevent infection.
Revascularization generally occurs between days three and five by reconnection of blood vessels in the graft to recipient site vessels or by ingrowth of vessels from the recipient site into the graft.9 Skin grafts generally will not take on poorly vascularized wound beds, such as bare tendons, cortical bone without periosteum, heavily irradiated areas or infected wounds.
However, virtually any tissue type with a vascular granulating bed is acceptable for grafting.2 Negative pressure wound therapy can bolster STSG success.9 This occurs by promoting granulation tissue, lowering bacterial counts and removing accumulated fluid, such as hematoma/seroma, both of which reduce the chronic inflammatory processes, such as elevated matrix metalloproteinases, that occur in chronic wounds.
Due to their readily available nature and minimal contraindications, STSGs should be a consideration for the healing of difficult to heal diabetic foot ulcerations.
Dr. Schmidt is affiliated with the Section of Podiatric Surgery in the Department of Orthopedics and Rehabilitation at Yale New Haven Hospital in New Haven, CT.
Dr. Blume is an Assistant Clinical Professor of Surgery in the Department of Surgery and an Assistant Clinical Professor of Orthopaedics and Rehabilitation in the Department of Orthopaedics, Section of Podiatric Surgery at the Yale University School of Medicine in New Haven, Ct. Dr. Blume is a Fellow of the American College of Foot and Ankle Surgeons.
1. Aerden D, Bosmans I, Vanmierlo B, Spinnael J, Keymeule B, Van den Brande P. Skin grafting the contaminated wound bed: reassessing the role of the preoperative swab. J Wound Care. 2013; 22(2):85-9.
2. Ramanujam CL, Han D, Fowler S, Kilpadi K, Zgonis T. Impact of diabetes and comorbidities on split-thickness skin grafts for foot wounds. J Am Podiatr Med Assoc. 2013; 103(3):223-32.
3. Donegan R, Schmidt BM, Blume PA. An overview of factors maximizing successful split-thickness skin grafting in diabetic wounds. Diabetic Foot and Ankle. 2014; epub Oct. 24.
4. Marston WA, Hanft J, Norwood P. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003; 26(6):1701-5.
5. Iorio ML, Goldstein J, Adams M. Functional limb salvage in the diabetic patient: the use of a collagen bilayer matrix and risk factors for amputation. Plast Reconstr Surg. 2011; 127(1):260-7.
6. Attinger CE, Ducic I, Hess CL, Basil A, Abbruzzesse M, Cooper P. Outcome of skin graft versus flap surgery in the salvage of the exposed Achilles tendon in diabetics versus nondiabetics. Plast Reconstr Surg. 2006; 117(7):2460-7.
7. Shores JT, Hiersche M, Gabriel A, Gupta S. Tendon coverage using an artificial skin substitute. J Plast Reconstr Aesthetic Surg. 2012; 65(11):1544-50.
8. Blume PA, Key JJ, Thakor P, Thakor S, Sumpio B. Retrospective evaluation of clinical outcomes in subjects with split-thickness skin graft: comparing V.A.C. therapy and conventional therapy in foot and ankle reconstructive surgeries. Int Wound J. 2010; 7(6):480-7.
9. Scherer LA, Shiver S, Chang M, Meredith W, Owings JT. The vacuum assisted closure device: a method of securing skin grafts and improving graft survival. Arch Surg. 2002; 137(8):930-3.