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Diabetes Watch

An Integrative Approach To Healing Diabetic Foot Wounds

According to the International Diabetes Foundation, diabetes mellitus affects an estimated 425 million adults (ranging between 20 to 79 years of age) worldwide. By 2045, this number will increase to 629 million.1 It is also estimated that one-half of the people (212 million) with diabetes are undiagnosed. Furthermore, diabetes is responsible for at least $727 billion or 12 percent of total United States health care spending on adults in 2017.

As we know, patients with diabetes are at risk of developing various complications, including diabetic foot ulcerations. In fact, approximately 15 percent of patients with diabetes will develop a diabetic foot ulcer (DFU) throughout the course of their lives.1-3 These foot wounds often lead to hospitalization and cause significant morbidity in patients with diabetes including amputation.1,3 About 50 to 70 percent of all lower limb amputations are a result of diabetic foot ulcers.2 Due to these statistics, there has been a considerable effort dedicated to understanding the etiology of DFUs as well as improving and evolving the management and treatment of these wounds.

The etiology of DFUs is certainly multifactorial. There are several risk factors that correlate to the development of a DFU, including increased age of the patient, diabetic peripheral neuropathy, peripheral vascular disease, foot deformity, high plantar pressures, infections, increased HbA1c level, a duration of diabetes longer than 10 years and high body mass index (BMI).1 When an ulceration develops, wound management should begin immediately and with a multifaceted approach.

In many situations while using traditional wound care therapies, including debridement, offloading and standard dressings, the healing course of the DFU can often stall. These stalled ulcerations are suspended in a chronic inflammatory state.2,3 While the inflammatory phase is a vital part of the normal wound healing cycle, this phase can become altered and wound healing can be impeded when there are imbalances with proteases, cytokines and other inflammatory cells and regulators.2,3 Arterial disease, bacterial burden and an impaired immune response are just some examples of conditions present in a diabetic foot that can lead to this imbalance and an arrested wound.2

A Closer Look At Emerging Modalities For Chronic DFUs

There have been several promising and innovative advanced wound treatments aimed specifically at these chronic ulcers. These advanced wound therapies include cellular and or tissue-based products as well as regenerative medicine remedies including stem cells and human placental membrane applications.3,4  

Placental tissue from the harvested amniotic membrane contains two separate layers: the amnion, the innermost layer, and chorion, the outer, thicker layer. Amnion is a thin avascular layer that regulates the amniotic fluid and supports the developing fetus during pregnancy.5,6 It is composed of five unique layers containing a number of different cells, proteins and collagen types.5,6 This layer also contains an elevated concentration of important growth factors, signaling molecules and cytokines that play a critical role in wound healing while controlling the inflammatory response.5,6

A study using an enzyme-linked immunosorbent assay (ELISA) of a dehydrated human amnion/chorionic membrane product showed measurable levels of platelet-derived growth factors AA and BB, transforming growth factors alpha and beta 1, basic fibroblast growth factor, epidermal growth factor and granulocyte colony-stimulating factor.5 Researchers have shown that DFUs treated with amnion heal faster than those treated with standard therapies.7,8

Additional studies highlight several critical factors that may contribute to enhanced wound repair with amniotic-derived tissues including extracellular matrix, cytokines and growth factors, stem cells, and immunomodulation of the wound environment.9,10 These studies add to the overall evidence supporting the use of amniotic-derived tissues in regenerative applications by highlighting the importance of processing techniques and how they influence the quality of wound healing.

There is an array of amniotic tissue products that one can use for the treatment of DFUs. Some products contain just the amnion layer while others contain both amnion and chorion tissue.

The differences between the amniotic products on the market have to do with the processing of the tissue, the type of the tissue and the viability of the tissue.5 At our practice, we typically use amniotic products for those stalled DFUs, including dehydrated allografts such as NuShield® (Organogenesis) as well as fresh amniotic membrane products like Affinity® (Organogenesis).

As mentioned above, increased bacterial burden can play a role in the development of a chronic wound in the diabetic foot. Biofilm is an organized collection of bacteria that adheres to the surface of wounds and is resistant to antibiotic therapy.2,3 In addition to debridement, there is an advanced wound product, PuraPly® Antimicrobial Wound Matrix (Organogenesis), which specifically aims to reduce the amount of biofilm present. We also use this treatment for DFUs if necessary, especially to prep the wound bed for an amniotic tissue graft.

Case Study: How The Use Of Advanced Therapies Facilitated The Healing Of A Large Dorsal Foot Defect

Here we present a case utilizing these integrative advanced wound therapies on a chronic diabetic foot ulcer.

A 65-year-old man with diabetes was admitted to the hospital with a diabetic foot infection and necrotizing fasciitis of the left foot. The patient underwent three left foot surgeries during his admission, which included incision and drainage of the left foot, excisional wound debridements and a partial third ray resection. He ultimately wound up with a large defect to the dorsal aspect of the left foot.

While in the hospital and over the following month, the patient received standard wound treatments including local debridements, VAC therapy (KCI/Acelity) and enzymatic debridement application (Santyl, Smith and Nephew) with each VAC therapy change. The VAC therapy use stopped after one month because of a lack of insurance coverage. Local care then consisted of Dakin’s Solution Quarter Strength daily along with serial sharp debridement. With encouragement, this patient initiated a good diet with improved blood glucose control and gradual weight loss.

Initially, this patient responded well but after three months, he still had a large defect to the dorsum of the left foot. We then initiated advanced wound therapy beginning with PuraPly Antimicrobial Wound Matrix to reduce the biofilm. We performed a total of three applications. After preparing the wound bed with PuraPly, we then used a dehydrated amniotic allograft. In this case, we applied a total of seven treatments of NuShield. The patient responded extremely well.

The patient had complete closure with remodeling at three to four months and returned to his diabetic shoes. After using the amniotic grafts for this patient, we noticed a diminished amount of scarring and improvement in skin turgor over the previous wound area.

In Summary

This case study involved an integrated approach to heal the stalled diabetic foot wound. In this case, we applied PuraPly to reduce the amount of biofilm present and employed subsequent serial NuShield applications of dehydrated placental allograft. We have consistently found this approach to be extremely effective in reinitiating and accelerating healing of the chronic DFU.

Dr. Tursi is in private practice at Foot and Ankle Specialists of South Jersey. He is the Chief of Foot and Ankle Surgery at Our Lady of Lourdes Medical Center in Camden, N.J. Dr. Tursi is the Podiatric and Wound Care Chairman for the annual New Cardiovascular Horizons conference, and the Chairman of the American Professional Wound Care Association.

Dr. Donnelly is in private practice at Foot and Ankle Specialists of South Jersey, and is on the attending staff at Our Lady of Lourdes Medical Center in Camden, N.J. Dr. Donnelly is an Assistant Clinical Professor at the University of Pennsylvania and the Podiatric Residency Program Director at the Presbyterian Hospital/University of Pennsylvania, New Jersey Division.

Dr. Seiler is in private practice at Foot and Ankle Specialists of South Jersey. She is board-certified by the American Board of Foot and Ankle Surgery. Dr. Seiler is on staff at Virtua Vorhees Hospital in Vorhees, N.J., and Our Lady of Lourdes Medical Center in Camden, N.J.

References
1.     Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53
2.     Nube V, Frank G, White J, Stubbs S, et al. Hard-to-heal diabetes-related foot ulcers: current challenges and future prospects. Chronic Wound Care Manage Res. 2016;3:133-146.
3.     Andrews KL, Houdek MT, Kiemele LJ. Wound Management of chronic diabetic foot ulcers; from the basics to regenerative medicine. Prosthet Orthot Int. 2015;39(1):29-39.
4.     Luck J, Rod T, Geierlehner A, Mosahebi A. Allogeneic skin substitutes versus human placental membrane products in the management of diabetic foot ulcers: A narrative comparative evaluation of the literature. Int J Low Extrem Wounds. 2019; epub Jan. 20. Available at https://doi.org/10.1177/1534734618818301 .
5.     McKenna B, Summers NJ. Amnion the ideal scaffold for treating full-thickness wounds of the lower extremity. Clin Podiatr Med Surg. 2018;35(1):1-9.
6.     Kogan S, Sood A, Granick MS. Amniotic membrane adjuncts and clinical applications in wound healing: A review of the literature. Wounds. 2018;30(6):168.
7.     Paggiaro AO, Fernandez De Carvalho V, Gemperli R et al. Biological effects of amniotic membrane on diabetic foot wounds: a systematic review. J Wound Care. 2018;27(Sup2):S19-S25.
8.     DiDomenico L, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic didactic foot ulcers: A prospective, randomized, multi-center clinical trial in 80 patients. Int Wound J. 2018;15:950-957.
9.     Litwiniuk M, Grzela T. Amniotic membrane: new concepts for an old dressing. Wound Repair Regen. 2014;22(4):451–456.  
10.     Silini A, Parolini O, Huppertz B, Lang I. Soluble factors of amnion-derived cells in treatment of inflammatory and fibrotic pathologies. Curr Stem Cell Res Ther. 2013;8(1):6–14.

Diabetes Watch
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By Frank J. Tursi, DPM, FACFAS, MAPWCA, Joseph V. Donnelly, DPM, FACFAS, and Danielle R. Seiler, DPM, FACFAS
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