It is well known that diabetic foot ulcers contribute to extensive morbidity and mortality in patients with diabetes.1 Advanced biological and topical drug treatments have been introduced over the last two decades in an attempt to expedite wound closure, thereby reducing the risk of infection, amputation and other complications. These products include topical growth factors (Regranex®, Systagenix) as well as bioengineered living cell products, with the most frequently applied being Apligraf® (Organogenesis) and Dermagraft® (Advanced Biohealing).
The success of advanced modalities is limited by a number of factors including but not limited to cost/reimbursement, offloading, wound debridement, the level of inflammatory cells and infection. Difficulties in successfully addressing all factors contributing to ulcer chronicity reduce both the efficacy and willingness of the clinician to apply advanced modalities to the majority of their patients. With appropriate offloading and a good standardized approach to wound care, many patients with diabetes will heal successfully. However, this does not mean that one should not consider biological materials and drugs in non-responders or patients who are more difficult to heal.
Patients with underlying bone deformities resulting in repetitive pressure, tissue damage and ulceration are subject to a high probability of recurrence after complete wound closure. Even if it were possible for the tissue to re-establish normal tensile strength, the risk of recurrence will not be significantly reduced if one does not address the underlying cause. Removal or remodeling of underlying bone through surgery may be the only remaining option to reduce the risk of recurrence, provided that the patient has adequate blood flow to undergo surgery and does not have other medical or personal contraindications.
Despite surgery, patients with diabetes may be slow to heal due to underlying deficiencies in tissue repair as well as metabolic considerations, including decreased fibroblast and macrophage activity, and decreased levels of glycosylated hemoglobin.2 New adjunctive treatments for a wound still present at the time of surgery include the use of bone marrow aspirate (BMA) derived stem cells in conjunction with a xenograft or allograft (non-human or human acellular tissue).
The more recent literature suggests the use of autologous stem cells derived from bone marrow have the potential to treat many disorders.3-5 This is due to the stem cells’ plasticity and ability to differentiate into various types of tissues, including endothelium, liver, muscle, skin, bone, cartilage, brain, fibroblasts and keratinocytes. The cells are known to assist with the tissue repair process by secreting large amounts of growth factors and cytokines. Badiavas and colleagues attained similar results in three patients, all of whom had complete closure of their ulcers, which had been present for a year or more.6 Patients received bone marrow aspirate and cultured cells within three months although one patient received bioengineered skin.
Yoshikawa and co-workers in 2008 conducted the largest study to date using BMA-derived mesenchymal stem cells with or without autologous grafts.7 The study included 20 patients with non-healing wounds of varying etiology. The authors reported complete healing in 18 patients and showed regeneration of native tissue by histologic examination.
Falanga and colleagues applied up to three applications of autologous, culture-expanded, mesenchymal stem cells with a fibrin glue system to acute and chronic wounds.8 The acute wounds healed within eight weeks and the chronic wounds decreased or healed in 16 to 20 weeks. However, healing times are not significantly better than other treatments that have been presented in the medical literature. While similar work has been reported in the literature, the reports and studies reviewed only a small number of patients, usually retrospectively and in a non-controlled, non-randomized fashion.
However, this data does suggest a potential application of BMA to assist with wound closure. Currently, following institutional review board approval, our institution will initiate an independent, non-company funded, randomized controlled study with ulcers randomized into post-excisional debridement and into BMA or no BMA in conjunction with appropriate xenograft coverage. We hope to better establish the efficacy of combining BMA with other optimal treatments.
The method of collection that our site has been using consists of aspirating the required amount of autologous bone marrow aspirate (approximately 1 cc per 3 cm2 of wound surface area) from the calcaneal bone of patients. One then places the BMA in the wound. Coat the syringe with a thin layer of heparin to prevent coagulation of the aspirate. Then coat the wound with a layer of the BMA.
(There are different methods as well as different industry-based products available when it comes to quantifying and concentrating the BMA. However, it is beyond the scope of this brief review to discuss and include these devices. I encourage readers to research the availability of different devices that assist with concentrating BMA.)
One would then cover the BMA with a collagen-based, decellularized equine pericardial dressing (Unite Biomatrix, Synovis Orthopedic and Woundcare). Staple the dressing to the wound margins to allow for prolonged cell activity and optimization of the wound healing environment. The BMA acts as a biomodulator during this time. Apply outer non-adherent dressings and dress the extremity with appropriate secondary gauze or other dressings. Follow up with standardized procedures, which entail visits at approximately one-week intervals.
Past experience using this approach as part of our advanced care regimen suggests expedited healing. However, any results at this point are anecdotal at best as no study has been conducted to date to evaluate this regimen for diabetic foot ulcers. Institutional review board approval is required for any use of this product in a trial or outside standard use. Currently, one may use autologous products without FDA approval although the patient’s best interests and care must always be the primary considerations.
This brief overview is only intended as a synopsis of another possible approach to the treatment of diabetic foot ulcers. Although autologous bone marrow aspirate has undergone study in wounds and there is interesting evidence to suggest that mesenchymal stem cells can assist in wound healing, there are insufficient, well-designed human studies with adequate numbers of patients to prove and support the validity and efficacy of this approach.
I hope that further studies by clinicians will provide a clear understanding of the benefits, scientific value and mode of action of this newer modality of care. I encourage the clinically based reader of this discussion to further pursue this interesting and promising modality.
Dr. Mulder is the Director of the Wound Treatment and Research Center at the University of California-San Diego (UCSD). Dr. Mulder is also a Professor of Surgery and Orthopedics in the Division of Trauma, Department of Surgery at UCSD.
1. Moulik PK, Mtonga R, Gill CV. Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology. Diabetes Care. 2003; 26(2):491-4.
2. Stadelmann WK, Digenis A, Tobin G. Impediments to wound healing. Am J Surg. 1998; 176(2A Suppl):39S-47S.
3. Bianco P, Mankani MH, Gronthos S, et al. Circulating skeletal stem cells; nature biology and potential applications. Stem Cells. 2001; 19:180-192.
4. Borue X, Lee S, Grove J, et al. Bone marrow-derived cells contribute to epithelial engraftment during wound healing. Am J Pathology. 2004; 165(5):1767-72.
5. Deng W, Han Q, Liao L, et al. Engrafted bone marrow-derived flk-(1b) mesenchymal stem cells regenerate skin tissue. Tissue Eng. 2005; 11(1-2):110-19.
6. Badiavas EV, Falanga V. Treatment of chronic wounds with bone-marrow derived cells. Arch Dermatol. 2003; 139(4):510-516.
7. Yoshikawa T, Mitsuno H, Nonaka I, et al. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg. 2008; 121(3):860-77.
8. Falanga V Iwamoto S, Chartier M, et al. Autologous bone marrow-derived cultured mesenchymal stemm cells delivered in a fibrin spray accelerate healing in murine and cutaneous wounds. Tissue Eng. 2007; 13(6):1299-1312.
For a related PodiatryLIVE™ video, see “Case Study: Combining The Unite Biomatrix Xenograft With Living Cell Materials” at www.podiatrylive.com/Unite_Biomatrix_Living_Cell  .