A Guide To Emerging Advances In Diabetic Foot Ulcer Healing
Over the past decade, the podiatric profession has seen an array of advances in diabetic foot ulcer healing. These advances ranged from the advent of a platelet-derived growth factor (Regranex, Johnson and Johnson) and negative pressure wound therapy (VAC therapy, KCI) to hydroscalpel debridement (Versajet, Smith and Nephew) and various prediction models (University of Texas Diabetic Foot Ulcer and Foot Risk Classifications).
Fortunately, there are even more modalities on the horizon that I believe will make an impact in the manner we treat these difficult problems. For the purpose of classification, I have divided these modalities into three simple categories: vascular, infection and pressure. Lawrence Harkless, DPM, taught me and many others that the first issues to address with any new diabetic foot wound are the “VIPs.” It is an easy acronym to remember for vascular, infection and pressure, and represents the wound’s macroenvironment. Most diabetic foot ulcers will heal in a timely fashion when we mitigate these three areas.
Key Diagnostic Tools For Assessing Microvascular Disease
While clinicians use the ankle-brachial index, segmental pressures and angiography to help diagnose macrovascular peripheral arterial disease (PAD), two new tools have emerged to aid in the diagnosis of microvascular disease. They are the SensiLase System (Vasamed) and the OxyVu® (HyperMed).
SensiLase measures skin perfusion pressure (SPP), which is the blood pressure at the capillary level in the skin. Normal SPP is greater than 50 mmHg. SPP measurement from 30 to 50 mmHg is diagnostic for PAD or microvascular disease and a reading of less than 30 mmHg denotes severe vasculopathy. Obtaining SPP can help predict diabetic wound healing. If SPP is greater than 40 mmHg, there is a high probability for wound healing. If it is 30 mmHg, there is only an 85 percent chance of healing. If it is 25 mmHg, the probability of healing drops to nearly 50 percent.1
The OxyVu uses hyperspectral imaging that was developed by the military to detect targets underneath forest canopies from sensors on aircraft above. The OxyVu is a camera that detects the wavelength of light emitted by oxyhemoglobin and deoxyhemoglobin in the skin. The computer interprets the readings and gives the values of these two molecules superimposed on a colorful photo of the foot. One study, which validated this device’s ability to predict healing in the foot wounds of patients with type 1 diabetes, found that an oxyhemoglobin level greater than 45 was a sensitive predictor of wound healing.2
What About Gene Therapy And Stem Cell Transplants?
In regard to the treatment of PAD, gene transfer therapy and stem cell transplantation are undergoing human trials. These may provide treatment options for patients who are not candidates for surgical revascularization or endovascular procedures.
Gene transfer therapy is promising as it may induce angiogenesis and inhibit restenosis, thereby restoring blood flow to ischemic tissue.3 One clinical trial is evaluating gene transfer via the injection of a plasmid DNA containing hepatocyte growth factor into the limbs of patients with non-reconstructable critical limb ischemia (CLI).4 Hepatocyte growth factor is an angiogenic growth factor secreted by vascular endothelial cells.5 Similarly, vascular endothelial growth factor (VEGF) is promising as a transfer gene for CLI.6
A recent search on www.clinicaltrials.gov revealed three trials that are actively recruiting patients with CLI or intermittent claudication for gene transfer therapy.
Researchers have shown that marrow-derived stem cells are effective in restoring contractility and perfusion after acute myocardial infarction.7 A randomized controlled study has assessed the injection of bone marrow mononuclear cells into the gastrocnemius muscle of ischemic limbs.8 The authors found improvements in transcutaneous oxygen measurements, pain-free walking times and rest pain in the treatment group.
In one open-labeled Phase I study currently enrolling patients at Heinrich-Heine University in Dusseldorf, Germany, investigators plan to inject bone marrow-derived stem cells intramuscularly and intra-arterially in those with CLI. They will measure ABI, walking distance, capillary oxygen saturation and venous plethysmography as outcomes.
RT-PCR: Is It Faster Than Waiting For Culture Results?
Of the events that can lead to a diabetic foot amputation, infection is probably the most rapid and life threatening factor. Therefore, it is imperative to recognize infection and begin effective treatment quickly. The diagnosis of foot infection in those with diabetes is a clinical one. Signs and symptoms include erythema, edema, purulence and odor. These signs and symptoms are sometimes accompanied by constitutional signs like fever, leukocytosis and a loss of glucose control. A culture is not necessary to diagnose a diabetic foot infection but clinicians should obtain it when an infection is clinically evident so they can narrow the antibiotic spectrum. Culture and sensitivity results generally take three to five days.
One can obtain a more rapid result with real-time polymerase chain reaction (RT-PCR). Clinicians can perform RT-PCR rapidly within an hour to a few hours. This modality enables physicians to identify pathogenic bacteria and characterize resistance. This in turn allows one to choose the appropriate antibiotic at the time of service or hospitalization. One report, highlighting the use of RT-PCR in a culture negative osteomyelitis, found that the method was able to differentiate S. aureus from S. epidermidis.9
Does Bacteriophage Therapy Have A Role In Managing Diabetic Foot Infections?
While there is no work currently being performed on diabetic foot infections and bacteriophage therapy, it deserves some consideration. Bacteriophages are viruses that infect bacteria and either destroy them or weaken them, allowing host defenses to destroy them.10 In essence, one is giving a bacterium a cold.
Phage therapy itself is not a new concept but the potential application to skin and skin structure infections is new. Phage therapy could emerge as an important advance against multi-drug resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA). In a bovine model, anti-Staphylococcus bacteriophage K facilitated an impressive reduction in MRSA strains and resulted in strong anti-staphylococcal activity.11
Granulocyte-colony stimulating factor (G-CSF) induces the release of neutrophils from the bone marrow and improves their function.12 As an adjunctive therapy to antibiotics, G-CSF can enhance the immune response. A meta-analysis of five randomized trials including 167 patients showed that adjunctive G-CSF therapy did not speed the clinical resolution of diabetic foot infections but it was associated with a reduced rate of amputation and subsequent surgical procedures.13 What is most impressive was the number needed to treat (NNT) ratio to gain these benefits was low, suggesting that using G-CSF in certain cases to prevent amputation in severe infections is beneficial and efficacious.
Rethinking Offloading For The Diabetic Foot
Pressure reduction is a key and often underemphasized component of diabetic foot ulcer treatment. Clearly, in most diabetic foot ulcers, it is the pressure of repetitive stress combined with sensory neuropathy that precipitates the foot ulcer. Researchers have tested various modalities for offloading the plantar foot and the total contact cast (TCC) still remains the gold standard.14
In a pilot study, researchers showed that the instant total contact cast (iTCC), which consists of a removable cast walker (RCW) rendered irremovable by wrapping it with cohesive bandage or fiberglass, was more effective than the RCW alone.15 In podiatry’s first National Institutes of Health R01 grant, Lavery and Armstrong will compare the TCC to the iTCC in the treatment of plantar diabetic foot wounds.
Additionally, tissue volumizing agents are under investigation to offload the plantar diabetic foot.16 Medical grade silicone has been injected safely deep to plantar prominences in diabetic feet.17 Wu and colleagues are investigating the use of poly-L-lactic acid (PLLA), which is an absorbable tissue volumizer. They are evaluating the pressure dispersal by F-Scan and the thickness of the plantar soft-tissue by weightbearing ultrasound.
Preventive Devices: Can They Have An Impact?
This column would be incomplete without a brief mention on the future of diabetic foot ulcer prevention.
Handheld, patient administered dermal thermometers are very promising in preventing diabetic foot ulcers. In most cases, a temperature spike can predict a diabetic foot ulcer days in advance. Coupled with proper education, the use of dermal thermometers as monitoring devices reduces the rate of diabetic foot ulcers.18 Up to this point, treatment for a “temperature spike” has consisted of rest and modification of footwear. Researchers have also proposed cooling the diabetic foot as a method of reducing preulcerative inflammation.19 Perhaps the combination of a dermal thermometer and a self-contained ice water splint will be valuable tools to reduce this complication.
Additionally, smart fabrics will play a role in the prevention and warning of diabetic foot complications. Zephyr Technologies (New Zealand) is currently testing its ShoePod Diabetic, a computerized shoe insert that takes periodic measurements of foot temperature in different zones and alerts the patient if there is a dangerous peak or temperature difference. Grants are pending for the study of a cell phone prototype that will function as a glucometer and a pedometer. This smart phone can manage data through graphing, etc. and wirelessly transmit results to the physician’s office.
The aforementioned prospects represent only a few areas that affect lower extremity complications of diabetes. New treatments for painful and painless diabetic neuropathy, stem cell and growth factor therapy for wound healing, and technological advances in imaging can all be expected.
While the prevalence of diabetes is increasing and its complications are unrelenting, our understanding of this disease will improve and our armamentarium of treatments will expand. New therapies should be supported by sound science before becoming uniformly accepted. Combining a keen awareness of the new treatments with healthy skepticism and a critical appraisal of the claims can help us determine potential benefits for our patients.
1. Castronuovo JJ, Jr., Adera HM, Smiell JM, Price RM. Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia. J Vasc Surg. Oct 1997;26(4):629-637.
2. Khaodhiar L, Dinh T, Schomacker KT, et al. The use of medical hyperspectral technology to evaluate microcirculatory changes in diabetic foot ulcers and to predict clinical outcomes. Diabetes Care. Apr 2007;30(4):903-910.
3. Opie SR, Dib N. Local endovascular delivery, gene therapy, and cell transplantation for peripheral arterial disease. J Endovasc Ther. Dec 2004;11 Suppl 2:II151-162.
4. Powell RJ, Dormandy J, Simons M, et al. Therapeutic angiogenesis for critical limb ischemia: design of the hepatocyte growth factor therapeutic angiogenesis clinical trial. Vasc Med. May 2004;9(3):193-198.
5. Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol. Dec 2005;25(12):2542-2547.
6. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. Mar 31 1998;97(12):1114-1123.
7. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation. Jun 8 2004;109(22):2692-2697.
8. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. Aug 10 2002;360(9331):427-435.
9. Kobayashi N, Bauer TW, Sakai H, et al. The use of newly developed real-time PCR for the rapid identification of bacteria in culture-negative osteomyelitis. Joint Bone Spine. Dec 2006;73(6):745-747.
10. Levin BR, Bull JJ. Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol. Feb 2004;2(2):166-173.
11. O’Flaherty S, Ross RP, Meaney W, et al. Potential of the polyvalent anti-Staphylococcus bacteriophage K for control of antibiotic-resistant staphylococci from hospitals. Appl Environ Microbiol. Apr 2005;71(4):1836-1842.
12. Yonem A, Cakir B, Guler S, et al. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Diabetes Obes Metab. Oct 2001;3(5):332-337.
13. Cruciani M, Lipsky BA, Mengoli C, de Lalla F. Are granulocyte colony-stimulating factors beneficial in treating diabetic foot infections? A meta-analysis. Diabetes Care. Feb 2005;28(2):454-460.
14. Armstrong DG, Nguyen HC, Lavery LA, et al. Off-Loading the Diabetic Foot Wound: a Randomized Clinical Trial. Diabetes Care. 2001;24(6):1019-1022.
15. 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):551-554.
16. Wu SC, Bevilacqua NJ, Rogers LC, Armstrong DG. Tissue volumizing agents: can we create an internal orthotic? Podiatry Today 19(10):58-63.
17. Balkin SW, Kaplan L. Silicone injection management of diabetic foot ulcers: a possible model for prevention of pressure ulcers. Decubitus. Nov 1991;4(4):38-40.
18. Lavery LA, Higgins KR, Lanctot DR, et al. Home monitoring of foot skin temperatures to prevent ulceration. Diabetes Care. Nov 2004;27(11):2642-2647.
19. Armstrong DG, Sangalang MB, Jolley D, et al. Cooling the Foot to Prevent Diabetic Foot Wounds: A Proof-of-Concept Trial. J Am Podiatr Med Assoc. March 1, 2005; 95(2):103-107.