Chronic Diabetic Ulcers Research Articles

Wound Bed Preparation for Chronic Diabetic Foot Ulcers

The escalating incidence of diabetic mellitus has given rise to the increasing problems of chronic diabetic ulcers that confront the practice of medicine. Peripheral vascular disease, neuropathy, and infection contribute to the multifactorial pathogenesis of diabetic ulcers. Approaches to the management of diabetic ulcers should start with an assessment and optimization of the patient's general conditions, followed by considerations of the local and regional factors. This paper aims to address the management strategies for wound bed preparation in chronic diabetic foot ulcers and also emphasizes the importance of preventive measures and future directions. The “TIME” framework in wound bed preparation encompasses tissue management, inflammation and infection control, moisture balance, and epithelial (edge) advancement. Tissue management aims to remove the necrotic tissue burden via various methods of debridement. Infection and inflammation control restores bacterial balance with the reduction of bacterial biofilms. Achieving a moist wound healing environment without excessive wound moisture or dryness will result in moisture balance. Epithelial advancement is promoted via removing the physical and biochemical barriers for migration of epithelium from wound edges. These systematic and holistic approaches will potentiate the healing abilities of the chronic diabetic ulcers, including those that are recalcitrant.

‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing

Post-transcriptional switches are flexible effectors of dynamic changes in gene expression. Here we report a new post-transcriptional switch that dictates the spatiotemporal and mutually exclusive expression of two alternative gene products from a single transcript. Expression of primate-specific exonic microRNA-198 (miR-198), located in the 3'-untranslated region of follistatin-like 1 (FSTL1) messenger RNA, switches to expression of the linked open reading frame of FSTL1 upon wounding in a human ex vivo organ culture system. We show that binding of a KH-type splicing regulatory protein (KSRP, also known as KHSRP) to the primary transcript determines the fate of the transcript and is essential for the processing of miR-198: transforming growth factor-β signalling switches off miR-198 expression by downregulating KSRP, and promotes FSTL1 protein expression. We also show that FSTL1 expression promotes keratinocyte migration, whereas miR-198 expression has the opposite effect by targeting and inhibiting DIAPH1, PLAU and LAMC2. A clear inverse correlation between the expression pattern of FSTL1 (pro-migratory) and miR-198 (anti-migratory) highlights the importance of this regulatory switch in controlling context-specific gene expression to orchestrate wound re-epithelialization. The deleterious effect of failure of this switch is apparent in non-healing chronic diabetic ulcers, in which expression of miR-198 persists, FSTL1 is absent, and keratinocyte migration, re-epithelialization and wound healing all fail to occur.

Dipeptidyl Peptidase 4 Inhibition May Facilitate Healing of Chronic Foot Ulcers in Patients with Type 2 Diabetes

The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, both micro- and macroangiopathy strongly contribute to the development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. With adequate treatment, some ulcers may last only weeks; however, many ulcers are difficult to treat and may last months, in certain cases years; 19–35% of ulcers are reported as nonhealing. As no efficient therapy is available, it is a high priority to develop new strategies for treatment of this devastating complication. Because experimental and pathological studies suggest that incretin hormone glucagon-like peptide-1 may improves VEGF generation and promote the upregulation of HIF-1α through a reduction of oxidative stress, the study evaluated the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase-4, such as vildagliptin, on angiogenesis process and wound healing in diabetic chronic ulcers. Although elucidation of the pathophysiologic importance of these aspects awaits further confirmations, the present study evidences an additional aspect of how DPP-4 inhibition might contribute to improved ulcer outcome.

Extracorporeal shockwave therapy in musculoskeletal disorders

The sources of shockwave generation include electrohydraulic, electromagnetic and piezoelectric principles. Electrohydraulic shockwaves are high-energy acoustic waves generated under water explosion with high voltage electrode. Shockwave in urology (lithotripsy) is primarily used to disintegrate urolithiasis, whereas shockwave in orthopedics (orthotripsy) is not used to disintegrate tissues, rather to induce tissue repair and regeneration. The application of extracorporeal shockwave therapy (ESWT) in musculoskeletal disorders has been around for more than a decade and is primarily used in the treatment of sports related over-use tendinopathies such as proximal plantar fasciitis of the heel, lateral epicondylitis of the elbow, calcific or non-calcific tendonitis of the shoulder and patellar tendinopathy etc. The success rate ranged from 65% to 91%, and the complications were low and negligible. ESWT is also utilized in the treatment of non-union of long bone fracture, avascular necrosis of femoral head, chronic diabetic and non-diabetic ulcers and ischemic heart disease. The vast majority of the published papers showed positive and beneficial effects. FDA (USA) first approved ESWT for the treatment of proximal plantar fasciitis in 2000 and lateral epicondylitis in 2002. ESWT is a novel non-invasive therapeutic modality without surgery or surgical risks, and the clinical application of ESWT steadily increases over the years. This article reviews the current status of ESWT in musculoskeletal disorders.

Tissue‐engineered provisional matrix as a novel approach to enhance diabetic wound healing

Inherent pathologies associated with diabetic wound microenvironment including increased proteolysis, inflammatory dysregulation, and impaired neovascularization prevent timely resolution of chronic diabetic ulcers. It is hypothesized that augmentation of local wound microenvironment with a stable provisional matrix formed by proteolysis-resistant angiogenic peptide nanofibers (NFs) will create permissive environment for attenuated inflammation, enhanced neovascularization, and improved diabetic wound healing. Using murine excisional wound healing models, full-thickness dorsal skin wounds were treated with either NFs or control solutions (phosphate buffered saline; hyaluronic acid) and analyzed for morphology, inflammatory response, neovascularization, and biomechanical properties. NF treatment of diabetic wounds stimulated formation of a robust pro-angiogenic in situ tissue-engineered provisional matrix leading to a significant decrease in wound inflammatory cell infiltration and proinflammatory interleukin-6 levels, a significant increase in endothelial and endothelial progenitor cell infiltration, vascular endothelial growth factor levels, and neovascularization (day 7), as well as improved wound morphology, accelerated wound closure, and significantly stronger repair tissue (day 28). These results suggest that appropriate design of provisional matrix may compensate for some of the complex disruptions in diabetic wound microenvironment and provide missing cues to cells and direct in situ responses toward improved healing, which is promising for future development of new therapies for diabetic ulcers.

SP5-14 A study to determine the knowledge and practice of foot care in patients with chronic diabetic ulcers

IntroductionDiabetic foot ulcers account for many hospital admissions and is a major cause of amputations. This is preventable by effective identification, education and preventive foot care practice.ObjectiveDetermine the level of...

Cytotoxicity and effects on inflammatory response of modified types of cellulose in macrophage-like THP-1 cells

The cytotoxicity and in vitro effects of six variously modified types of cellulose (OC – oxidized cellulose, NaOC – oxidized cellulose sodium salt, DAC – dialdehyde cellulose, CMC – carboxymethyl cellulose, MFC – microfibrilated cellulose, and MCC – microcrystalline cellulose) on the inflammatory response in macrophage-like THP-1 cells were examined, with special focus on their ability to influence gene expression and the production of TNF-α. The study provides evidence that DAC exerts a marked effect on the induction of TNF-α gene expression and its subsequent production in human macrophages. Thus, the use of DAC for anti-hemorrhagic or wound-healing therapy should be considered carefully with regard to its pro-inflammatory activity. On the contrary, MCC showed significant anti-inflammatory effects in the LPS-induced conditions, which might be beneficial for the treatment of non-healing chronic wounds, e.g., diabetic or venous ulcers.

Vacuum Assisted Closure Improves the Quality of Life in Patients with Diabetic Foot

Background : Diabetes Mellitus (DM) is the most common endocrine disease worldwide. One of the most important chronic complications of this disease is the development of diabetic foot. The management of diabetic foot wounds is quite important with respect to public health.Aims : To determine the effect of Vacuum Assisted Closure (VAC) therapy on the quality of life in the treatment of diabetic foot ulcers and compare it with standart wound care.Methods : Between May 2007 to December 2008, 67 consecutive patients with diabetic foot ulcers were randomly assigned to VAC therapy (Group1, n: 30) or standart wound care (Group 2, n: 37). The SF-36 questionnaire was administered the day before and in the month following wound healing. Global analyses of the 8 domains and 2 comprehensive indexes of SF-36, Physical Component Summary (PCS) and Mental Component Summary (MCS) were performed. Clinical measures included standard antidiabetic treatment, daily wound care including antiseptic bath, debridement, toe removal for gangrene when necessary, and wound care with conventional methods or VAC. Healing time was calculated as the time from hospital admission to the time of re-epithelization.Results : There were no differences in the mean age, ulcer size and pulse status of the patients in both groups. Healing time in the VAC group was significantly reduced (p < 0.05). All 8 domains of SF-36 and MCS and PCS scores improved remarkably after VAC therapy.Conclusion : Vacuum Assited Closure therapy was found to be effective in the treatment of chronic diabetic ulcers. The improvement of quality of life demonstrates a clear-cut indication in this particular group of patients.

A novel dermal tissue construct: Development and in vitro characterization

A dermal tissue construct composed of human dermal fibroblasts and a chitosan sponge has been developed, targeted towards the treatment of diabetic nonhealing ulcers. The construct has been designed in a way that the dermal fibroblasts are arranged as a three-dimensional sheet adhered entirely on one side of the chitosan sponge. This design would allow maximal diffusion of growth factors from the cells to the wound bed when the construct is applied on the wound with the cellular sheet side making contact with the wound bed. The diffusion of secreted growth factors would take place directly from cells to the wound bed without being impeded by a matrix. The cells are present at a high density in the dermal construct, which would aid in accelerated wound healing. The construct has a porous chitosan sponge base, which would allow gas exchange, and renders the dermal construct very flexible so that it would take the shape of the wound contours well, while having mechanical integrity. The viability of cells in the construct is greater than 90%. The dermal construct produces a high amount of vascular endothelial growth factor, from 42 ng to 31 ng in 24 h. The construct also produces high amounts of Interleukin-8 (IL-8), from 375 ng to 1065 ng in the first 24 h. Both VEGF and IL-8 have important roles in the healing of chronic diabetic ulcers.

Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers

Lower extremity ulcers are a serious complication of diabetes mellitus (DM). These ulcers show decreased angiogenic response and production of growth factors. Recombinant human platelet derived growth factor (rhPDGF) has been found to decrease the time to healing. This study was conducted to evaluate its efficacy in the treatment of diabetic foot ulcers. A total of 50 patients with type 1 or type 2 DM and chronic ulcers, of at least 4 weeks duration, were studied. They were randomised into two groups, of 25 patients each. The patients in group 'A' (test group) received treatment with topical application of rhPDGF gel and those in group 'B' (control group) were treated with local application of KY Jelly as a placebo. A standardised regimen of good wound care was provided to both groups. Healing or reduction in size of the wound, over a period of 10 weeks after commencement of treatment was recorded. The mean age of the patients was 49.9 years in the control group and 56.2 years in test group. The median duration of ulcer at time of enrolment in the study was 6 weeks in control and 5 weeks in test group. Fifteen ulcers in control group belonged to IAET (International Association of Enterostomal Therapy) class III and 10 ulcers to class IV where as 16 ulcers were in IAET class III and 9 ulcers in IAET class IV in the test group. The mean size of the wounds was 26.5 ± 2.5 cm(2) in control group and 29.9 ± 3.4 cm2 in test group. All patients tolerated the test medication well. At the end of 10 weeks, 18 (72%) ulcers had healed in control group and 15 (60%) in test group (p > 0.05). Three ulcers in control group showed >75% reduction in size compared to 2 in the test group (p > 0.05). This study did not show any statistically significant improvement in ulcer healing rates after the use of topically applied rhPDGF.

Fusarium solani: An Emerging Fungus in Chronic Diabetic Ulcer

Fusarium species, a mold which causes disease mainly in plants has emerged as pathogen in immunocompromised patients. Fusarium is known to cause keratitis, onychomycosis, and endophthalmitis. Fusarium solani, is the most common isolate from clinical specimen. Here is a case, a 65-year-old male with type II diabetes mellitus since 10 years presented with a large ulcer on the left leg since 8 months following trauma. The fungal culture of the escar of the ulcer isolated a mold, Fusarium solani. The patient's leg was amputated and was treated with amphotericin B. The patient was discharged on healing of the stump. This case gives emphasis on fungal culture in chronic diabetic ulcer.

Definition of infection in chronic wounds by Dutch nursing home physicians

In the above paper, the following errors appeared: On page 267, abstract, line 7, the sentence was, ‘All NHPs treated three or less chronic post-surgical wounds, whereas 68.4% treated none.’ This should have read, ‘Of the responding NHPs, 31.6 % treated at least one, but never more than two chronic post surgical wounds , whereas 68.4% of the NHPs treated none.’ On page 269, column 2, line 2, the sentence was ‘All NHPs treated three or less chronic postsurgical wounds, whereas 68.4% of the NHPs treated none (Table 1).’ This should have read, ‘Of the responding NHPs, 31.6 % treated at least one, but never more than two chronic post surgical wounds, whereas 68.4% of the NHPs treated none (Table 1).’ On page 269 column 2, line 10, the sentence was ‘Of the NHPs, 97.4% treated one or less chronic VLU, whereas 76.9% treated none (Table 1), and 88.1% of the NHPs considered none of the treated chronic VLU to be infected (Table 2).’ This should have read, ‘Of the responding Dutch NHPs, 17% actually treated at least one, but no more than two chronic arterial ulcers whereas 82.9% treated none (Table 1). 90.5% of the NHPs considered none of the arterial ulcers to be infected (Table 2).’ On page 269 column 2, line 16, the sentence was ‘Many NHPs (94.9%) treated one or less chronic diabetic ulcer, whereas 80.2% treated none (Table 1).’ This should have read, ‘Of the responding Dutch NHPs 19.9% actually treated at least one, but no more than three chronic diabetic ulcers, whereas 80.2% treated none (Table 1).’ We would like to apologize for these errors.

Definition of infection in chronic wounds by Dutch nursing home physicians

This study investigated the number and type of chronic wounds actually treated by Dutch nursing home physicians (NHPs). It was also the goal to know how many of the treated chronic wounds they considered infected. The NHPs were asked to choose and rank their top five out of several provided criteria for chronic wound infection. After this, the ranking was compared with the choices an international multidisciplinary Delphi group of wound experts made in 2005. A cross-sectional descriptive survey was conducted using the information from a self-reported questionnaire in a representative sample of Dutch NHPs. About 361 NHPs (25%) were sent a questionnaire. Of the 361 physicians, 139 (38.5%) filled in and returned the questionnaire of which 121 were valid. Of the NHPs, 73.5% actually treated at least one chronic pressure ulcers (PU), whereas 26.5% did not treat any. Of the responding NHPs,31.6 % treated at least one, but never more than two chronic post surgical wounds , whereas 68.4% of the NHPs treated none [corrected]. Chronic venous leg ulcers, arterial ulcers and diabetic ulcers scored infrequently and less than the other two sorts of chronic wounds. Of the Dutch NHPs, 53% considered that none of the PU infected. The other chronic wounds were judged far less frequently to be infected. Dutch NHPs appeared to use more 'traditional' criteria such as 'puss/abscess' and 'malodour' to identify infection and did not change their criteria by wound type. According to this study, NHPs do not frequently see many chronic wounds. The most frequent type of wounds treated was PU. For NHPs, the identification of infection of all types of chronic wounds is difficult. The use of criteria that is not in line with consensus documents may lead to ineffective treatment and even seriously damage patients: the clinical identification of infection is still dependent on experts' opinion. Further research on triggers for the suspicion of wound infection and the development of an evidence-based guideline is necessary.

Phototherapy promotes healing of chronic diabetic leg ulcers that failed to respond to other therapies

We tested the hypothesis that combined 660 and 890 nm LED phototherapy will promote healing of diabetic ulcers that failed to respond to other forms of treatment. A double-blind randomized placebo controlled design was used to study 23 diabetic leg ulcers in two groups of 14 patients. Group one ulcers were cleaned, dressed with 1% silver sulfadiazine cream and treated with "placebo" phototherapy (<1.0 J cm(-2)) twice per week, using a Dynatron Solaris 705(R) device. Group two ulcers were treated similarly but received 3 J cm(-2) dose. At each of 15, 30, 45, 60, 75, and 90 days of healing, mean ulcer granulation and healing rates were significantly higher for group two than the "placebo" group (P < 0.02). While "placebo" treated ulcers worsened during the initial 30 days, group two ulcers healed rapidly; achieving 56% more granulation and 79.2% faster healing by day 30, and maintaining similarly higher rates of granulation and healing over the "placebo" group all through. By day 90, 58.3% of group two ulcers had healed fully and 75% had achieved 90-100% healing. In contrast, only one "placebo" treated ulcer healed fully by day 90; no other ulcer attained > or =90% healing. Combined 660 and 890 nm light promotes rapid granulation and healing of diabetic ulcers that failed to respond to other forms of treatment.

Chronic diabetic ulcers under the first metatarsal head treated by staged tendon balancing

We studied a cohort of 26 diabetic patients with chronic ulceration under the first metatarsal head treated by a modified Jones extensor hallucis longus and a flexor hallucis longus transfer. If the first metatarsal was still plantar flexed following these two transfers, a peroneus longus to the peroneus brevis tendon transfer was also performed. Finally, if ankle dorsiflexion was < 5 degrees with the knee extended, a Strayer-type gastrocnemius recession was performed. The mean duration of chronic ulceration despite a minimum of six months' conservative care was 16.2 months (6 to 31). A total of 23 of the 26 patients were available for follow-up at a mean of 39.6 months (12 to 61) after surgery. All except one achieved complete ulcer healing at a mean of 4.4 weeks (2 to 8) after surgery, and there was no recurrence of ulceration under the first metatarsal. We believe that tendon balancing using modified Jones extensor hallucis longus and flexor hallucis longus transfers, associated in selected cases with a peroneus longus to brevis transfer and/or Strayer procedure, can promote rapid and sustained healing of chronic diabetic ulcers under the first metatarsal head.

Akt1 Controls Insulin-Driven VEGF Biosynthesis from Keratinocytes: Implications for Normal and Diabetes-Impaired Skin Repair in Mice

Here we investigated the potential role of protein kinase B (Akt) in normal or diabetes-impaired wound healing in mice. Interestingly, Akt1 was predominant in skin, wound tissue, and human keratinocytes cell line. Acute skin repair was characterized by an increase of Akt1 phosphorylation in wound margin keratinocytes. By contrast, phosphorylated Akt1 was nearly completely absent and paralleled by a poor phosphorylation of the eucaryotic initiation factor 4E-binding protein 1 (4E-BP1) and reduced levels of vascular endothelial growth factor (VEGF) protein in chronic wounds of diabetic ob/ob mice. Inhibition of the phosphatidyl-inositol-3 kinase/Akt pathway by wortmannin and specific abrogation of Akt1 protein using small-interfering RNA revealed a regulatory function of Akt1 in insulin-mediated VEGF biosynthesis in keratinocytes. Insulin-induced VEGF protein biosynthesis in keratinocytes was mediated by Akt1 from a constitutive VEGF-encoding mRNA pool at the posttranscriptional level through a downstream phosphorylation 4E-BP1. Moreover, transfection experiments introducing a constitutively active mutant of Akt1 into keratinocytes revealed the mammalian target of rapamycin kinase as a downstream mediator of Akt1-linked 4E-BP1 phosphorylation and translational control. Our data suggest that the endocrine hormone insulin contributes to VEGF release in skin wounds through an Akt1-mediated posttranscriptional mechanism in keratinocytes.

The Role of Negative Pressure Wound Therapy With Reticulated Open Cell Foam in the Treatment of War Wounds

The treatment of war wounds poses many unique challenges to all healthcare providers (surgeons, flight medics, nurses, etc.), whether they are located at the far forward trauma hospitals located in or near areas of conflict, at regional hospitals such as Landstuhl Medical Center in Germany, or the larger military hospitals in the United States. These complex wounds often involve massive loss of soft tissue and bone, are contaminated, and are unlike most injuries seen at civilian hospitals. Treatment guidelines, or doctrine, are the result of lessons learned in conflicts over the past few centuries dating back to early 19th century Europe through the Vietnam and recent Persian Gulf war. Advances in surgical and medical treatment have resulted from the complex challenges presented to the war trauma surgeon. More than 1 million patients have been treated for chronic pressure ulcers, abdominal wounds, diabetic ulcers, and acute civilian trauma wounds with negative pressure wound therapy with reticulated open cell foam (NPWT/ROCF) as delivered by V.A.C.(R) Therapy (KCI, San Antonio, TX) for over the past decade. However, the use of NPWT/ROCF for the care of war wounds at battlefield trauma hospitals and/or in the aeromedical evacuation transport system aboard aircraft is a new application of this wound treatment not yet accepted as doctrine. Investigational studies are ongoing to study the safety and efficacy of the treatment of battlefield wounds with NPWT/ROCF both for those national citizens treated at the trauma hospitals in Iraq and Afghanistan and for those wounded American and coalition patients who are transported through the aeromedical transport system to medical centers in the United States.

Polymicrobial Nature of Chronic Diabetic Foot Ulcer Biofilm Infections Determined Using Bacterial Tag Encoded FLX Amplicon Pyrosequencing (bTEFAP)

BackgroundDiabetic extremity ulcers are associated with chronic infections. Such ulcer infections are too often followed by amputation because there is little or no understanding of the ecology of such infections or how to control or eliminate this type of chronic infection. A primary impediment to the healing of chronic wounds is biofilm phenotype infections. Diabetic foot ulcers are the most common, disabling, and costly complications of diabetes. Here we seek to derive a better understanding of the polymicrobial nature of chronic diabetic extremity ulcer infections.Methods and FindingsUsing a new bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP) approach we have evaluated the bacterial diversity of 40 chronic diabetic foot ulcers from different patients. The most prevalent bacterial genus associated with diabetic chronic wounds was Corynebacterium spp. Findings also show that obligate anaerobes including Bacteroides, Peptoniphilus, Fingoldia, Anaerococcus, and Peptostreptococcus spp. are ubiquitous in diabetic ulcers, comprising a significant portion of the wound biofilm communities. Other major components of the bacterial communities included commonly cultured genera such as Streptococcus, Serratia, Staphylococcus and Enterococcus spp.ConclusionsIn this article, we highlight the patterns of population diversity observed in the samples and introduce preliminary evidence to support the concept of functional equivalent pathogroups (FEP). Here we introduce FEP as consortia of genotypically distinct bacteria that symbiotically produce a pathogenic community. According to this hypothesis, individual members of these communities when they occur alone may not cause disease but when they coaggregate or consort together into a FEP the synergistic effect provides the functional equivalence of well-known pathogens, such as Staphylococcus aureus, giving the biofilm community the factors necessary to maintain chronic biofilm infections. Further work is definitely warranted and needed in order to prove whether the FEPs concept is a viable hypothesis. The findings here also suggest that traditional culturing methods may be extremely biased as a diagnostic tool as they select for easily cultured organisms such as Staphylococcus aureus and against difficult to culture bacteria such as anaerobes. While PCR methods also have bias, further work is now needed in comparing traditional culture results to high-resolution molecular diagnostic methods such as bTEFAP.

Verrucous Carcinoma Originating from a Diabetic Foot Ulcer: A Case Report

Background: It has been well-documented that chronic pressure or friction in the area of sensory loss might cause verrucous skin lesions especially on the feet of diabetic neuropathy victims. However, malignant change of these skin lesions have not yet been frequently reported. We report here a rare case of verrucous carcinoma originating from a diabetic ulcer and review the literature. Case Presentation: A 49-year-old male is a victim of diabetes mellitus. Due to osteomyelitis, he had received left third toe amputation, left second metatarsal sequestrectomy, and fourth toe shortening at distal phalangeal shaft two years before admission. He noted a fungating ulceration on his left dorsal foot which was at the base of the second toe 8 months before his coming for help. Initial skin biopsy was done and preliminary pathology results revealed verruca vulgaris. However, the fungating mass enlarged even after several scalpel shavings with topical antibiotics ointment. A second skin biopsy was done 3 months later. Unfortunately, histology results showed verrucous carcinoma. Sectional margin-free wide excision was done and full thickness skin graft was used to cover the soft tissue defect. Conclusion: In treating chronic diabetic ulcers, the possibility of potentially malignant change of the wound must be taken into consideration once the lesions persist or aggravate without infection or other offending factors. Any violating infection should be controlled by aggressive antimicrobial therapy with surgical debridement. Further biopsy should be performed to clarify any suspected malignant changes.

CELL PROLIFERATION INDUCTION (CPI®) WOUND THERAPY IN THE OUTPATIENT WOUND CLINIC SETTING

RATIONALE: Chronic diabetic ulcers often require advanced wound technology. Most patients are ambulatory and cared for in an outpatient setting, limiting the usefulness of treatments, which require skilled nursing care or in-patient facilities. This study was designed to evaluate the clinical effect