LOCAL WOUND CARE

LOCAL WOUND CARE








Local Wound Care

Large soft tissue deficits are a challenge in wound care and decreasing complex wound closure time is very important to return patients to normal life.

Updated 2008

Debridement

Debridement is the process of removing slough, non viable tissues and scars in order to permit healing. Wound debridement is a crucial step in wound management and an essential component of wound bed preparation paradigm. Debridement enhances healing by providing the possibility for accurate wound assessment, decreasing the risk of infection and activating cells by removing senescent fibroblast and non migratory epithelial cells from the wound; this has the benefit of converting chronic wounds to acute wounds with improved wound bed perfusion. Devitalized tissue on chronic wounds enhances bacterial growth, inhibits the formation of granulation tissue and prevents the closure of wound edges. Prior to performing debridement, vascularity of the wound must be assessed.

The types of debridement currently used in clinical practice include sharp, mechanical, enzymatic, autholytic and biotherapy. In sharp debridement which is a rapid and precise method, non viable tissue are removed until normal vascularised tissue appears. Sharp debridement is cost effective and preferred method for appropriate patients. Mechanical debridement including wet to dry gauze involves placing saline gauze over the wound and then removing the dried gauze with tissue adhered. This method is often questioned due to association with high degree pain and limited selectivity of non viable tissue. Autholytic debridement is separation of necrotic tissue from wound bed in a moist wound environment. Enzymatic debridement involves placing exogenous enzymes on wound bed to remove necrotic tissue. Overall, debridement is part of best standard care in the treatment of chronic wounds.

Identify and Treat the Cause Level of Evidence
1 Obtain a careful history and assess the patients’ ability to heal before debridement Not Assessed
2 Optimize the wound environment to support healing – ensure adequate blood supply, control infection and inflammation, provide moisture balance Not Assessed
Address Patient Centered Concerns Level of Evidence
3 Assess /prevent and control pain: persistent (chronic) and procedural wound pain by using appropriate pain management techniques. Not Assessed
4 Consider patient preferences and establish realistic expectations for wound pain management. Not Assessed
Provide Local Wound Care Level of Evidence
5 Assess the wound; Document baseline wound size and characteristics along with changes on reassessment. Not Assessed
6 Ensure bleeding control and use of appropriate haemostatic technique. Not Assessed
7 Cleanse wounds with low-toxicity solutions such as normal saline or water. Topical antiseptic solutions should be reserved for wounds that are non healable or those in which the bacterial burden is of greater concern than the stimulation of healing. Not Assessed
8 Select an appropriate method of wound debridement for each wound. Not Assessed
9 Debride healable wounds: remove nonviable, contaminated or infected tissue (surgical, autholytic, enzymatic, mechanical, and larval).Non healable wounds should have only non viable tissue removed; active debridement to bleeding tissue is contraindicated. Not Assessed
10 Assess and control increased bacterial burden and infection Not Assessed
Provide Organizational Support Level of Evidence
11 Develop an inter professional approach with appropriate consultation to improve patient outcomes. Not Assessed
12 Consider cost effectiveness of proper debridement and their potential to promoting wound healing and wound closure over time. Not Assessed

Essential Publications

1 Sharp debridement on recalcitrant nonhealing venous leg ulcer Quality Indicator Type: Cohort study (2 groups)
Williams D, Enoch S, Miller D, Harris K, Price P, Harding K. Effect of sharp debridement using curette on recalcitrant nonhealing venous leg ulcers: A concurrently controlled, prospective cohort study. Wound Rep Reg, 2005; 13(2):131-137.
This prospective cohort study was conducted to evaluate the effect of sharp debridement on the progression of recalcitrant chronic venous leg ulcers (CVLU) and to assess the feasibility of performing this procedure in an outpatient setting. The study group with sloth, nonviable tissue and no granulation tissue (n=28) underwent sharp debridement, while the control group (n=27) received the same but had minimal granulation tissue a not sloth or nonviable tissue. Between weeks 8 and 20 post-debridement 16% of the study group versus 4.3% of the control group ulcers achieved complete healing. The infection rates and antimicrobial usage were similar between the two groups. Based on these findings sharp debridement is effective in stimulating healing of recalcitrant CVLU and is safe, well tolerated and can be applied in an outpatient setting.
2 EMLA topical anesthetic for debridement of venous leg ulcers Quality Indicator Type: RCT
Lok C, Paul C, Amblard P, Bessis D, Debure C, Faivre B, Fuillot B, Ortonne JP, Huledal G, Kalis B. EMLA cream as a topical anesthetic for the repeated mechanical debridement of venous leg ulcers: A double-blind, placebo-controlled study. Journal of the American Academy of Dermatology, 1999; 40(2): 208-13
In this randomized, double-blind, placebo controlled study the effectiveness of EMLA cream was compared with placebo on the number of debridements required to obtain a clean ulcer, on pain during debridement and to determine its safety following repeated dosses. Results showed that application of EMLA cream prior to debridement decreased the medium number of debridements required for a clean ulcer (EMLA 11.5, placebo > 15, P = 0.019) and decreased pain by 50% (P = 0.003). Thus EMLA treatment provides effective pain relief for debridement of venous leg ulcers and decreases the time necessary to achieve a clean ulcer.
3 Chemical debridement ointment debridement of pressure ulcer Quality Indicator Type: RCT
Alvarez OM, Fernandez-Obregeon A, Rogers RS, Bergamo L, Masso J, Black M. A prospective, randomized, comparative study of collagenase and Papain-Urea for pressure ulcer debridement. Wounds, 2002; 14(8):293-301.
This prospective, randomized clinical trial compared two chemical debridement ointments, collagenase and Papain-Urea, for their effective removal of devitalized tissue and promotion of granulation in pressure ulcers requiring debridement. Two groups treated with one of the two ointments and results showed the papain-urea debriding ointment to be significantly more effective (p < 0.0167) than the collagenase ointment in reducing the amount of necrotic tissue. Development of granulation tissue in wounds treated with papain-urea was significantly enhanced as compared to wounds treated with collagenase. Despite the advantages exhibited from the papain-urea debriding ointment, a strong scientific conclusion cannot be made because of the small sample size (n=26).
4 Debridement of diabetic foot ulcers Quality Indicator Type: Systematic review
Edwards J. Debridement of diabetic foot ulcers. Cochrane Database of Systematic Reviews 2002, Issue 4.
The aim of this review was to access the effectiveness of debridement as treatment for diabetic foot ulcers. 12 RCTs measuring complete wound healing or rate of healing were examined. Only hydrogel proved more effective then gauze or standard care in healing diabetic foot ulcers (Relative Risk 1.84, 95% CI 1.30- 2.6). While surgical debridement or larval therapy showed no significant benefit over standard treatment and hydrogel treatment. Based on these finding hydrogel appears to increase healing rate of diabetic foot ulcers, but more research is needed to evaluate the effects of a range of widely used debridement methods.
5 Wound bed preparation Quality Indicator Type: Narrative Review
Kirshen C, Woo K, Ayello EA, Sibbald RG. Debridement: A Vital Component of Wound Bed Preparation. Adv Skin Wound Care, 2006; 19(9):506-17.
This recent overview aims to provide physicians and nurses with condensed information about debridement and its role in wound healing. It focuses on educating the practitioner on how to effectively choose a method of debridement whether it be surgical, autolytic, mechanical, maggot or enzymatic debridement based on the clinician, patient and the wound. In this paper the evidence supporting the role of debridement in the removal of nonviable necrotic tissue in order to effectively prepare the wound bed for healing is discussed.
6 MIST ultrasound therapy debridement for chronic wounds Quality Indicator Type: Non-randomized controlled trial
Ennis WJ, Valdes W, Gainer M, Meneses P. Evaluation of Clinical Effectiveness of MIST Ultrasound Therapy for the Healing of Chronic Wounds. Adv Skin Wound Care, 2006; 19(8):437-46.
This non-comparative clinical outcomes trial examines the effectiveness of using MIST Ultrasound Therapy for the cleaning, closure and debridement of chronic wounds. As well, this study aims at determining the optimal treatment duration and to analyze the impact of said treatment on the microcirculatory flow patterns within the wound bed. 23 outpatients were treated with low-frequency non-contact ultrasound therapy and compared with historical controls. It took 7 weeks for the treatment group to heal, compared to 10 weeks for the historical controls. Since the control group consisted of patients who required wound-related hospitalizations and surgical procedures to achieve complete closure its comparability with the study group is questionable. These results require further investigation to assess this technology via a well-designed health economic-based trial.
7 Debridement Quality Indicator Type: RCT
König M, Vanscheidt W, Augustin M, Kapp H. Enzymatic versus autolytic debridement of chronic leg ulcers: a prospective randomised trial. J Wound Care 2005;14(7):320-3
The efficacy of two debriding approaches for chronic leg ulcers were compared in this study. The two approaches were TenderWet 24, an autolytic degradation treatment (n=15), and Iruxol N (Santyl), an enzymatic approach (n=27). The authors were unable to recruit 29 subjects per group, the sample size required to detect 30% superiority. Therefore, the difference between the two products was not statistically significant. This article illustrates some of the difficulties researchers face in trying to compare the effectiveness of wound care products.

Edge Effect

Chronic wounds do not always follow the normal healing trajectory. Healing is stalled due to many reasons including senescent cells that are indolent to cellular signaling, decreased growth facts, increased proteases and other pro-inflammatory mediators, and impaired cell migration. The epidermal edge of nonhealing chronic wounds often have a steep cliff-like appearance (edge effect) making it difficult for the keratinocytes to migrate across the granulation base for healing. To stimulate latent healing potential, cellular therapies and other complementary therapies may augment and replace the components that are deficient in nonhealing wounds. However, advanced therapies should only be considered in wounds that have the ability to heal and after debridement, inflammation or infection, and moisture balance should be addressed and optimized. To remember this, think DIM before DIME.

Biological agents

  • Growth factors
  • Tissue matrix components/smart matrix

Skin grafting

  • Autologous epidermis
  • Allografts
  • Living skin equivalents

Complimentary therapies

  • Hyperbaric oxygen therapy
  • Negative wound pressure therapy
  • Electrical stimulation
  • Therapeutic ultrasound

Summary of Advanced therapies Options

Substantiated Advanced therapies Indication RCT or meta-analysis available Results

Smart matrix (Oasis) VLU Yes Complete healing

DFU Yes Complete healing equal to PDGF

Apligraf (epidermal cells, dermal fibroblasts DNFU Yes Complete healing

VLU Yes Complete healing

Dermagraft (fibroblasts) DNFU Yes Complete healing

Hyperbaric oxygen therapy (HBOT) DNFU Yes Prevent amputation

Electrical stimulation PU Yes Complete healing

Therapeutic ultrasound VLU Yes Faster healing

DNFU Yes Complete healing

Negative pressure wound therapy (NPWT) (post surgical) Yes Complete healing

Promogran VLU Yes Decrease wound size

DNFU=diabetic neurotrophic ulcers; VLU=venous leg ulcers;

PU=pressure ulcers

Identify and Treat the Cause Level of Evidence
1 Ensure wounds have the ability to heal and optimize debridement, inflammation or infection, and moisture balance prior to advanced therapies. Not Assessed
2 Think DIM before DIME. Not Assessed
Address patient-centered Concerns Level of Evidence
3 Involve patients and caregivers to consider different advanced therapies Not Assessed
4 Take into consideration of cost (reimbursement if applicable) and convenience factors (frequency, location, length of treatment) for each therapy Not Assessed
Provide Local Wound Care Level of Evidence
5 Consider advanced therapies after debridement, infection/inflammation, and moisture balance have been optimized. Not Assessed
Provide Organizational Support Level of Evidence
6 Consider cost effectiveness of advanced therapies and their potential to promoting wound healing and wound closure over time; not simply cost itself. Not Assessed
7 Critically evaluate of each advanced therapies based on the scientific evidence, expert opinion, and patient preference. Not Assessed

Essential Publications

1 Quality Indicator Type: Narrative Review
Woo K, Ayello EA, Sibbald RG. The edge effect: Current therapeutic opt1ions to advance the wound edge. Adv Skin Wound Care 2007;20(2):99-117.
The purpose of this paper is to examine the edge effect of chronic wounds and advanced treatment options available to practitioners. Keratinocytes are identified as having an important role in wound healing by restoring the epithelium as a protective barrier. Treatment options discussed in this paper include the use of keratinocytes, acellular preparations, cellular therapy, complementary therapies, and epidermal, dermal, and composite products.
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Negative-Pressure Wound Therapy

Large soft tissue deficits are a challenge in wound care and decreasing complex wound closure time is very important to return patients to normal life. Vacuum Assisted Closure (VAC) system is one type of Negative Pressure Wound Therapy (NPWT) that has been extensively studied in the healing of complex acute and chronic wounds other negative pressure wound therapy systems have been developed with very little scientific evidence published to date.

The VAC system was developed by Argenta and Morykwas to assist the healing of complex or stalled open wounds often associated with excess exudates. The unit is programmed to deliver controlled negative pressure on wound surface ranging from 50 to 200 mmHg applied with either a continuous or intermittent pressure setting.

NPWT provides a moist wound environment. The negative (sub-atmospheric) pressure applied to the wound site enhances cell proliferation and migration. Negative pressure wound therapy promotes wound healing by preparing the wound bed for closure, removal of wound exudates, reducing edema, altering the wound fluid composition, promoting blood perfusion, and assisting granulation tissue formation. The recent introduction of NPWT has provided new possibilities for the management of complex wounds including pressure ulcers, diabetic neuropathic foot ulcers, and leg ulcers, abdominal and sternal wounds. There are very few established absolute contraindications; however, the VAC is not recommended over necrotic tissue, non healable wounds such as tumors and individuals with coagulopathies. The use of NPWT for the treatment of deep wound infection is currently under debate.

There is a need to determine realistic clinical outcomes such as a decrease in wound depth or size (chronic wounds that are 30% smaller by week 4 are likely to heal by week 12), The VAC or other NPWT should be discontinued as soon as the outcomes have been achieved. As well all other modalities, there is a need for continued research and expanding evidence for optimal use of NPWT.

Guidelines and consensus statements provided by KCI have been reviewed and appraised using the AGREE Instrument.

The following figure indicates the AGREE domain scores for these negative pressure wound therapy guidelines, specifically vacuum-assisted closure (V.A.C.) and one consensus statement.

The following recommendations are intended to help busy clinicians provide excellent care. They are based on the guidelines, consensus statements and technical reports that are referenced.

Identify and Treat the Cause Level of Evidence
1 Obtain a careful history and assess the patient’s ability to heal before application of NPWT. 5
2 Optimize the wound environment to support healing – ensure adequate blood supply, control infection, maximize nutrition. 2
Address Patient Centered Concerns Level of Evidence
3 Consider patient preferences and establish realistic expectations with patients and their family. 5
4 Assess and control pain: persistent (chronic) and acute with dressing changes or procedures. 3
Provide Local Wound Care Level of Evidence
5 Assess the wound for appropriateness of NPWT, Document baseline wound size and characteristics along with changes on reassessment. 5
6 Provide an optimum wound environment: Debridement, infection control, moisture balance. Not Assessed
7 Protect underlying structures in the application of NPWT. Determine initial pressure and mode (continuous versus intermittent) and select proper foam dressing. Maintain the seal over the foam dressing to enhance effectiveness. 5
8 Consider the use of other adjunctive therapies, skin grafts, and surgical closure if wound healing fails to progress at the expected rate and after appropriate re-assessment of the cause and patient centered concerns. Not Assessed
Provide Organizational Support Level of Evidence
9 Develop an interprofessional approach with appropriate consultation to improve patient outcomes. Not Assessed

Essential Publications

1 Pressure Ulcers Quality Indicator Type: CPG (Clinical Practice Guideline)
Gupta S, Baharestani M, Baranoski S, deLeon J, Engel SJ, Mendez-Eastman S, Niezgoda JA, Pompeo MQ. Guidelines for Managing Pressure Uulcers with Negative Pressure Wound Therapy. Adv Skin Wound Care 2004;17(Suppl 2):1-18
This clinical practice guideline provides an algorithm as well as questions and answers for treating pressure ulcers using NPWT. Although this document was sponsored by KCI, the guideline developers were clinicians serving on an independent panel.
2 Diabetic Foot Ulcers Quality Indicator Type: CPG (Clinical Practice Guideline)
Andros G, Armstrong DG, Attinger CE, Boulton AJM, Frykberg RG, Joseph WS, Lavery LA, Morbach S, Niezgoda JA, Toursarkissian B. Consensus Statement on Negative Pressure Wound Therapy (V.A.C.® Therapy) for the Management of Diabetic Foot Wounds. Wounds 2006; Suppl:1-32.
This clinical practice guideline provides an algorithm for treating diabetic foot wounds using NPWT.
3 Open Abdomen Ulcers Quality Indicator Type: CPG (Clinical Practice Guideline)
Kaplan M, Banwell P, Orgill DP, Ivatury RR, Demetriades D, Moore FA, Miller P, Nicholas J, Henry S. Guidelines for the Management of the Open Abdomen. Wounds 2005; Oct Suppl:1-24
This clinical practice guideline provides an algorithm and other helpful information about treating open abdomen wounds using NPWT
4 Complex Chest Wounds Quality Indicator Type: CPG (Clinical Practice Guideline)
Orgill DP, Austen Jr WG, Butler CE, Fine NA, Horvath KA, Mihaljevic T, Song DH, Wolfe WG. Guidelines for Treatment of Complex Chest Wounds with Negative Pressure Wound Therapy. Wounds 2004; Dec Suppl:1-23.
This clinical practice guideline provides an algorithm and other helpful information about treating complex chest wounds using NPWT
5 Pressure Ulcers Quality Indicator Type: Concensus Statement
Baharestani M, de Leon J, Mendez-Eastman S, Powell G, Weir D, Niezgoda J, Payne W, Nanney LB, Pelham F, Gupta S. Consensus Statement: A Practical Guide for Managing Pressure Ulcers with Negative Pressure Wound Therapy Utilizing Vacuum-Assisted Closure – Understanding the Treatment Algorithm. Advances in Skin & Wound Care 2008;21(Suppl 1):1-20
This is a very recent consensus statement that involved numerous stakeholder groups in its development. It is clearly presented and provides algorithms for treating pressure ulcers. Information about patient optimization, methods of debridement, and a reconstructive surgical ladder
6 Deep Sternal Wound Infections Quality Indicator Type: CPG (Clinical Practice Guideline)
Fleck T, Gustafsson R, Harding K, Ingemansson R, Lirtzman MD, Meites HL, Moidl R, Price P, Ritchie A, Salazar J, Sjo¨ gren J, Song DH, Sumpio BE, Toursarkissian B, Waldenberger F, Wetzel-Roth W. The management of deep sternal wound infections using vacuum assisted closureTM (V.A.C. ®) therapy. Int Wound J 2006;3:273–280.
This clinical practice guideline provides an algorithm for treating deep sternal wound infections using NPWT

Moisture

Since Winter’s seminal work, numerous studies had confirmed the importance of moisture balance in wound healing irrespective of the dressing categories. Most wounds produce exudate as an integral part of inflammatory response along the normal wound healing trajectory. It is generally accepted that wound drainage diminishes as inflammation subsides followed by a progression to the granulation and re-epithelialization stages of the wound healing process. Chronic wound fluid analysis has demonstrated persistently elevated levels of inflammatory cytokines and proteases over and beyond normal acute wounds. Removal of moisture from wound surface may help to sequester excess proteases to avoid degradation of extracellular matrix and growth factors. On the other hand, inadequate moisture promotes wound desiccation, cell death, and eschar formation. Wound healing is impaired as epithelial cells are required to burrow their way from the wound periphery into the wound center. A balanced moist wound surface may facilitate the activities of leukocytes, fibroblasts, keratinocytes and their metabolites including growth factors and cytokines that are crucial to tissue proliferation.

Selection of dressing materials and frequency of dressing change must be tailored to meet the needs of the patients and the wound characteristics. From a functional perspective, dressings can be categorized on a continuum according to their abilities to absorb fluid and donate moisture.

In general, foam dressing and hydrofiber are absorbent while hydrogel is used to provide moisture to wounds. Film and hydrocolloid are occlusive to entrap moisture.

Identify and Treat the Cause Level of Evidence
1 Diagnose and correct or modify treatable causes of tissue damage. Not Assessed
2 Differentiate the wound’s ability to heal: healable, maintenance, or nonhealable wound. Not Assessed
Address Patient-Centered Concerns Level of Evidence
3 Assess and support the management of patient-centered concerns to enable healing. Not Assessed
4 Provide patient education and support to increase adherence to treatment plan. Not Assessed
Provide Local Wound Care Level of Evidence
5 Assess and monitor the wound history and physical characteristics (location and measure). Not Assessed
6 Debride healable wounds, removing nonviable, contaminated or infected tissue (surgical, autolytic, enzymatic, mechanical, and larval). Not Assessed
7 Cleanse wounds with low-toxicity solutions (eg, normal saline or water). Topical antiseptic solutions should be reserved for wounds that are nonhealable or those in which the bacterial burden is of greater concern than the stimulation of healing. Not Assessed
8 Assess and treat the wound for increased bacterial burden or infection. (Distinguish from persistent inflammation of nonbacterial origin.) Not Assessed
9 Select a dressing that is appropriate for the needs of the wound, the patient, and the caregiver or clinical setting. Not Assessed
10 Monitor the quantity and quality of wound exudation to prevent periwound maceration. Not Assessed
11 Evaluate expected rate of wound healing. If suboptimal, reassess the patient according to recommendations 1 to 9. Not Assessed
Provide Organizational Support Level of Evidence
12 For improved outcomes, education and evidence base must be tied to interprofessional teams with cooperation of health care systems. Not Assessed

Essential Publications

1 Dressings Quality Indicator Type: Narrative Review
Harding KG, Jones V, Price P. Topical treatment: which dressing to choose. Diabetes Metab Res Rev 2000;16(Suppl 1):S47-50.
Various dressings that provide a moist environment for the wound area are discussed in this paper. There is a lack of evidence showing that these dressings improve healing of chronic wounds, but these dressings have been proven to be beneficial to patients due to reduction in pain, odour, and wound leakage. Types of moist dressings described in this paper include films, foams, hydrogels, hydrocolloids, alginates, and medicated dressings.
2 Dressings Quality Indicator Type: Narrative Review
Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clinical Infectious Diseases 2004;39(Suppl 2):S100-3.
In this paper, various dressings are evaluated based on the needs of patients with diabetic foot ulcers. Types of dressings analyzed in this paper include nonadhesive dressings, foam and alginate dressings, hydrogels, dressings containing inidine and silver, and occlusive dressings.
3 Dressings – Foam Quality Indicator Type: Prospective Correlation study
Zoellner P, Kapp H, Smola H. A prospective, open-label study to assess the clinical performance of a foam dressing in the management of chronic wounds. Ostomy Wound Manage 2006;52(5):34-6, 38, 40-2 passim.
The purpose of this study was to evaluate the efficacy of polyurethane foam dressing in wound healing and patient pain tolerance. The use of foam dressings was associated with improved wound healing and reduced pain levels. The authors conclude that foam dressings are effective for treating exuding chronic wounds.
4 Moist wound healing Quality Indicator Type: Prospective Correlation study
Winter GD. Formation of the scab and the rate of epithelization of superficial wounds in the skin of the young domestic pig. Nature 1962;193:293-294.
This is the original study of wound healing in the skin of pedigree Large White pigs 12-14 weeks old. Experimental wounds were kept moist using polythene film while the control wounds on the same animals were kept open to the air. The moist wounds were found to epithelialize more quickly than the dry wounds. This study has influenced our understanding of the importance of moisture in wound healing.
5 Moisture balance Quality Indicator Type: Narrative Review
Okan D, Woo K, Ayello EA, Sibbald RG. The role of moisture balance in wound healing. Adv Skin Wound Care 2007;20(1):39-53.
An overview of moisture balance and its importance in wound healing is presented in this article. Detailed recommendations for wound assessment and treatment that incorporate moisture balance were provided. Absorbent and hydrating dressings, various other dressings such as crystalline saline, and wound pouching and negative pressure therapy are discussed as treatment options.
6 Platelet-derived growth factor Quality Indicator Type: RCT
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plastic and Reconstructive Surgery 2006;117(7S):143S-149S.
The efficacy and safety of platelet-derived growth factor in wound care was evaluated in this study. 922 patients participated in this blinded study that compared platelet-derived growth factor with a placebo. Treatment with platelet-derived growth factor significantly increased complete healing (p < 0.001) and significantly reduced healing time (p = 0.01). Both groups experienced similar adverse events and recurrence rates. The author concluded that platelet-derived growth factor was effective at treating diabetic foot ulcers.