Tag Archives: Diabetic Ulcers

Staphylococcus simulans Osteomyelitis of the Foot: A case report

by Al Kline, DPM1

The Foot and Ankle Online Journal 3 (1): 4

Staphylococcus simulans, a coagulase-negative pathogen is not commonly seen in the foot. The pathogen has been isolated in chronic osteomyelitis and infected internal fixation. This case describes a 65 year-old, diabetic male with recalcitrant osteomyelitis following partial metatarsal head resection. Staphylococcus simulans was the primary pathogen isolated. This may be the first reported case of Staphylococcus simulans osteomyelitis of the foot.

Key words : Osteomyelitis, Diabetic foot infection, Staphylococcus infection.

Accepted: December, 2009
Published: January, 2010

ISSN 1941-6806
doi: 10.3827/faoj.2010.0301.0004

Staphylococcus simulans is a common, coagulase-negative (CoNS) pathogen linked to animals, including cattle. [1] The pathogen is common in normal flora and is primarily acquired through contact with domestic animals. In animals, the pathogen has been isolated and implicated in a condition called “bumble foot”. [2,4] Bumble foot, or ulcerative pododermatitis, has been described in both rats and birds. [2,3,5] In humans, the pathogen has been isolated in intravascular and indwelling catheters and conditions including urinary tract infections, septicemia, conjunctivitis, and endocarditis. [1,6,7,8] In the past 15 years, the organism has been isolated in cases of osteomyelitis, prosthetic joint infections, and infected internal fixation devices. [1,7,8] The author has found no reported cases of Staphylococcus simulans osteomyelitis of the foot. This report describes a patient who presented with a draining wound after having a previous partial metatarsal resection for acute osteomyelitis.

Case Report

A 65 year-old diabetic male presented to our office with a draining dorsal abscess of the right foot. In May 2006, he underwent a partial metatarsal resection of the 3rd right metatarsal by another podiatrist. Unfortunately, the area became infected. He states the surgery was performed through the ‘top of the foot’ and the ulcer was left to close on the bottom. He reports the dorsal incision, which was primarily closed, opened just days after surgery and began to drain. The plantar ulcer did not close. The patient reports he had a dog. It appeared that hair from the dog constantly adhered to his wound because of walking bare foot on the carpet. His treatment included antibiotic therapy and local wound care. He was on an oral Ciprofloxacin He continued on local wound care and oral antibiotics until he presented to our office in January, 2007. He has had a draining sinus for the past eight months. Radiographic evaluation revealed reactive bone changes to the base of the 3rd proximal phalanx consistent with recalcitrant osteomyelitis. (Fig. 1)

Figure 1  Radiographs of the foot revealed a previous metatarsal resection.  Reactive, osteolytic changes were seen of the 3rd proximal phalanx base consistent with chronic osteomyelitis.

Magnetic resonance imaging (MRI) was performed using high field 1.5 Tesla without contrast. Multiplanar, multisequence images were obtained through the previous partial amputation of the distal right third metatarsal bone and proximal phalanx. On T1 coronal and axial views abnormal bone marrow signal intensity was seen involving the proximal phalanx of the third toe and third metatarsal at the distal shaft. On the respective STIR coronal images and T2WI, there was diffuse high signal intensity. MRI confirmed osteomyelitis to the base of the 3rd proximal phalanx as well as the 3rd end of the remaining metatarsal stump. (Fig. 2A and 2B)


Figure 2A and 2B   MRI axial (a), coronal (b) images revealed abnormal image intensity to the base of the 3rd proximal phalanx and 3rd metatarsal bone.

The patient was admitted to the hospital and scheduled for incision and drainage of the wound with deep tissue and bone cultures with partial resection of the metatarsal stump and base of the proximal 3rd digital phalanx. At surgery, the patient had significant scarring with chronic osteomyelitis of the 3rd metatarsophalangeal joint (MPJ) space. Deep tissue cultures were performed around the base of the 3rd proximal phalanx. Bone was then resected from the base of the 3rd phalanx and 3rd metatarsal stump. Bone was then sent for culture and sensitivity. The wound was left open and packed with plain gauze and saline.

Surgical Culture Report

Surgical culture results revealed Staphylococcus simulans as the primary organism. Bone cultures were also consistent with the same organism. Culture sensitivities reported resistance to Ampicillin, Ciprofloxacin, Clindamycin, Erythromoycin, Oxacillin, Penicillin, Primaxin, Cefazolin and Ceftriaxone. The organism was susceptible to Gentamycin, Tetracylcine, Vancomycin and Bactrim.


Osteomyelitis associated with Staphylococcus simulans is rarely reported. This appears to be the first documented case of Staphylococcus simulans osteomyelitis from a chronic plantar foot ulcer. In 1985, Males, et al., documented a case of fibular, malleolar osteomyelitis after removal of a syndesmotic screw that led to Staphylococcus simulans septic ankle arthritis and septicemia. [8] Before 1985, many species of staphylococcus, including S. simulans, were not identified as a separate strain of staphylococcus and were often labeled Staphylococcus epidermidis. This may explain the lack of reported cases from this pathogen. Staphylococcus simulans is also known to produce a strong slime layer. The production of a strong slime layer and its adherence to smooth surfaces, is linked to the organisms ability to colonize, especially in prosthetic devices, shunts and catheters. [8,9,10] In cases of chronic osteomyelitis, this slime layer is also observed in grossly colonized abscesses. In this case, we also observed a mucoid, slime layer adherent to the packing material. We lavaged and repacked the wound daily. It has also been shown that the encapulated forms of Staphylococcus simulans (i.e. slime layer), as compared to unencapsulated forms of the pathogen, have a antiphagocytic effect on human PMN’s. Little phagocytosis was observed during a 2 hour incubation of PMN’s , even when the ratio of PMN’s to bacteria was increased from 1:1 to 10:1.11 This would explain the virulence of this organism and its ability to colonize wounds and prosthetic devices.


The patient responded well to intravenous (IV) Vancomycin during his hospital course. He remained in the hospital setting for 16 days on IV antibiotic therapy until the dorsal incision closed. This patient returned to a diabetic shoe without further complication. To date, no signs of recurrent osteomyelitis have been reported.


1. Razonable RR, Lewallen DG, Patel R, Osmon DR: Vertebral osteomyelitis and prosthetic joint infection due to staphylococcus simulans. Mayo Clinic Proc. 76 (10): 1067 – 1070, 2001.
2. McArthur J: Bumble Foot, ulcerative pododermatitis. [Online] Unable to find complete reference – the website address has been closedown.
3. McLeod L: Bumblefoot in Rats. About: Exotic Pets, [Online] Unable to find complete reference – the website address has been closedown.
4. Vorgelgt V, Pfanzelt D: Epidemiologie boviner staphylococcus epidermidis isolate: Pravalenz Virulenz-assoziierter Gene und klonale Verwandtschaft mit humanen Isolaten. Hannover, 2006 [Online] Unable to find complete reference.
5. Clauer PJ: Leg and Foot Disorders in Domestic Fowl. Small Flock Factsheet No 35. Virginia Cooperative Extension [Online] Unable to find complete reference – website unavailable.
6. Marrie TJ, Kwan C, Noble MA, West A, Duffield L: Staphylococcus saprophyticus as a cause of urinary tract infections. J Clin Microbiology 16: 427 – 431, 1987.
7. Wilson M: Microbial inhabitants of skin, their ecology and role in health and disease. Cambridge Press, November, 2004.
8. Males BM, Bartholomew WR, Amsterdam D: Staphylococcus simulans Septicemia in a Patient with Chronic Osteomyelitis and Pyarthrosis. J Clin Microbiology 21 (2): 255 – 257, 1985.
9. Byston R, Penny SR: Excessive production of mucoid substance in Staphylococcus IIA: a possible factor in colonization of Holter shunts. Dev Med Child Neurol 14 (suppl 27): 25 – 28, 1972.
10. Christensen GD, Simpson WA, Bisno AL, Beachey EH: Experimental foreign body infections in mice challenged with slime-producing staphylococcus epidermidis. Infect. Immun. 40: 407 – 410, 1982.
11. Ohshima Y, Schumacher-Perdreau F, Peters G, Quie PG, Pulverer G: Antiphagocytic effect of the capsule of staphylococcus simulans. Infection and Immunity, 58 (5), 1350 – 1354, 1990.

Address correspondence to: Al Kline, DPM
3130 South Alameda, Corpus Christi, Texas 78404.
Email: alklinedpm@gmail.com.

Adjunct Clinical Faculty, Temple University School of Podiatric Medicine, Barry University School of Podiatric Medicine. Private practice, Chief of Podiatry, Doctors Regional Medical Center. Corpus Christi, Texas, 78411.

© The Foot and Ankle Online Journal, 2010

EBMR: Comparison of Negative Pressure Wound Therapy using Vacuum-Assisted Closure with Advanced Moist Wound Therapy in the Treatment of Diabetic Foot Ulcers

Evidence Based Medicine Review

Blume P., Walters J., Payne W., Ayala J., and Lantis J.

Diabetes Care 31:631-636, 2008

Michael Turlik, DPM

The Foot & Ankle Journal 1 (12): 5

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.  It permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ©The Foot & Ankle Journal (www.faoj.org)


This was a multi-center randomized controlled efficacy trial of 342 diabetic subjects who were followed for a minimum of 112 days. The study was performed across 37 diabetic foot clinics and hospitals principally in the United States. The primary outcome was complete ulcer closure. There was a thorough description of the method of randomization as well as, concealment allocation. Subjects and investigators were not blinded and it was unclear if data collectors and analysts were blinded. Safety and effectiveness analysis was conducted by the company sponsoring the study.


A sample size calculation was carried out with the expectation of a 20% difference between groups (Absolute Risk Reduction). Enough subjects were enrolled in the study to satisfy the sample size calculation. Baseline data examination reveals no difference between groups. Data from the primary outcome were analyzed as intention to treat as well as, per protocol. Efficacy of the intervention was reported as statistically significant both for intention to treat and per protocol analysis favoring the vacuum assisted closure method. Point estimates were reported for the primary outcome but 95% confidence intervals were not reported.


The manufacturer of the wound closure vacuum assisted device (KCI) supported the study. It was not indicated if the study was registered. The primary author has received payments from the manufacturer for speaking engagements. No other disclosures were noted for other authors or investigators. The article has been marked as an advertisement by the publisher.


The study contains several well described methodological techniques to limit bias, randomization, concealment allocation, and intention to treat analysis. However, due to the nature of the study investigators and subjects were unable to be blinded.

Although unblinded studies are associated with an increased treatment effect this is less likely when the primary outcome is objective such as resolution of an ulcer as opposed to soft measurements such as patient reported outcomes. [1] However, no mention was made regarding blinding of data collectors and analyzers.

The data from the study was analyzed by the company funding the study. This may be perceived as a potential source of bias, it is more reassuring to the reader when the data is analyzed by a neutral third party. The results of the primary outcome were presented as intention to treat and per protocol. It appears the author chose to assign the worst case scenario for the data lost to follow-up for the ITT analysis. Both methods were statistically significant however differed in their point estimate. Was this study clinically significant? The authors expected a 20% difference (ARR) between groups when they calculated their sample size. If the 20% difference is to be accepted as a clinically significant result then the result of the primary outcome using the intention to treat analysis was not clinically significant but only statistically significant. The per protocol analysis was both clinically and statistically significant. Furthermore, it is difficult to analyze the results with only point estimates and not 95% confidence intervals (CI). Why 95% CI were reported for secondary measures and not the primary outcome was unclear.

There appears to be a fairly high loss to follow-up in both arms of the study (approximately 30% per treatment arm). The prognosis for subjects lost to follow-up is thought to be different than the patients who remain in the study. [2] This loss of data may compromise the randomization sequence. Did the loss of follow-up effect the results of the study? The strength of the inference drawn from the study is modified by the magnitude of the difference between the intention to treat and per protocol analysis. It would have been instructive for the reader if the authors addressed this point during their discussion of the results.

Interpretation the study’s results would be better understood with a clear clinically important difference stated by the authors and with 95% CI reported about the point estimate of the primary outcome.

Using the data from this study 95% CI can be calculated for the Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT) for both the intention to treat and per protocol analysis. [3] (table 1)

Table 1

The ARR only exceeds 20% during the per protocol analysis. The lower end of the 95% CI for both ITT and PP is greater than 0 which is consistent with a statistically significant result. Although the point estimate (ARR) for the intention to treat analysis is less than 20% , a risk reduction of more than 20% cannot be ruled out by evaluating the upper end of the 95% CI and would suggest a larger study is necessary or less loss of follow-up.

The NNT is a more clinician friendly metric to access efficacy in studies with dichotomous outcomes. The NNT for both are similar 5 (PP) and 8 (ITT) however, the upper limit of the 95% CI or worse case scenario is 12 (PP) and 24 (ITT). This appears to be a large difference.

Although the use of the vacuum assisted closure appears to be more efficacious the magnitude of the effect is unclear and the inference reduced. It is up to the reader to determine if the loss to follow-up, lack of blinding and lack of clinical significance reduces the inference of the results of this study.

In addition, since the study was designed as an efficacy rather than an effectiveness study, generalizing the results to clinical practice should be undertaking with caution.

The safety data were presented as treatment related rates at six months. However, the trial evaluated treatment until day 112 or ulcer closure by any means. It would be informative to the reader to review the data on safety prior and post intervention termination. There have been two meta-analysis published this year for vacuum assisted closure and diabetic foot ulcers this year. [4,5]


1. Woods L, Egger M, Lotte Gluud L, Schulz KF, Jüni P, Altman DG, Gluud C, Martin RM, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 336 (March): 601 – 605, 2008.
2. Montori VM, Guyatt GH. Intention-to-treat principle. Can Med Assoc J 165 (10): 1339 – 1341, 2001.
3. Graphpad. http://www.graphpad.com/quickcalcs/NNT1.cfm Accessed 11/3/2008.
4. Gregor S, Maegle M, Sauerland S, Krahn JF, Peinemann F, Lange S. Negative pressure wound therapy a vacuum of evidence? Arch Surg 143 (2): 189 – 196, 2008.
5. Bell G, Forbes A. A systematic review of the effectiveness of negative pressure wound therapy in the management of diabetes foot ulcers. Int Wound J 5 (2): 233 – 242, 2008.

© The Foot & Ankle Journal, 2008

Creating the Ideal Microcosm for Rapid Incorporation of Bioengineered Alternative Tissues Using An Advanced Hydrogel Impregnated Gauze Dressing: A Case Series

by Jonathan Moore, DPM, MS1

The Foot & Ankle Journal 1 (9): 2

The purpose of this article is to demonstrate the effectiveness of a novel hydrogel impregnated gauze dressing in creating the ideal microcosm around a bioengineered alternative tissue to prevent tissue dehydration and cell death, accelerate angiogenesis, prevent infection and facilitate the interaction of growth factors with the target cells. Using the BRAIN principles along with this hydrogel impregnated gauze dressing in 50 diabetic patients with neuropathic foot ulcerations (including the six cases presented herein) resulted in substantially improved incorporation rates, increased frequency of wound closure, decreased time to achieve wound closure and a reduction in overall costs. Based on a log transformation the typical healing time is 17.8 days with a 95% confidence interval of 15.6 days to 20.2 days.

Key Words: Bioengineered alternative tissue, diabetic wounds, neuropathic wounds, Amerigel®, BRAIN principle

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.  It permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ©The Foot & Ankle Journal (www.faoj.org)

Accepted: August, 2008
Published: September, 2008

ISSN 1941-6806
doi: 10.3827/faoj.2008.0109.0002

The efficacy of bioengineered alternative tissue (BAT) for lower extremity ulcers (diabetic and non-diabetic) is well described in the literature. [1-6] As the use of BATs continue to grow world wide, it is important that the wound care specialist consider the principles and tools that will maximize the effectiveness of these tissues to enable wounds to heal faster. Using the BRAIN principles (Table 1) will be fundamental in improving incorporation rates and maximizing the effectiveness of BATs. [7]

Table 1  The BRAIN principles to maximize BAT incorporation and wound healing.

Treating wounds in patients with diabetes is more complex than simply choosing what dressing to use. Emerging technologies over the past decade have not only helped improve our understanding of how wounds heal, but more importantly why wounds do not heal. Understanding and addressing the physiological alterations of the wound healing cycle in the diabetic patient is fundamental. As diabetic wounds become stalled in the inflammatory phase of wound repair, chronic wound fluid with elevated levels of matrix metalloproteinases (MMPs) increases proteolytic activity in the wound, which in turn inactivates growth factors.

In addition, with decreased collagen synthesis and impaired cellular activity due to hyperglycemia, there is less nitric oxide available and less endothelial cell proliferation. [8]

With this impaired wound healing physiology, it is vital for the wound care specialist to provide the wound what it lacks (i.e. growth factors, BATs, etc.) and decrease excess chronic wound fluid. Consequently, providing the wound with what it needs at the right time is imperative.

So how can we create the perfect environment for wounds to heal? What is the perfect environment to incorporate BATs into to the wound? Although there is no one right answer, we do know that creating the perfect “microcosm” around the wound will not only actively modify the physiology of the wound environment, but it will also stimulate cellular activity and growth factor release. While no perfect dressing exists for every type of wound, understanding the properties necessary to create the ideal microcosm for the BAT and the periwound area is crucial. [9] (Table 2)

Table 2  The properties of the ideal wound dressing to help incorporate BATs into the wound.

With these characteristics in mind, the AmeriGel® Hydrogel Saturated Gauze Dressing (Amerx Health Care Corp., Clearwater, FL) has, in my experience, been the product of choice in creating the ideal microcosm for both the BAT (cellular or acellular) and the periwound area.

This product utilizes a polyethylene glycol base (polyethylene glycol 400 and polyethylene glycol 3350) that has the ability to remain moist without causing maceration. Because the product is still technically a gauze dressing, it will also absorb excess wound fluid into its fibers while keeping the wound moist for up to 5-7 days.

Although there are other hydrogel impregnated gauze products on the market, such as Aquagauze TM (DeRoyal, Powell, TN), Curafil® Hydrogel Impregnated Gauze (Kendall, Mansfield, MA) and Derma Cool® (Afassco, Carson City, NV), none of these products possess the antimicrobial or antifungal properties that are in the AmeriGel® Hydrogel Saturated Gauze Dressing. [10] While most hydrogel impregnated gauze products are capable of absorbing excess fluid, the AmeriGel® Hydrogel Saturated Gauze Dressing (AmeriGel®) can effectively reduce the bioburden through not only its intrinsic antimicrobial and antifungal properties, but also through its absorptive capabilities that trap debris and bacteria in its fibers. AmeriGel® is an easy to apply, non-woven 4-ply, 2×2 inch dressing that is non-cytotoxic, nonadherent, and antimicrobial.

The antimicrobial agent is Oakin®, an oak extract containing tannins. Its mode of antimicrobial action is through its ability to inactivate microbial adhesins, enzymes, and cell envelope transport proteins. [11,12] Tannins are astringent compounds that act locally by precipitating proteins to the wound, decreasing cell membrane permeability, and exerting anti-inflammatory and bactericidal properties.

The use of AmeriGel® over the BAT application site will facilitate not only a closer adherence of the living or acellular tissue to the wound bed, it will also have an “anchoring” effect by its adherence to the surrounding tissues thus reducing the incidence of hematoma or seroma formation under the BAT.

Although some controversy exists regarding the use of certain products with or on a living skin equivalent, there is no definitive evidence that demonstrates that hydrogels (especially the one being proposed in this paper) are cytotoxic. The objective of using any adjunctive wound care product (i.e. AmeriGel® Hydrogel Saturated Gauze Dressing) with a BAT (cellular or acellular) is to enhance its incorporation into the wound while maintaining the ideal environment in and around the wound site. Using the right product is key, but putting the right product on the wound in and of itself won’t get wounds healed.

The following is a series of case reports utilizing the BRAIN principles along with the AmeriGel® Hydrogel Saturated Gauze Dressing as the product of choice for local BAT incorporation into the wound.

We utilized a variety of products for a variety of particular wound beds. Strict protocol to maintain the consistency of wound preparation and BAT application was followed. The following protocol was used for every BAT application:

1. Conservative topical wound care was performed in every case (collagen wound care products, enzymatic agents etc. ) prior to every BAT application.
2. Sharp debridements were performed regularly to prepare the wound base for the application of the chosen BAT.
3. Care was taken to assure that no active bleeding was occurring prior any BAT application
4. Wound margins were thoroughly debrided to remove any hyperkeratosis and or any undermined tissue.
5. All patients in this series were diabetic, although some wounds treated using this protocol were of venous origin.
6. The BAT was placed on the wound bed such that the entire wound was covered.
7. BATs were not applied to wounds in which tendon or bone was exposed.
8. BATs were not applied in cases of infection or active drainage.
9. BATs were not applied to arterial leg ulcers.
10. AmeriGel® was applied directly over the BAT, followed by a secondary dressing (or some cases a compressive wrap in cases of edema)
11. More than one AmeriGel® Gauze Dressings were used in cases were one did not cover the wound site entirely.
12. All wounds were appropriately offloaded according to the BRAIN principles.
13. In cases where there was lower extremity edema, compression was applied over the BAT site using either an Unna’s boot, or a ProFore® Bandage System (Smith & Nephew, Largo, FL)
14. The patient was instructed to leave the dressing intact and dry for one week after application.
15. The patients returned for follow-up no more than 10 days after application, most returned at 7 days.
16. GammaGraft® (Promethean LifeSciences, Inc., Pittsburgh, PA) was chosen in most cases for two reasons; The product has a greater than 2 year shelf life and it is easy to apply and manage.
17. AmeriGel® Gauze Dressing was used daily until wound closure in every case after BAT application.

Case 1

A 63-year-old female with diabetes and rheumatoid arthritis presented with a chronic venous ulceration (2 cm X 2.6 cm) to the dorsal aspect of the right leg. (Fig. 1A) The wound had been present for over two months despite application of compression therapy and topical agents. The GraftJacket® (Wright Medical Technology, Inc., Arlington, TX) was sutured to the wound site followed by AmeriGel® placed directly over the BAT site. (Fig. 1B)


Figures 1AB  Application of GraftJacket® and AmeriGel® Dressing over this non-healing venous ulceration. Sutures were applied to assure fixation of the BAT under a compressive wrap.

A 4” X 4” fluff and an elastic bandage were applied over the AmeriGel® for moderate compression. After one week, the initial dressing was removed (Fig. 1C) and was changed daily thereafter with AmeriGel® at home by the patient. The secondary dressing was dry sterile gauze. Four weeks after application of the GraftJacket®, the wound site along with all of the surrounding erythema was completely resolved. (Fig. 1D) It was surmised that AmeriGel® facilitated significant reduction of the erythema that had been persistent around the wound.


Figures 1CD  The wound site 1 week and 4 weeks after application of BAT. Compression and continued use of AmeriGel® played a pivotal role.

Learning points: Treating wounds on the leg in the presence of venous insufficiency will require compression in conjunction with proper local wound care. Although care must be taken not to apply too much compression such that the BAT is disrupted, no compression or too little can be equally harmful.

Tip: Size and trim the BAT prior to application to ensure the BAT is capable of covering the deepest portion of the wound without tenting.

Case 2

A 42-year-old poorly controlled diabetic male presented with a chronic interdigital ulceration (1.6 cm X .9 cm) to the right foot. (Fig. 2A) The ulcer started as a result of a severe Tinea pedis infection. After the fungal infection was cleared, the ulceration was recalcitrant to traditional topical wound care agents and regular debridements. Thus, a GammaGraft® was chosen to close the wound. The GammaGraft® was anchored securely to the surrounding tissue followed by the AmeriGel® carefully placed to serve as a spacer interdigitally as well as to cover the BAT to promote more rapid healing. (Fig. 2B) After one week, the initial dressing was removed and the patient was instructed to change the dressing daily by applying AmeriGel® over the wound site followed by dry sterile gauze as a secondary dressing. After 3 weeks and 4 days, the wound site completely closed. (Fig. 2C)


Figures 2ABC  In case 2, GammaGraft® was used with AmeriGel® to advance closure of this chronic interdigital ulcer that occurred from a long standing and ignored fungal infection.

Learning points: Desiccation of the BAT is a major concern when treating distal extremity wounds where there is often autonomic impairment common in patients with diabetes. A dressing like AmeriGel® will supplement moisture to the wound site.

Tip: Because of the previous fungal infection, the antifungal properties of AmeriGel® served well to provide the ideal environment for healing.

Case 3

A 54-year-old diabetic male with a long history of Charcot deformity presented with a plantar ulcer (2.1 cm X 2.5 cm) of greater than 6 months duration. After the patient was offloaded in a Bledsoe® Walker (Bledsoe Brace Systems, Grand Prairie, TX), a granular bed was achieved after two weeks of aggressive debridement and topical wound care agents. (Fig. 3A) A GammaGraft® was then chosen to bring total closure to the wound site. The GammaGraft® was anchored to the wound site followed by AmeriGel®. (Fig. 3B) After one week, the initial dressing was changed and the patient was instructed to apply AmeriGel® every day thereafter, using dry sterile gauze as a secondary dressing. 3 weeks and 1 day later, the patient achieved complete healing. (Fig. 3C) Patient compliance with offloading and proper use of the prescribed dressings played a major role in this patient’s quick healing time.


Figures 3ABC  In case 3, GammaGraft® was used with AmeriGel® to facilitate healing of this plantar ulcer that occurred due to Charcot deformity.

Learning points: Offloading wounds like the one above is the cornerstone to success in wound healing. Encourage patients to agree and be compliant with your treatment regimen.

Tip: Avoid using questionable cytotoxic agents over or on the BAT site.

Case 4

A 68-year-old diabetic female on dialysis presented with a chronic right heel ulcer (3.4 cm X 3.1 cm) of greater than 3 months duration. After thorough wound bed preparation over the course of 2 weeks (Fig. 4A), GammaGraft® and AmeriGel® was chosen to bring closure to the wound site. (Fig. 4B) The patient’s dressing was changed at one week followed by daily applications of AmeriGel®, using dry sterile gauze as a secondary dressing. After 5 weeks and 3 days, the patient achieved total healing. (Fig. 4C)


Figures 4ABC  GammaGraft® and  AmeriGel® were used to together to facilitate closure of this chronic heel ulceration that occurred as a result of dyshidrosis and neuropathy. 

Learning points: Initial dressing changes after application of a BAT should occur between 5-7 days. This may vary depending on the presence of drainage or infection.

Tip: The heel can be a very difficult place to heal a chronic wound for many reasons. Hydration was really the key to healing this wound as this patient developed the wound initially from excess dryness, cracking and fissuring.

Case 5

A 71-year-old diabetic male smoker with severe peripheral arterial disease presented with a dorsal foot ulceration (2.5 cm X 2.4cm) that had been chronically open for nearly 2 years. After months of treatment at 2 different wound care centers and several interventions by local vascular specialists, the patient was referred for consultation. After 2 weeks of aggressive wound debridements and the use of a collagen topical dressing, the wound bed improved to the point of accepting a BAT. (Fig. 5A) The GammaGraft® was anchored to the surrounding tissues with Steri-Strips™ (3M, St Paul, MN) (Fig. 5B) and covered with AmeriGel®. (Fig. 5C) After one week, the initial dressing was changed and daily applications of the AmeriGel® was performed using dry sterile gauze as a secondary dressing. The patient achieved complete healing in 6 weeks. (Fig. 5D)


Figures 5AB  Application of GraftJacket® and AmeriGel® in the presence of vascular disease.


Figures 5CD  Despite poor vascular status, early intervention and rigorous wound care helped heal this longstanding foot ulceration.

Learning points: This patient’s ABI demonstrated dismal PVR’s, yet despite this, a rigorous wound care regimen was instituted that eventually led to complete healing.

Tip: Thoroughly assessing vascular status with each and every wound care patient is not only good practice; it can prevent limb loss with timely intervention.

Case 6

A 47-year-old diabetic patient with profound peripheral neuropathy developed a blister on the plantar aspect of her right heel that became recalcitrant to conservative treatment. The patient’s wound was debrided weekly and had Promogran™ (Johnson & Johnson Wound Management, Somerville, NJ) applied to the site until the wound developed a healthy granular base.  Apligraf® (Organogenesis, Inc., Canton, MA) was chosen to close the wound. It was secured in place with Steri-Strips™ and covered with AmeriGel®, along with the use of a Bledsoe® boot and wheel chair.

Due to the patient’s severe neuropathy, among other balance concerns, the patient could not use crutches. (Fig. 6A) One week post application, the absorptive capability of the AmeriGel® was evident (Fig. 6B) as well as its ability to maintain a moist, healthy wound base. (Fig. 6C) At 4 weeks and 4 days, after daily applications of AmeriGel® and dry sterile gauze as the secondary dressing, the wound was healed. (Fig. 6DE)


Figures 6ABC  After regular debridements,  aggressive offloading and conservative treatments including the use of collagen dressings, Apligraf® was chosen for closure along with AmeriGel® per the BRAIN principals.  Excellent incorporation was noted as early as one week (Fig. C). 


Figures 6DE At two weeks, the wound size had been reduced by half and following daily applications of AmeriGel®.  The wound was closed 4 weeks and 4 days after the BAT was applied. 

Learning points: The above case illustrates well the concept of meeting the needs of the wound through the use of more than one product. Aside from regular wound debridements, collagen dressings were initially used to promote a healthy wound base followed by the Apligraf® and AmeriGel®.

Tip: Do NOT mechanically debride the wound bed for at least 4-6 weeks after applying a BAT [this may vary depending on the type of BAT being utilized (i.e. GammaGraft®)] unless the presence of significant exudate and colonization is present.


Since using the BRAIN principles in my own clinics, successful incorporation rates have substantially improved when compared to conventional protocols used previously (i.e. petrolatum impregnated gauze, 4X4’s and roll gauze). Over the past two years, 50 diabetic patients with similar ulcerations were treated using the BRAIN principles along with AmeriGel®. Approximately 90% of those patients had allograft tissue (GammaGraft® and GraftJacket®) applied while the other 10% had Apligraf® applied. To date, only two of the 50 patients have demonstrated BAT failure (non-healing of the wound). Failure in these two patients was attributed to peripheral vascular disease in one and non-compliance in the other.

BATs applied to the legs healed quicker clinically than those applied to the foot. The legs being better vascularized in most cases constitute a viable reason for the comparably faster healing times. For chronic venous insufficiency ulcer patients, compression and a BAT covered by AmeriGel® allowed for healing in the majority of cases within two to three weeks. In some cases wounds were healed at one week. (Graph 1)

Graph 1 This histogram shows that, with the exception of the extreme value (55 days to healing), healing times are reasonably normally distributed, represented by the dashed curve. Based on a log transformation the typical healing time is 17.8 days with a 95% confidence interval of 15.6 days to 20.2 days.

In all cases, only one BAT was used during the entire course of treatment, which certainly reduced costs. After application of the BAT, AmeriGel® continued to be employed as the primary dressing over the wound until closure.


Successfully combining BAT application along with other adjunctive therapies is not a new concept. Armstrong combined Dermagraft® (Advanced BioHealing, Inc., La Jolla, CA) with a vacuum-assisted closure system demonstrating quicker healing rates. [13]

One may also combine BAT’s with hyperbaric oxygen treatment in wounds with local ischemia in turn improving the likelihood of BAT incorporation. [14] Furthermore, venous ulcerations in patients with edema may benefit from compression bandages in turn reducing healing times.

Clinical protocols incorporating the BRAIN principles will not only improve outcomes, but will also improve efficacy and patient satisfaction. No matter what your BAT of choice is, using the BRAIN principles to maximize the incorporation or transfer of the contents in the tissue to the wound will improve outcomes. [7] It has been evident in my patient population that the AmeriGel® gauze significantly helped to provide the ideal microcosm for the BAT after application. Reducing healing times will decrease wound infection rates and lowers the risk of amputation. When patients have faster healing wounds, the necessity for adjunctive diagnostic studies diminishes and patients may return more quickly to normal function thus reducing the costs associated with the increased number of supplies and physician office visits. [15]


This study was retrospective and conducted out of a single multi-office practice. Furthermore, this study did not ascertain the impact of age, length of time the ulcer was present, nor previous treatment modalities. Although this case series is small, the results suggest that this protocol may be beneficial in ulcers from multiple causes, including those of diabetic and venous origin. Future studies may determine efficacy of this protocol as compared to a placebo group with traditional application of the BAT alone. The rapid healing noted in this study can be attributed not only to the use of the BRAIN principles, but also to the meticulous wound bed preparation and proper offloading that took place in every case prior to and after the BAT application.


1. Kim PJ, Dybowski KS, Steinberg JS. A Closer Look at Bioengineered Alternative Tissues. Podiatry Today – ISSN: 1045-7860 – Volume 19 – Issue 7: Pages: 38 – 55, July 2006.
2. Pham HT, Rich J, Veves A, Using Living Skin Equivalents for Diabetic Foot Ulceration: Lower Extremity Wound 1(1); 27-32, 2002.
3. Falanga V, Sabolinski M. A bilayered living skin equivalent construct (Apligraf) accelerates complete closure of hard to heal venous ulcers. Wound Repair Regen 7:201-7, 1999.
4. Bello YM, Falabella AF, Eaglstein WH. Tissue-engineered skin, current status in wound healing. Am J. Clin Dermatol 2(5):303-313, 2001.
5. Claxton MJ, Armstrong DG, Boulton AJM. Healing the diabetic wound and keeping it healed: modalities for the early 21st century. Cur Diab Rep. 2(6):510-8, December 2002.
6. Lee KH. Tissue-engineered human skin substitutes; development and clinical application. Yonsei Medical Journal 41(6):774-779, 2000.
7. Moore, J. The BRAIN Principle: Managing Wounds After Application of Bioengineered Alternative Tissues to Maximize Incorporation and Wound Healing, doi: 10.3827/faoj.2008.0105.0003, The Foot & Ankle Journal, 1(5):3, 2008
8. Loots MA, Lamme EN, Zeegelaar J, et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 111:850–7, 1998.
9. Dinh T, Pham H, Veves A. Emerging Treatments in Diabetic Wound Care. Wounds 14(1) 2-10, 2002.
10. Eisenbud D, Hunter H, Kessler L, et al. Hydrogel Wound Dressings: Where Do We Stand in 2003. Ostomy/Wound Management 49(10) 52-57, 2003
11. Akiyama, H., Kazuyasu, F., Yamasaki, O., Oono, T., Iwatsuki, K., Antibacterial action of several tannins against staphylococcus aureus, Journal of Antimicrobial Chemotherapy 48: 487-491, 2001.
12. Cowan, MM: Plant Products as Antimicrobial Agents; Clinical Microbiology Reviews, 12(4) 564-582, 1999.
13. Espensen EH, Nixon BP, Lavery LA, Armstrong, DG.  Use of subatmospheric (VAC) therapy to improve bioengineered tissue grafting in diabetic foot wounds. Journal of the American Podiatric Medical Association. 92(7): 395-401, 2002.
14. Hopf HW, Humphrey LM, Puzziferri N, et al. Adjuncts to preparing wounds for closure hyperbaric oxygen, growth factors, skin substitutes, negative pressure wound therapy (vacuum-assisted closure). Foot and Ankle Clinics. 6: 661-682, 2001.
15. Harold Brem, MD; Jeroen Balledux, MD et al. Healing of Diabetic Foot Ulcers and Pressure Ulcers With Human Skin Equivalent, A New Paradigm in Wound Healing, Arch Surg. 135:627-634, 2000.

Address correspondence to: Jonathan Moore, DPM, MS. Cumberland Foot & Ankle Center.
117 Tradepark Drive, Somerset, KY 42503

1Cumberland Foot & Ankle Center. 117 Tradepark Drive, Somerset, KY 42503.

© The Foot & Ankle Journal, 2008

The Use of Marigold Therapy for Podiatric Skin Conditions

by Robert A. Hadfield, BS1, Tracey C. Vlahovic, DPM2 , M. Tariq Khan, PhD (Lond), BSc (Pod Med), BSc (Hons), MChS, DFHom (Pod), FBAHChP PFLS3

The Foot & Ankle Journal 1 (7): 1

Marigold therapy has been used for over 30 years in the United Kingdom and has been evaluated by numerous randomized double-blind placebo-controlled studies for various skin issues on the lower extremity. Various species of marigold are naturally anti-viral, keratolytic, and anti-inflammatory when applied topically to the affected area. Marigold therapy offers a non-invasive and gentle treatment for difficult to treat plantar verruca, painful hyperkeratotic lesions, and inflamed bursa secondary to hallux abducto valgus.

Key words: Phytotherapy, Marigold, verrucae, foot ulcer, Tagetes species, Calendula species, hyperkeratotic lesions, bunion, bursitis

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.  It permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ©The Foot & Ankle Journal (www.faoj.org)

Accepted: May 2008
Published: July 2008

ISSN 1941-6806
doi: 10.3827/faoj.2008.0107.0001

Two marigold species, Tagetes and Calendula, have been used for centuries as herbal remedies for various ailments. (Figs.1ab) Phytotherapy, or the use of plants for their medicinal properties, is the basis for most pharmaceutical products. In particular, the marigold has an interesting history as both a topical and an oral remedy.


Figures 1ab  The Tagetes (a) and Calendula (b)  marigold species.

Marigold therapy was first described in the podiatric literature as a treatment for plantar hyperkeratotic lesions in 1980. [1] The Tagetes species of marigold has been found to be strongly keratolytic. The keratolytic and anti-inflammatory properties of Tagetes in the treatment of verrucae and hyperkeratotic lesions have been well documented in the literature. [2-8] Tagetes has also been described as a treatment for carbuncles and eye infection in India as well as for joint pain and muscular spasms in Brazil and Mexico. [9,10] In addition to being a treatment for verruca, this species has also been used in the treatment of allergic contact dermatitis as well as radiation dermatitis associated with breast cancer therapy. [11,12]

In contrast, the English pot Marigold (Calendula species) has been described in the treatment of cuts, wounds and ulcerations as early as 1838. [13] More recently, anti-tumor and anti-oxidant properties of Calendula species have been established and utilized in researching treatments for various cancers. [14,15] This species has also been found to have hepatocytoprotective properties in the treatment of CCI4 poisoning as well as anti-microbial properties.16-18 In recent years, investigators outside the United States have studied the properties of the Calendula species in healing diabetic foot ulcerations. [19,20]

This article will review the literature for the use of Tagetes and Calendula species on the most common podiatric conditions treated and will show their usefulness as an effective and non-invasive therapy. The chemicals found in the multiple Tagetes species described will demonstrate keratolytic, anti-viral, and anti-inflammatory properties. The use of the Calendula species of marigold will be described, including a case study demonstrating its use in non-healing ulcerations.

Hyperkeratotic Lesions

Painful hyperkeratotic lesions, arising from both mechanical stressors and boney deformity, are extremely common podiatric conditions. Treatments range from conservative debridement, change of shoe gear, orthotics, and topical keratolytics to surgical correction of the underlying deformity.

A marigold based paste has been used successfully as topical therapy for these lesions for many years in the United Kingdom. (Figs. 2, 3)

Figure 2   Painful plantar hyperkeratotic lesions prior to marigold therapy.

Figure 3  Clearance of lesions after four treatments; one month after initial therapy.

Davidson reported M. Taufiq Khan’s work with the Tagetes species and its ability to inhibit cell activity in the stratum corneum. [1] A chemical analysis of Tagetes isolated tagetone, d-limonene, acimene, linalyl-acetate, linalol 9.8%, and other terpenes. [21] Tagetone acts as a catalyst to inhibit the rapid production and transmission of keratinocytes. [22,23]

Tagetes’ effect on podiatric skin, bone, and nail conditions was further described by Khan and White followed by numerous randomized, double-blind placebo controlled studies on those conditions. [24]

In 1996, Tagetes erecta was used for a double blind placebo controlled study for thirty patients with painful plantar hyperkeratotic lesions. [4] They were separated into three groups: marigold therapy with an aperture pad, marigold therapy without an aperture pad, and placebo marigold therapy with aperture pad. The placebo paste was formulated to look and feel identical to the active paste but with no active chemical ingredients. In the semi-compressed felt aperture pad, a paste of fresh plant combined with isopropyl alcohol was applied by the podiatric practitioner once a week for four weeks over the painful lesions. The patients wore the poultice dressing for a week and returned weekly for lesion debridement by the practitioner. At the end of the treatment period, patients received either active or placebo tincture and ointment to use on the test area at home for four weeks.

The active paste group with a pad showed a significant decrease in hyperkeratotic lesion width, length, and pain when compared to the placebo group.

The active paste group with pad versus the active paste group without pad also had a significant difference in width, length and pain showing that the aperture pad had helped to offload the lesions as well as compartmentalize the marigold paste to the affected area. Reducing the trauma at the painful hyperkeratosis site is believed to decrease cytokine production thus decreasing kertinocyte production. This coupled with the natural keratolytic property of Tagetes (containing tagetone among other chemicals) proved to be a promising therapy, which could be used prior to custom molded orthotic therapy or as an alternative to surgical correction.

The keratolytic property of Tagetes was further explored in several published case studies. [5,13,25] Patients receiving a similar therapy as previously described reported pain relief after 48 hours of the first dressing application. Interestingly, the patients who used the home therapy and orthotic control after the initial eight week period had no recurrence of the lesions after one year.

Plantar Verrucae

Plantar verrucae cause patients to seek treatment when the lesions become painful or do not resolve on their own. Treatments range from topical to surgical and are typically painful. Marigold therapy can also be added to the many topical treatments for verrucae. (Figs. 4,5)

Figure 4  Recalcitrant plantar verruca prior to marigold therapy.

Figure 5  Clearance of the lesion after four treatments.

Forty patients were randomly placed into one of four groups; active, placebo, active with pad, and pad only with no paste. [26] Patients were treated twice a week for two weeks and then used home therapy consisting of the tincture and ointment for four weeks. The lesion surface area pre-treatment and post-treatment was analyzed with a wound mapping system. Results showed that the active group had a significant difference in appearance, pain, and size compared with the placebo group.

Additionally, the proposed antiviral property of Thuja occidentalis, a member of the conifer tree family, was studied using thirty randomly selected patients. [27] Patients were chosen with lesions older than eighteen months. An extract containing T. occidentalis was applied daily for three weeks and followed for six months after initial treatment. Ninety percent of patients had resolution of their lesion after one month from the initial treatment. At six months, the same number of patients had no recurrence. After the assessment, a double blind placebo controlled study was done. Results showed 80% of the active group had resolution while the placebo group had just 33% resolution. [27]

A combination of the Tagetes and Thuja into a paste has been used extensively since the separate controlled studies were completed. A small case study showed the usefulness of the paste in immunocompromised patients with mosaic type verrucae. [28] All of the patients were HIV positive with detectable viral loads and verrucae that did not respond to conventional treatment. Four applications of the combination paste eradicated the verrucae in two of the three patients. (Figs. 6,7) Although further research is warranted in this population, it is a hopeful outcome for a non-invasive treatment.

Figure 6    Immunocompromised patient with mosaic plantar verruca prior to therapy.

Figure 7  Clearance of mosaic verruca after four treatments.

Soft Tissue Inflammation Associated with Hallux Valgus

The tissue underlying the prominent medial eminence seen in hallux valgus can become inflamed and be the source of a patient‘s discomfort. This bursitis is often treated with injections, padding, and shoe gear change. For patients that do not want surgery to correct the underlying boney deformity, marigold offers a gentle alternative to decrease inflammation and pain associated with hallux valgus. (Figs. 8,9) There is strong evidence that a particular species of Tagetes exerts anti-inflammatory action towards acute and chronic conditions. [29]

Figure 8  Patient with significant bursitis pain over bunion prior to marigold therapy.

Figure 9  Decrease of erythema and inflammation at bunion site after therapy.

A randomized double-blind placebo controlled study utilized sixty patients with either bilateral or unilateral inflammation was performed. [30] Twenty patients with bilateral inflammation were randomly placed into one of two groups: active paste with aperture pad and placebo paste with protective pad. Forty patients with unilateral bursitis were randomly placed into similar groups with an identical treatment plan. All patients followed the paste and pad therapy with either an active or placebo home therapy consisting of tincture and ointment spray to use on the area daily. Soft tissue swelling at the medial eminence of the bunion was assessed using calipers pre and post treatment. Patients in both of then active groups had complete relief of pain after eight weeks and a 35% reduction in soft tissue swelling at the bursitis site. In the placebo group showed minor reduction in pain which was most likely due to the presence of the aperture pad. However, their original symptoms returned at a week 4 when the patients started the placebo home therapy.

Marigold’s ability to reduce bursitis inflammation was further studied in a group of 45 patients with unilateral pain. [22] Patients were randomly placed into five groups: six groups with active marigold paste (each group had various extracts in organic solvents) and aperture pad and three groups with placebo without aperture pad.

After a similar treatment plan described in the previous study, Group A (active paste in ethanolic extract with pad) had 100% in level of pain (using the visual analogue pain scale) while Group G had 30% reduction in their level of pain.

Both of these studies support the combined use of marigold therapy with a protective aperture pad for patients with painful medial eminence bursitis who are not surgical candidates or do not wish to undergo surgical correction.

Superficial Ulceration

Khan states, in his 1982 publication in World Medicine on the uses of various species of marigolds, that Calendula species promote healthy granulation tissue. [13] There are currently clinical projects underway at the School of Pharmacy at the University of London on these properties of Calendula. There was a single reported case of use in a diabetic ulcer, by Khan in the United Kingdom, using the formulation that was utilized in the following case study.

A larger study, by Duran, et al., was published in Serbia in 2005, using Calendula extract on 34 venous stasis ulcerations. [20]

They reported a statistically significant difference in reduction of total wound area compared with the control (p<0.05), showing an overall decrease of 41.71% in the experimental group compared with 14.52% in the control group. They conclude that application of Calendula extract significantly increases epithelization in chronic venous ulcerations.

This study by Duran, et al., lends scientific credence to the use of Calendula extract as a treatment to decrease the healing time of chronic ulcerations. However, randomized control studies have to yet to be completed.

Case Study

A thirty year old Caucasian male presented with concern of an ulcer on the anterior right leg. The superficial wound was over the site of an external fixator pin tract scar, which had occurred fifteen years earlier. The injury was a result of a blunt blow on a coffee table, shearing off the hypertrophic scar. The patient reported bleeding globally across the lesion at the time of injury. He denied a personal or family history of family diabetes, hypertension, coagulopathy and peripheral vascular disease.

Treatment initiated by the patient consisted of triple antibiotic ointment and a bandage. The patient reported that approximately one week after the injury, in the course of cleansing the wound, eschar that had previously formed self-debrided, and the wound appeared as it did on the day it was sustained. The same treatment was resumed, with a similar course of routine healing. Two weeks following the injury, a similar loss of eschar was duplicated. The second event led the patient to seek treatment.

On initial examination, the patient had a 2.5 cm x 2 cm x 0.5 cm circular lesion over the crest of the anterior tibia in the central one third of the leg. The lesion had a mixed granular and fibrotic base, with mild surrounding erythema and no edema (Figure 10).

Figure 10  Anterior leg ulcer on intital presentation prior to marigold therapy.

No undermining was present, and there was no maceration of the wound edges. There was no purulence or malodor. The scars from the other pin tract sites were also examined and were labeled hypertrophic.

The patient received a regimen of marigold therapy for the wound. The medication used was the HTS 087 Tincture and Ointment. (Marigold Footcare Ltd, UK) The therapy regimen consisted of a combination of the tincture and ointment placed in an aperture pad which was then covered with medical tape and gauze over the lesion for three consecutive days. The same regimen was followed every other day after the initial three day period for two weeks.

The patient related no pain or discomfort for the duration of the treatment. Reduction in wound size (approximately 25%) was noted 48 hours after marigold therapy was initiated. (Fig. 11)

Figure 11  The lesion with decreased erythema and increased granulation tissue 48 hours after therapy.

Eschar information with a decrease in wound size was noted on subsequent dressing changes for six days afterwards. The directions for application were followed until epithelization was noted, which was accomplished in eight days. Complete resolution was obtained in approximately four weeks. (Fig. 12)

Figure 12  The resolved lesion.

The complex nature of this wound, having formed over a pre-existing scar and in a traditionally difficult-to-heal area anatomically, caused a delay in wound healing despite the patient’s uncomplicated medical history. The wound’s recalcitrance in healing warranted additional therapy than just antibiotic ointment and patience.


It should be noted that over the counter and/or health food store creams and preparations of marigold do not have the same effect as the previously discussed studies show. The extracts used for the controlled and case studies were researched and developed by M Taufiq Khan and M Tariq Khan over thirty years. They developed specific extracts that are directly applied by the podiatric physician to the patient: an anti-viral paste (for verruca), an anti-inflammatory paste (for bursitis and tendonitis), a keratolytic paste (for hyperkeratosis), and an anti-fungal paste (for nails). The patients then continue with home therapy that consists of tinctures and ointments with the same properties. These products were only recently introduced to the United States. The second author was the first United States podiatric physician to become certified in the use of the marigold products from Marigold Footcare, Ltd., and the Royal London Homeopathic Hospital, London, UK and will be able to certify (in conjunction with the Hospital) other podiatric physicians in the future. In order to ensure appropriate use of the extracts, certification will only be available to podiatric physicians and is required for both the usage and purchasing of the products. Further research will continue into using the extracts on genodermatoses, onychomycosis, and other podiatric conditions.


The superficial ulceration case study and immunocompromised patients with verruca case study combined with studies performed outside of the United States show the promise of the continued investigation of marigold therapy as a treatment for various podiatric conditions. Marigold therapy has consistently been shown to provide gentle, non-invasive treatment that allows patients a painless alternative treatment.


1. Davidson L., “Marigold rediscovered: a cure for callosities,” Therapy. Pg 1, 1980.
2. Khan M., et al., “Homeopathic treatment of common foot conditions,” British Journal of Dermatology Nursing. 1: 20-23, 2003.
3. Khan M., et al., “Marigold Treatment of foot conditions,” Dermatology in Practice. 10 (3): 28-30, 2002.
4. Khan M., et al.,“Podiatric Treatment of hyperkeratotic plantar lesions with marigold Tagetes erecta,” Phytotherapy Research. 10: 211-14, 1996.
5. Khan, et al., “Treatment of plantar hyperkeratosis with homeopathic podiatry,” Podiatry Now. Dec. 502-505, 2000.
6. Talhouk R., et al., “Anti-inflammatory bioactivities in plant extracts,” J Med Food. 10 (1): 1-10, Mar 2007.
7. Herold A., et al., “Antioxidant Properties of some hydroalcoholic plant extracts with anti-inflammatory activity,” Roum Arch Microbiol Immunol. 62(3-4): 217-227, 2003.
8. Fuchs S., et al., “Protective effects of different marigold (Calendula officinalis L.) and rosemary cream preparations against sodium-lauryl-sulfate-induced irritant contact dermatitis, “ Skin Pharmacol Physiol. May 20, 2005.
9. Hernandez F. “Historia de las plantas de nueve Espana.” Mexico Irmenta Universitaria. 1: 90-91, 1942.
10. Caius J. “The Medical and Poisonous Compsoitae of India, “ J Bombay Natural History Society. 41: 90-91, 1940.
11. Pommier P., et al., “Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer, “ J Clin Onco.l 22 (8) ; 1447-1453, Apr 15, 2004.
12. Pirker C., et al., “Cross-reactivity with Tagetes in Arnica contact eczema,” Contact Dermatitis. 26 (4): 217-219, Apr 1992.
13. Khan M. “Why marigolds can be a corny treatment: A pilot study of the effects of marigold in the treatment of painful corns,” World Medicine. 42-43, Feb 1982.
14. Jimenez-Medina E., et al., “A new extract of the plant Calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor and activity and lymphocyte activation,” BMC Cancer. 6: 119, 2006.
15. Wang M., et al., “Antioxidant activity, mutagenicity/anti-mutagenicity, and clastogenicity of lutein from marigold flowers,” Food Chem Toxicol Epub Sp; 44(9) : 1522-1529, Apr 25, 2006.
16. Barajas-Farias L., et al., “A dual and opposite effect of Calendula officinalis flower extract: chemoprotector and promoter in a rat hepatocarcinogenesis model” Planta Med. 72(3) 217-221, Feb 2006.
17. Rusu M., et al., “The hepatoprotective action of ten herbal extracts in CCl4 intoxicated liver,” Phytother Res. 19(9): 744-749, Sep 2005.
18. Radioza S., et al., “Antimicrobial activity of Calendula L. plants,” Ukranian Journal of Microbiology. 21-25, 2007.
19. Khan M., et al., “Treatment of Diabetic foot ulcer with Homeopathic Podiatry,” Poster Presentation, Symposium on Advances in Skin and Wound Care, Las Vegas, 2005.
20. Duran V., et al., “Results of the clinical examination of an ointment with marigold (Calendula officinalis) extract in the treatment of venous leg ulcers,” Int J Tissue React. 27(3) ; 101-6, 2005.
21. Leung A Encyclopedia of Common Natural Ingredients, Used in Food, Drugs and Cosmetics. Academic Press, New York, 1980.
22. Khan M. “Phytochemical and biologic studies of Tagetes erecta and its clinical evaluation in the treatment of hallux abducto valgus and its associated condition bunion,” PhD Thesis, Faculty Medicine, Centre for Pharmacognosy, School of Pharmacy, University of London, 1999.
23. Sharma A. “Tagetes genus,” Wealth of India. Vol X, SP W p 109, 1961.
24. Khan M., et al., “Comparative clinical studies of Calendula offcinalis and Tagetes varieties of marigold,” 35th LMHH Congress, Sussex, 488-492, 1982.
25. Khan M., et al., “Clinical evaluation of Tagetes erecta in the treatment of parakeratosis,” Phytotherapy Res. 10: 186-188, 1996.
26. Khan M. Jnr. “Tagetes signata in the treatment of verruca pedis,” J British Pod Med. 51: 118b, 1996.
27. Khan M., et al., “A double blind placebo study of topical Thuja occidentalis on verruca pedis in children and adults,” JEADV. 1: S251, 1999.
28. Vlahovic T., et al., “The Use of Marigold Therapy on Mosaic Verrucae in the HIV population,” Presented at AAD, San Antonio, TX 2008. JAAD. 58(2): AB34, 2008.
29. Kasahara Y., et al., “Effect of methanol extract from flower petals of Tagetes patula L. on acute and chronic inflammation model,” Phytother Res. 16(3): 217-222, 2002.
30. Khan M. “The podiatric treatment of hallux abducto valgus and its associated condition bunion with Tagetes patula,” J Pharm Pharmacol. 48: 768-770, 1996.

Address correspondence to: Tracey C. Vlahovic, DPM
Associate Professor, Temple University School of Podiatric Medicine, Philadelphia, Pa. 19107
email: traceyv@tample.edu

1Fourth year student, Temple University School of Podiatric Medicine, Philadelphia, Pa. 19107.
2Associate Professor, Temple University School of Podiatric Medicine, Philadelphia, Pa. 19107.
3Deputy Director of Moeopathic Podiatry, The Marigold Clinic, Royal London Homeopathic Hospital, London, UK.

© The Foot & Ankle Journal, 2008

The BRAIN Principle: Managing Wounds After Application of Bioengineered Alternative Tissues to Maximize Incorporation and Wound Healing

by Jonathan Moore, DPM, MS1

The Foot & Ankle Journal 1 (5): 3

The efficacy of bioengineered alternative tissue (BAT) for lower extremity ulcers (diabetic and non-diabetic) is well described in the literature. What is not present in the literature is a concise description of how to manage these fragile biological tissues after application. This paper introduces the BRAIN principle for adjuvant management of wounds after application of bioengineered alternative tissues. Based on the experience of the author, utilizing the principles found in the BRAIN protocol have not only demonstrated improved BAT incorporation rates, it also increased the rate of wound closure.

Key words: Diabetic wounds, bioengineered alternative tissues, wound healing

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.  It permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ©The Foot & Ankle Journal (www.faoj.org

Accepted: April 1, 2008
Published: May 1, 2008

ISSN 1941-6806
doi: 10.3827/faoj.2008.0105.0003

Bioengineered Alternative Tissues (BAT’s) have revolutionized the science of wound healing. These new technologies offer the wound care specialist an important tool in the battle to prevent nearly 90,000 amputations that occur annually among diabetic patients. [7] However, this technology is of little value when not used as a part of a comprehensive approach to wound healing. This includes assessing nutrition, metabolic status, vascular status, off loading options, and choosing the right wound healing product.

As new bioengeenered alternative tissue products enter the market it is important to consider patient expectations and treat the patient with the best product available for their specific wound. While there are procedures described for many of the better-known BAT’s on the market, they differ in many respects. The table in the study demonstrates the differing protocols for “after-care” following applications of these products. (Table 1)

Table 1 Application and Aftercare Instructions to Providers from the Manufacturer.

Choosing the right BAT along with the appropriate topical wound care agent is critical not only to improve healing times, but to also lower costs.

It has been estimated that 15 to 20 percent of individuals with diabetes will suffer from lower extremity ulceration during their lifetime. [8] Furthermore, half of the diabetic patients who have had a leg amputated will loose the other leg in three to five years. In 1997 it was estimated that total costs for both direct and indirect health care for the persons with diabetes was $98 billion. Of this total, direct medical costs including hospitalization, medical care, and dressing supplies, accounts for $44.1 billion. [9] What is more startling is the annual $5 billion dollar price tag estimated for the cost of dressings for these conditions. With the increased cost of wound care, the wound care specialist should consider using protocols that not only maximize wound healing, but also minimize the risk of BAT failure by providing the best tools to maintain the optimum environment for the wound.

While it is not the purpose of this paper to review every type of BAT on the market, it is vital to understand the characteristics of these products in order to understand how they work and how they should be adjunctively managed after application.

For purposes of defining terms, BAT’s are products that have been produced artificially or modified in some way that alters the biology and its interaction with the wound bed with the goal of creating an optimal environment to stimulate healing.

These tissues include both allograft, xenografts and manufactured/engineered biologic products like Apligraf® (Organogenesis, Inc., Canton, MA). The purpose of these tissues has been well established in the medical literature. However, the primary goal in using a BAT is to stimulate granulation of a chronic wound and augment the wound’s intrinsic healing pathway, thus creating a bridge to epithelialization of the wound.

The literature has well described the process of preparing the wound bed for application of a BAT. The TIME acronym as proposed by the International Wound Bed Preparation Advisory Board provides an exceptional framework for the physician to improve the opportunity for wounds to heal. The TIME principle in essence describes an approach to remove the barriers to the wound-healing process in order to optimize wound repair and healing. Removal of these barriers will not only help to establish a well-vascularized wound bed, but they will also be vital for the incorporation and success of a BAT. (Table 2). [10]

Table 2   International Wound Bed Preparation Advisory Board – TIME principles.

While the principles of TIME described above remains important a new set of principles are needed to assure the BAT has the best chance of incorporation and healing the wound in a timely manner.

Thus, the following acronym called BRAIN is proposed. (Table 3)

Table 3   The BRAIN principles to maximize BAT incorporation and wound healing.

The BRAIN Principle

B (Bioburden)

Despite having properly prepared the wound bed before application of the bioengineered tissue through debridement, among other modalities, maintenance of the bioburden after BAT application remains important. Non-cytotoxic antimicrobials should be considered to prevent colonization after application of bioengineered tissues.

Proper assessment to the needs of the wound is vital after application of the BAT in order to reduce the chances of infection. In the event of a clinical infection of a chronic wound, aggressive treatment is recommended to prevent limb loss. The following are recommendations that should be considered after application of a BAT for the prevention of infection:

1. Sharp debridement is the fundamental component in preparing the chronic wound for the BAT, whether it is an allograft or a bioengineered skin equivalent, like Apligraf®. Sharp debridement too early after application of the BAT may result in destruction of the bioengineered tissue or disruption of the materials the BAT was able to establish in the wound bed. Debridement post BAT application should only be considered if there is necrotic or infected tissue present.

2. Application of a topical antimicrobial agent for use on the wound bed prior to application of the BAT (at least 2 weeks prior), in order to decrease bacterial colonization, should be considered for both cellular engineered tissues and allografts. Use of a silver containing antimicrobial agent, as a part of wound bed preparation should not be a problem, as the silver will be inactivated by wound fluid among other wound components. Application of a topical antimicrobial agent post application of a BAT remains controversial

Living skin equivalents like Apligraf® should not be used in conjunction with any silver-based topical antimicrobial agent as these can be, at certain levels, cytotoxic to keratinocytes and fibroblasts.11 While there is debate about other types of topical agents used on or with a living skin equivalent like Apligraf®, I have used Bacitracin ointment as well as AmeriGel®

Hydrogel Saturated Gauze Dressing (Amerx Health Care Corporation, Clearwater, FL) pre and post application of Apligraf® pose no adverse clinical effects. Agents that are known to be cytotoxic to living skin equivalents include: Dakin’s solution, Mafenide Acetate, Scarlet Red Dressing, Tincoban, Zinc Sulfate, Povidone-iodine solution, Polymyxin/Nystatin and Chlorhexidine.

3. Care must be taken to control swelling and edema with careful compression over the BAT site taking care not to compromise circulation. Edema can significantly compromise wound healing and incorporation of the BAT.

4. Systemic antibiotics should be considered in the presence of malodorous drainage, friable necrotic tissue, increased levels of wound exudate, increasing pain, surrounding cellulitis, crepitus, necrosis and lymphadenopathy. Fever, chills, malaise, leukocytosis, and an elevated erythrocyte sedimentation rate are also common systemic manifestations of wound infection. Superficial contaminants are not always representative of the wound status, as healing wounds will have some contamination. Macerated tissue culture or curettage is a reliable way to determine the etiology of a serious wound infection. Infected wounds will typically respond to aggressive debridement with appropriate systemic antibiotic therapy. Indiscriminate use of oral antibiotics will not decrease infection rates, but can result in resistance. Gram-negative bacterial infections can be severe and need to be treated aggressively. [12]

R (Reduction of pressure and shear force)

In order for incorporation of the BAT to take place in the chronic wound, excess pressure, motion and shearing must be eliminated. Unless the bioengineered tissue maintains adherence to the wound bed with proper pressure redistribution, BAT incorporation will fail. The medical literature is replete with articles that stress the importance of offloading during wound healing. [13]

Although there are many devices on the market that can be employed to remove plantar pressure {Bledsoe® Walker (Bledsoe Brace Systems, Grand Prairie, TX), DH Walker® (Royce Medical, Inc., Camarillo, CA) or total contact casting}, care must further be taken when applying the BAT to the wound site.

Although most BAT manufacturers recommend some type of anchoring of the bioengineered tissue to the wound (i.e. sutures, staples, etc.), specific protocols are lacking. The following are recommendations to consider for the development of your protocols:

1. Determine the best and the most secure application method based upon the quality of the tissues and the location of the BAT. Plantar pressures will deteriorate the BAT unless properly offloaded and secured. With dorsal wounds, anything creating pressure or shear over the site will also result in the failure of the BAT.

2. Although suturing the BAT to the wound bed is ideal, in cases of severe tissue atrophy or poor skin perfusion, Steri-Strips™ (3M, St Paul, MN) should be considered to prevent worsening of the wound site.

3. If sutures or staples are employed, be careful to make sure the bioengineered tissue has been adequately fenestrated in order to prevent hematoma or seroma formation under the BAT.

4. Plantar ulcers MUST be offloaded in order for the BAT to incorporate. Ideally, no pressure should be applied to the wound site, if possible. Surgical shoes with a Velcro®(Velcro Industries B.V., Manchester, NH) latch should be considered for dorsal foot wounds in order to prevent rubbing or shearing forces.

5. Regular shoes, flip-flops or any like footwear are contraindicated after application of any BAT and should NOT be employed.

A (Adapting to the moisture needs of the wound and the bioengineered tissue.)

Any BAT must stay hydrated in order to achieve wound incorporation. Early desiccation of the wound bed and the surrounding tissues will ultimately lead to BAT failure and subsequent slower healing times. The concept of keeping wounds moist in order to accelerate wound healing has been known now for over 50 years. [14,15] Contrary to conventional wisdom, keeping the wound site and the BAT moist does not increase the risk of infection. In fact, a moist wound environment has been shown to improve wound healing by up to 50% compared with exposure to air. [16]

Many factors will determine the amount of wound fluid present in the wound bed. Venous ulcers, for instance, are more likely to produce more moisture than an ulcer on the top of the foot. Close assessment of the moisture balance in the wound is critical for the success of the BAT. Fluid from chronic wounds will block cellular proliferation and angiogenesis, and will ultimately impair wound healing through the build up of excessive amounts of matrix metalloproteinases (MMPs) that break down critical matrix proteins. [17]

The dressing choice after the application of the BAT to the wound site is vital in order to properly adapt to the moisture needs of the wound. Here are some considerations:

1. Upon review of many bioengineered tissue dressing protocols, as provided by the manufacturers of the top BAT’s on the market, regular gauze is recommended as a secondary dressing in nearly all. (Table 1) Although the purpose of the gauze is understood to provide some level of absorption of drainage from the wound, this concept is not ideal for several reasons. No matter how much hydrogel or mineral oil you use under a regular piece of dry gauze, most of this will be absorbed by the gauze and thus provide minimal moisture to the wound bed over time.

Regular gauze alone, even with a nonadherent dressing of some sort, cannot provide consistent and long lasting moisture to the wound site. Hydrogels and hydrogel impregnated gauzes formulated with substrates allowing for longer and controlled moisture balance reduces the incidence of adhesion to the BAT and wound site. Saline or glycerin-based hydrogels or hydrogel impregnated gauzes frequently result in premature desiccation and should be avoided.

2. In those cases where excessive wound fluid is evident, more frequent dressing changes is recommended.

3. In cases of severe exudate and draining from the wound site, the presence of infection needs to be addressed and antibiotics should be prescribed.

4. The ideal wound dressing will remove the excess amounts of wound exudates while retaining a moist environment that accelerates wound healing.

Keep in mind that healing wounds are always characterized by high mitogenic activity, low inflammatory cytokines (less chronic wound fluid), low proteases, mitotically competent cells and a moist environment.

I ( Incorporation and Identification)

Successful incorporation of a BAT hinges upon the molecular environment of the wound. Incorporation of the acellular BAT into the wound bed through a collagen matrix allows for the recruitment of cells into the wound and facilitates the induction and expression of growth factors and cytokines necessary for wound healing. The balance between collagen degradation and synthesis can be disrupted by disease states like diabetes. This can result in defective collagen metabolism and disrupted wound healing.

In contrast, cellular BAT’s are designed to accelerate tissue regeneration by stimulating the recipient’s own wound bed derived skin cells. [18,19] Some authors have called the BAT an interactive “drug” delivery system by the transfer of MMPs and cytokines from the BAT into the wound. [20] Acellular BAT’s work by effectively providing a cover for the wound that prohibits desiccation and fluid loss within the wound, thus decreasing the bacterial burden and promoting angiogenesis and allowing vascular ingrowth into the dermal layer of the allograft.

Identification and correction of factors that can cause tissue damage is essential after application of a BAT. Keep in mind that cellular bioengineered alternative tissues work by biochemically balancing the wound environment to promote tissue regeneration. This provides the “primordial soup” of mediators and growth factors. [21]

Among the many things that can impair wound healing (systemic steroids, non-steroidal anti-inflammatories, immunosuppressive drugs), several other factors must be recognized:

1. Localized edema from venous insufficiency or lymphedema must be addressed before and after application of a BAT. Compression therapy or a referral to a certified lymphedema specialist should be considered.

2. Low albumin can have a significant impact on wound healing. A deficiency in serum albumin, which accounts for more than 50% of total serum proteins, impairs the inflammatory and proliferative stages of wound healing while also decreasing wound perfusion.22 A dietary or nutritional consult should be ordered to maximize the body’s own potential to heal.

3. Autonomic Neuropathy resulting in over drying of the wound and surrounding tissues will impair wound healing in many ways. Desiccation within the wound site will slow epithelial cell migration and thus prevent the incorporation of the BAT.

4. Infection within the wound site can present many challenges to the incorporation of the BAT. Infection must be treated without delay through either debridement, antibiotics, wound cleansing, or wound disinfection.

5. Hyperglycemia must be addressed in order to have successful incorporation of the BAT. Although the wound care specialist may not be able to directly influence this factor, all efforts need to be made to communicate with the primary care provider and patient to gain better control the patient’s blood sugar. Behavior modification regarding diet and exercise is always an immense challenge in the diabetic population. [23]

N ( Nonadherent Dressing)

It has been said that the choice of the wound dressing at one stage of the wound may well influence subsequent events in the later phases of healing. [24] In reviewing the protocols set forth by most BAT manufacturers, the one common denominator among all of them is the recommendation of a “nonadherent dressing” as the primary dressing to be used over the bioengineered tissue. (Table 1)

While the goal of the nonadherent dressing is to prevent trauma or adhesion of the secondary dressing to the BAT (or underlying tissues), few of these products possess the characteristics ideal for covering a bioengineered tissue. While it is possible for several different types of dressings to be employed over the BAT at once (i.e. petrolatum impregnated gauze, antibiotic cream, hydrogel, mineral oil followed by an absorptive 4” X 4” pad or a foam), this is impractical and expensive.

Ideal Characteristics of the Primary Dressing for Coverage over a BAT:

1. Nonadhesive
2. Antimicrobial
3. Ability to absorb exudate
4. Maintains moisture on the BAT and within the wound site
5. Non-cytotoxic
6. Cost-effective

Of the myriad of different dressing options available that meet some of the criteria mentioned above, the AmeriGel® Hydrogel Saturated Gauze Dressing is an excellent option that meets most if not all of the characteristics above.

Case Example using the BRAIN Principal

A 47 year-old diabetic patient with profound peripheral neuropathy developed a blister on the plantar aspect of her right heel that became recalcitrant to conservative treatment. The patient’s wound was debrided weekly and had Promogran™ (Johnson & Johnson Wound Management, Somerville, NJ) applied to the site until the wound developed a healthy granular base. Apligraf® was chosen to close the wound, secured in place by Steri-Strips™. AmeriGel® Hydrogel Saturated Gauze Dressing covered the BAT to provide an antimicrobial barrier. A dry sterile secondary dressing was then applied. The bioburden of the BRAIN principle had been accomplished. (Fig. 1)

Figure 1  The Bioburden of the wound has been addressed with debridement and diligent local wound care.

To achieve the reduction of pressure and shear force, a Bledsoe® boot was utilized along with a wheel chair. Due to the patient’s severe neuropathy, as well as other balance concerns, the patient could not use crutches. The primary and secondary dressings remained dry and intact for one week. (Fig. 2)

Figure 2  Reduction of pressure and shear force is essential for incorporation of the BAT.

Once the AmeriGel® Hydrogel Saturated Gauze Dressing was removed, the absorptive capability was evident as well as its ability to maintain a moist wound environment. (Fig. 3) This demonstrates adapting to the moisture needs of the BAT and of the wound.

Figure 3  Adapting to the moisture needs of the wound.  Here, a healthy moisture balance has been achieved using AmeriGel® Hydrogel Saturated Gauze Dressing after BAT application.

The patient returned at two weeks and Incorporation was achieved. The wound had already started to reduce in size and was considered to be a healthy granulating wound. There was no evidence of bleeding or absence of tissue caused by traumatic dressing changes. (Fig. 4)

Figure 4  Incorporation of the Apligraf®.  Reduction of wound size is already appreciated.

At 4 weeks and 4 days, after daily applications of the AmeriGel® Hydrogel Saturated Gauze Dressing and dry sterile gauze as the secondary dressing, the wound was healed.

The nonadherent secondary dressing played a significant role in healing this wound quickly and without the need for subsequent applications of the BAT. (Fig. 5)

Figure 5  Nonadherence of the surrounding secondary dressings will help ensure the viability of the BAT.  Using the AmeriGel® Hydrogel Saturated Gauze Dressing as a secondary dressing provides a non adherent and antimicrobial barrier to facilitate rapid wound healing.


Effective management of lower extremity ulcerations using bioengineered alternative tissues requires a multidisciplinary approach, patient involvement and the right use of the proper adjunctive tools available to the wound care specialist.

Diabetic foot ulceration is a limb and life threatening condition that requires the establishment of sound, evidence-based protocols. It is the hope of the author that protocols be established in every wound care clinic that are based upon patient outcomes, cost and ease of use for the wound care specialist and the patient.

A protocol as described above certainly may be modified depending on many factors that may or may not be present in the wound, however the core principles as presented in the acronym BRAIN should provide a road map to maximizing the effectiveness of bioengineered tissues before, during and after BAT application.


1. Kim PJ, Dybowski KS, Steinberg JS. A Closer Look at Bioengineered Alternative Tissues. Podiatry Today – ISSN: 1045-7860 – Volume 19 – Issue 7 – Pages: 38 – 55, July 2006.
2. Pham HT, Rich J, Veves A, Using Living Skin Equivalents for Diabetic Foot Ulceration: Lower Extremity Wound 1(1);27-32, 2002.
3. Falanga V, Sabolinski M. A bilayered living skin equivalent construct (Apligraf) accelerates complete closure of hard to heal venous ulcers. Wound Repair Regen 7:201-7, 1999.
4. Bello YM, Falabella AF, Eaglstein WH. Tissue-engineered skin, current status in wound healing. Am J. Clin Dermatol 2(5):303-313, 2001.
5. Claxton MJ, Armstrong DG, Boulton AJM. Healing the diabetic wound and keeping it healed: modalities for the early 21st century. Cur Diab Rep. 2(6):510-8, Dec 2002.
6. Lee KH. Tissue-engineered human skin substitutes; development and clinical application. Yonsei Medical Journal 41(6):774-779, 2000.
7. Reiber GE: Epidemiology and health care costs of diabetic foot problems. From: The Diabetic Foot: Medical and Surgical Management, edited by Veves A, Giurini JM, LoGerfo FW, Humana Press, Totowa NJ, 2002
8. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America, Second Edition. Washington, DC: National Diabetes Data Group, National Institutes of Health, 409-28, 1995.
9. American Diabetes Association. Economic consequences of diabetes mellitus in the U.S.in 1997. Diabetes Care 21:296–309, 1998.
10. Sibbald RG, Williamson D, Orsted HL, Campbell K, Keast D, Krasner D, Sibbald D, Preparing the Wound Bed-Debridement, Bacterial Balance and Moisture Balance. Ostomy Wound Mgt 46: 14-35, 2000.
11. Poon, VKM, Burd A. In vitro cytoxicity of silver: Implications for clinical Wound Care. Burns 30: 140-147, 2004.
12. Edmonds, ME, Foster AM, Sanders L A. Practical Manual of Diabetic Footcare. Oxford: Blackwell Publishing, 2004.
13. Armstrong, DG, Ngugen, HC, Lavery LA, et al. Offloading the diabetic foot wound: a randomized clinical trial. Diabetes Care 24:1019-1022, 2001.
14. Winter GD: Formation of scab and rate of epithelialization of superficial wounds in the skin of the young domestic pig. Nature 193:293-294, 1962.
15. Haimowitz JE, Margolis DJ: Moist wound healing, in Krasner D, Kane D (eds): Chronic Wound Care: A Clinical Source Book for Healthcare Professionals. Wayne, PA, Health Management Publications, 49-55, 1997.
16. Geronemus RG, Robin P. The effect of two new dressings on epidermal wound healing. J Derm Surg Oncol 8:850-2, 1982.
17. Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation by chronic wound fluid. Wound Rep Reg 1:181-6, 1993.
18. Coulomb B, Dubertret L. Skin cell culture and wound healing. Wound Repair Regen 10:109-12, 2002.
19. Rosales MA, Bruntz M, Armstrong DG. Gamma-irradiated human skin allograft; a potential treatment modality for lower extremity ulcers. Int. Wound J 1:201-206, 2004.
20. Shen JT, Falanga V. Innovative therapies in wound healing. J Cutan Med Surg 7(3):217-24, May-Jun 2003.
21. Eisenbud D. Huang, NF, Luke S. Silberklang M. Skin Substitutes and Wound Healing: Current Status and Challenges. Wounds 16(1): 2-17, 2004.
22. Sussman C, Bates-Jensen B. Wound healing biology and chronic wound healing. In: Wound Care- A Collaborative Practice Manual for Physical Therapists and Nurses. Gaithersburg, Md.: Aspen Publication 49–82, 1998.
23. Shultz GS, Sibbald GR, Falanga V, et al. Wound bed preparation: a systemic approach to wound management: Wound Rep Reg 11:1-28, 2003.
24. Kerstein MD. The scientific basis of healing. Adv Wound Care 10:30-6, 1997.

Address correspondence to: Jonathan Moore, DPM, MS, Cumberland Foot & Ankle Center. 117 Tradepark Drive, Somerset, KY 42503

1Cumberland Foot & Ankle Center. 117 Tradepark Drive, Somerset, KY 42503.

© The Foot & Ankle Journal, 2008

Delayed Primary Closure of Diabetic Foot Wounds using the DermaClose™ RC Tissue Expander

by David L. Nielson, DPM1, Stephanie C. Wu, DPM, MSc2, David G. Armstrong, DPM, PhD3

The Foot & Ankle Journal 1(2):3

Closure of large wounds has been a challenge in podiatric surgery, especially after large defects created by ulcer debridement, metatarsal resection and amputation. The DermaClose™ RC tissue expander allows for closure of large defects without the need for traditional complex skin closure, tissue grafting or creation of skin and tissue flaps. Skin anchors made of surgical steel clips are used with a tension controller to allow for gentle skin stretching on the subcutaneous planes of the wound or defect. It also has special application in the closure of chronic wounds. Two case reports are presented to describe this technique.

ISSN: 1941-6806/08/0102-0003
doi: 10.3827/faoj.2008.0102.0003

Mechanically assisted delayed primary closure of large foot wounds following emergency or ablative surgery will result in faster healing and assist in enhanced closure of a large tissue defect. The technique of rapid wound closure is enhanced with the use of the DermaClose™ RC tissue expanding device. The application of the device is simple and provides for a less complex treatment course than secondary wound closure.

Tissue expansion was first employed by placing straight wires (0.045-0.062) though the skin adjacent to the wound. Special ratcheting devices, suture, or 28 gauge wire are used to bring the straight wires closer thus exploiting stress relaxation inherent in skin. [1-4] A variety of companies make several devices to accomplish the same goal today. Mechanically assisted wounds have been shown to close up to 40% quicker than traditional secondary intention healing. [1]

When a wound is created, healing is either by primary closure if enough tissue is available or by secondary intention healing. Many times, in podiatry, large wounds and defects are created after ulcer debridement, metatarsal or bone resection and amputation. Secondary intention wound healing can be facilitated by a variety of modalities including local wound care, negative pressure vacuum therapy, hyperbaric therapy, tissue growth factors and application of bioengineered tissue equivalents. However, secondary intention healing of the defect often take weeks or months adding to the cost of wound and palliative care.

Delayed primary closure can also be challenging, especially in the foot. Many times this will include complex tissue closure, tissue grafts and adjacent tissue flaps to promote full wound closure.

The tissue expansion device now allows for rapid closure. It can also provide cost savings in respect to decreasing the need for prolonged wound care. We present two case reports describing the use of the DermaClose™ tissue expanding device.

Case #1

A 59 year old Caucasian male presents to our clinic with a chronic 3 year wound after a hallux and 2nd digital amputation. The patient has a long history of diabetes mellitus and has undergone kidney transplantation.

Application of the DermaClose™ device was initiated and it required about 3 months to close completely. The patient was taking immunosuppressive medication during this time, which may explain the prolonged closure rate.

The surgical site is thoroughly cleansed before application of the tissue anchors. A suture loop is then placed through the anchors and tension is applied by the device. In this case, a figure-8 suture was used to apply uniform tension perpendicular to the skin edges. (Fig.1)

Figure 1 Case #1 shows the patient post amputation with local dehiscence of the wound edges. Here, the DermaClose Clips are placed around the wound and the wound edges are approximated under tension. The suture is applied in a circular or figure-8 fashion. It is important to also protect the foot with foam from the overlying tension device.

Case #2

A 42 year old African-American male presents to our clinic after stepping on a bottle cap in March 2007. The patient is a poorly controlled diabetic with serum glucose running between 250 and 350 mg/dL. His medications include oral hypoglycemics, injectable Insulin and cholesterol lowering drugs. Unfortunately, he developed infection and underwent incision and drainage of deep space abscess with second partial metatarsal resection and digital amputation.

Prior to delayed closure and use of the DermaClose™ device, the patient underwent a series of wound care treatments, negative pressure wound VAC and application of Graft Jacket. After several months, the amputation site failed to close and a large, granulating defect remained. (Fig. 2)

Figure 2 Case #2 represents a large, chronic post-amputation defect.

In order to promote final closure, the DermaClose™ tissue expanding device was applied. Preparation of the wound consists of surgical debridement of all non-viable tissue. The wound edges are undermined about 2cm from the wound edge. (Fig. 3)

Figure 3 The wound must be surgically debrided of all non-viable tissue prior to application of the device. The device is applied and within 3 days the dorsal defect closed. Here, the anchors are tensioned in a shoe-lace fashion.

During the tension phase, the patient remained in a CAM boot and underwent daily dressing changes. Final closure of the defect was accomplished within just a few days of application. (Fig. 4,5)

Figure 4 Closure of the chronic wound using the DermaClose device.

Figure 5 Plantar view of the closed wound. A separate DermaClose device was applied plantarly.


The device describe, (DermaClose™, Wound Care Technologies, Chanhassen, MN, USA) consist of skin anchors made of 316L surgical stainless steel and placed circumferential to the wound 1-1.5 cm from the wound edge.

The anchors penetrate the skin and into the subcutaneous tissue. Each anchor is held in place with two skin staples. A monofilament, high strength suture is then woven around each anchor.

The suture is then tightened to approximately 1.3kg of force, bringing the wound edges closer together. Once the dynamic tension is reached, additional tightening is not needed.

Patients should be seen every 3-5 days for evaluation of the device and the tissue movement. Care should be noted that the anchors do not envelop or imprint into the skin.

The DermaClose™ tension controller is attached around each skin anchor and the knob of the tension device is rotated until a clutch mechanism provides an audible indication that full tension has been achieved. The device now maintains the proper amount of tension to gently stretch the skin on the subcutaneous planes around the wound until the edges of the wound are brought close enough together for final suturing and closure.


In both cases, the wounds are considered chronic, diabetic wounds. The rate of closure varied in case #1 due to immunosuppressive therapy. In general, the DermaClose™ device will provide rapid closure of an otherwise chronic or stagnant wound.

In one of the first studies to evaluate rates of mechanically assisted closure, Armstrong and Lavery reported that closure can be assisted approximately 40% faster than by secondary intension healing alone. [1]

Optimal results were obtained by strict off-loading of the foot during the tension phase of treatment, debridement with meticulous and frequent wound care. Armstrong and Lavery also identified the average healing time of a standard wound was similar to total contact casting.

Both cases represent a cross-sectional example of a small, chronic wound and a larger defect after amputation. Both responded favorably to mechanically induced delayed primary closure.


As one advances from the simple to the complex wound, the theoretical risk for complications increases. Therefore, specialist working in this area should always try to expand his or her armamentarium to assist in wound simplification and closure. Skin stretching devices are among some of these tools. At the Center for Lower Extremity Ambulatory Research (CLEAR), we are experiencing success in utilizing such devices to augment the closure of wounds. Members of CLEAR were amongst the first to evaluate this technique in the lower extremity more than a decade ago. We believe that the quality and breadth of these devices are improving. This can only benefit us as we move forward.


1. Armstrong DG, Lavery LA. Mechanically Assisted, Delayed Primary Closure of Diabetic Foot Wounds. JAPMA;88(10):483-488, 1998.
2. Armstrong DG, Sorensen JS, Bushman TB. Exploiting the viscoelastic properties of pedal skin with the sure-closure skin stretching device. JFAS;34(3):247-253, 1995.
3. Armstrong DG, Wunderlich RP, Lavery LA. Reaching closure with skin stretching. Applications in the diabetic foot. Clin Podiatr Med Surg;15(1):109-116, 1998.
4. Hirshowitz B, Lindenbaum E, Har-Shai Y. A skin-stretching device for the harnessing of the viscoelastic properties of skin. Plast Reconst Surg.;92:260-267, 1993.

1,2,3 Scholl’s Center for Lower Extremity Ambulatory Research (CLEAR) at Rosalind Franklin University of Medicine and Science.

© The Foot & Ankle Journal, 2008

[Download PDF File for Printing]