A Prospective, Open-Label, Nonrandomized Clinical Trial Using Polyvinyl Alcohol Antibacterial Foam for Debridement of Diabetic Foot Ulcers

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DFUs are ominous for patients and can result in chronic inflammation, reduced mobility, and chronic pain. These wounds are particularly susceptible to both superficial and deep infection, and high costs are associated with their care and treatment. Although DFUs are less common in the United States than in other countries, the cost of care is higher in the United States. In the United States, an estimated 29.1 million people have diabetes,^1,2 and the estimated lifetime incidence of DFU is 25%.³ DFUs continue to be a major cause of morbidity and immobility, and they are a leading cause of nontraumatic lower extremity amputation.

From an economic standpoint, the health care system and work productivity are most negatively affected by the societal burdens of DFUs. In the United States, the estimated cost of DFUs is between $9 billion and $13 billion annually. The annual direct cost of diabetes in the United States alone is $237 billion, with an additional $90 billion in lost productivity. Approximately one-third of the direct costs were for the care of patients with complications of pedal diabetes. The 3-year mortality rate of this population is approximately 28.4%.⁴

Treatment of chronic DFUs is arduous, demanding a comprehensive approach that encompasses multiple therapies, including debridement, negative pressure wound therapy, hyperbaric oxygen therapy, and offloading^.5-17 It is worth noting that there is no universally accepted standard of care or established best clinical practice for managing diabetic foot wounds.¹² However, of the available treatment options, the criterion standard comprises weekly debridement and the use of total contact casting. Astonishingly, despite being the preferred clinical practice, total contact casting comprises only 2% of the treatments used in patients with a DFU.

A wide variety of dressings are available for use in the management of both acute wounds and chronic nonhealing wounds. The US wound dressing market alone is predicted to exceed $2.5 billion annually by 2027,¹⁸ which demonstrates the magnitude of the effect of acute and chronic nonhealing wounds on public health. The use of PVA foam with GV/MB has been previously discussed in the literature for wound management based on its properties of super absorption, promotion of autolytic debridement, bioburden reduction, ease of use, and decreased frequency of dressing changes.^19-21

The precise mechanisms of the antibacterial properties of GV/MB foam dressings remain somewhat elusive, yet several proposed mechanisms shed light on their mode of action. GV and MB organic dyes possess redox potentials within the range of various electron transport components involved in oxidative metabolism. This has led to the postulation that these dyes function by disrupting electron transport pathways, effectively creating a "short circuit." Bacteria rely on a delicate balance between reductive and oxidative processes to survive, and GV/MB dressings are believed to disrupt this balance, rendering bacterial life unsustainable. Studies have indicated that GV/MB dressings modify the wound environment to inhibit bacterial growth. Both GV and MB dyes are positively charged, with differential activity observed against gram-negative and gram-positive bacteria.

One contributing factor to the effectiveness of GV/MB foams is the selective binding of the dyes to the PVA or PU components of the dressing. This prevents them from being washed away and diluted, resulting in a concentrated local dye presence that has proved highly effective in eradicating bacteria. This reduction in bacteria can lead to decreased odor as well. The dye transfers from the PVA or PU to bacterial cells on contact with the dyed foam, with initial experiments confirming that GV/MB foams impregnated with dye do not support bacterial growth and do effectively eliminate living bacteria, thus verifying their bactericidal properties.²²

The nonresidual nature of GV/MB dressings distinguishes them from other antimicrobial dressings; GV/MB dressings do not degrade and release particles into the wound bed. Instead, the antibacterial action occurs within the foam itself. The dyes bind to the bacteria before exerting their bactericidal effects. Laboratory staining techniques using high concentrations of these dyes to identify specific bacterial and viral strains exemplify this mechanism. The dye is released from the PVA or PU and binds to bacteria only when necessary, thus conserving its antibacterial activity.²³

This single-center study conducted at West Boca Center for Wound Healing in Coconut Creek, Florida involved 20 patients. Age, sex, race, and weight were self-reported to the investigator to ensure proper demographic groups would be represented, however, the clinical study group was taken from the investigator’s patient populations at the time of study initiation. The author was the sole investigator for the study population. Data analysis of prospective longitudinal data collected from the single center was performed. New England Independent IRB (now part of WCG Clinical) reviewed this study and approved it under the Basic US Department of Health and Human Services Policy for Protection of Human Research Subjects (21 CFR 50 and 45 CFR §46).

The current clinical trial was conducted in accordance with the principles of Good Clinical Practice as designed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and applicable regulatory requirements. The trial was designed to ensure the safety, rights, and well-being of all participating human subjects, maintain the integrity and reliability of the data generated, and adhere to ethical principles throughout the trial conduct.

Records of patients with full-thickness chronic lower extremity wounds (DFU, venous leg ulcer) who received treatment with a PVA foam with GV/MB antimicrobial dyes (PVA GV/MB) (Hydrofera Classic; Hydrofera LLC) applied in an outpatient setting (West Boca Center for Wound Healing) between September 2019 and December 2020 were included in the prospective longitudinal analysis. All patients provided written informed consent prior to study initiation.

PAD was assessed using the Peripheral Vascular Disease Screening Quesionnaire (Figure 1). This form was used to standardize patients as having PAD independent of their diabetes history during the study period.

The PVA GV/MB foam was applied during TVs 1 through 4 (Figure 2). Application duration was 30 days, with repeated application once weekly for 4 weeks; the ulcer and affected lower extremity were evaluated at each visit. At each TV, the wounds were analyzed for bacterial fluorescence using a fluorescence imaging device (MolecuLight i:X; MolecuLight, LLC). Images were obtained both before and after application of the PVA foam. The fluorescence imaging device was also used to collect wound measurements per the instructions-for-use indications (Figure 2). Patients were followed up at 3 and 6 months. At the TVs, the study dressing was applied to the study ulcer and then covered with 4-inch × 4-inch gauze and Kerlix (Cardinal Health). All imaging done using the fluorescence device was performed per manufacturer specifications and training governing use of the device.

Demographic data are detailed in Table 1. The study included 13 males and 7 females, with an overall average age of 64.2 years (range, 45–83 years). The average BMI was 29.5. Of the 20 patients, 1 was African American, 17 were White, and 2 were Hispanic. The average ABI was 1.2, and the average SPP was 63.2 mm Hg. The average duration of DFU was 9.0 weeks. No patients were lost during the data collection period, and no patient voluntarily or involuntarily exited the study during its duration.

Seventeen patients were diagnosed with diabetic peripheral neuropathy. Three patients had undergone prior partial amputation of the affected foot. All 20 patients had clinical evidence of risk factors for PAD, and 18 patients had markedly elevated ABIs with associated segment SPP below 50 mm Hg. As noted previously, PAD independent of diabetes history was established using the Peripheral Vascular Disease Screening Quesionnaire.

Patients underwent weekly wound cleansing with normal saline, assessment of wound fluorescence and digital measurement using the fluorescence imaging device, and reapplication of PVA GV/MB foam dressing along with sterile 4-inch × 4-inch gauze and Kerlix.

Initial average DFU size was 5.22 cm² (range, 1.2–9 cm²). After 4 weeks of therapy with PVA GV/MB foam dressings, average wound size had decreased 53% to 2.5 cm² (range, 0–11.25 cm²). Four patients achieved complete wound closure at week 4. The median percentage area reduction was 39% across all patients with DFUs. Ten patients achieved greater than 40% reduction in ulcer size by week 4. Compared with patients without prior amputation, the 3 patients with prior amputation had the lowest percentage area reduction in ulcer size: 14%, 32%, and 34%.

A Pearson Coefficient was performed relative to the week 4 area reduction measurements against the initial measurements taken at week 0. The coefficient of 0.81 demonstrates a strong relationship between reduction in ulcer size with use of surgical debridement and PVA GV/MB foam in this setting. This statistical relationship is consistent with the hypothesized use of the dressing in this study format.

Wound fluorescence data demonstrated reduction of red- and cyan-colored bacterial presence in all 20 patients by end of study (ie, week 4). Only 1 patient (patient 4) continued to exhibit bacterial fluorescence by week 4. In all 20 patients, fluorescent imaging showed moderate to heavy red- or cyan-fluorescing bacterial loads at weeks 1 and 2. By week 3, 16 patients had no or low fluorescence of bacteria. No false negatives were observed or recorded.

At 3- and 6-month follow-up, all 20 patients retained evidence of their DFU either by visual inspection or follow-up examination regardless of closure therapies provided after the 4-week trial period. No patient experienced a worsening of their DFU, nor did any patient sustain a second DFU in the affected extremity within the designated follow-up at 3 or 6 months.

Overall, debridement, offloading, and the use of PVA GV/MB foam were successful for debridement of DFUs in a population of advanced age with diabetes and with above normal BMI, with an average decrease in DFU size of 53% in these 20 patients. Follow-up at 3 and 6 months showed no residual or recurrent ulcerations in any of the 20 patients. This compares to most standard of care modalities as mildly advanced and accelerated, as standard of care rarely shows greater than 30% to 35% wound area reduction by week 12.²⁴

During the 4-week treatment period, aggressive surgical debridement and application of PVA was hypothesized to encourage rapid reduction of protease activity in the wound and to reduce the inflammatory burdens on diabetic ulcer metabolism. It is widely known that increased levels of MMP-9 are present in wounds and are implicated in delayed healing.^16,17 It is also pertinent that the 2 pigments of PVA foam—GV and MB—are well known to have antiseptic characteristics that help protect the wound environment from outside influences of bacterial colonization.^13,19,20

The use of the fluorescence imaging device was successful in this study; it showed decreased bacterial fluorescence in wounds properly managed with cleansing, debridement, and antibacterial PVA foam application. The low amounts of fluorescence detected by week 4 demonstrate the effectiveness of PVA GV/MB foam in this environment and is a useful tool for detecting bacteria at levels greater than or equal to 10⁴ CFU/g in the early weeks of DFU treatment. This clinical information is necessary to help the provider maintain control of the inflammatory mediators that destroy and damage the wound bed.²⁵ As a diagnostic tool, immunofluorescent imaging helps aid the health care provider in targeted debridement of the wound and wound edges, determining the course of therapy, and may inform the ability to plan surgical skin grafting readiness of the target area and/or help establish potential cellular tissue product application protocol.^21,26

The current study did not differ from previous studies in terms of rate of wound reduction with use of PVA GV/MB foam.¹³ In previously described clinical cases, the efficacy of GV/MB antibacterial foam dressing affirmed the clinical success of GV/MB, medical-grade honey, and moist dressing control in debriding eschar in porcine wound models.¹³

The results of the current study indicate that robust healing of chronic DFUs can be achieved with the use of sound surgical debridement and application of a PVA GV/MB foam in patients with advanced age, increased BMI, and abnormal ABI/SPP.

In the current study, at 4 weeks, the average percentage area reduction was 43% in the 12 patients with confirmed PAD on screening vascular testing, compared with 60% in the 8 patients without PAD (Table 2). This finding highlights the need to properly screen patients for PAD in the presence of any history of diabetes, particularly in patients with DFU. Although the patients with PAD in the current study did not need vascular intervention, it is important that the treating physician understands the necessity of innate angiosomal flow to achieve healing in these patients.

This study had limitations. Although the results are promising, this was a noncontrolled, nonrandomized, single-site study with no comparator and with patient selection bias. A larger, controlled, comparative study could be useful to understand the incremental effect of using PVA GV/MB foam in patients with a DFU. The smaller population in the current study is similar to other single-center cohort studies. A larger patient cohort would lend itself to better mean sampling and reduction of deviation bias, but the management of those additional patients would not change the findings based on this 20-patient study. Since the current study did not include data on cost, amputation, or death in relation to the standard of care, it could not address any type of predictive model that can accurately assess the cost relationship with this prescribed treatment.²⁷

In the current study, the percentage area reduction of chronic DFUs was achieved with local surgical debridement and 1 or more applications of a PVA GV/MB foam in patients with advanced age, above-normal BMI, and wounds with greater than 4 weeks of nonprogressive healing. Further, at 3- and 6-month follow-up, all 20 ulcers remained closed and had not re-ulcerated. The treatment protocol described in the current study can be used in varying types of facilities in which patients receive wound care services to accelerate wound healing in these at-risk patients with diabetes.

Author: Eric Lullove, DPM, CWSP, DABLES

Affiliation: West Boca Center for Wound Healing, Coconut Creek, FL

ORCID: 0000-0001-7844-7767

Disclosure: This clinical study was funded by an unrestricted educational investigator research study grant by Hydrofera, LLC. The clinical research was performed independently and without influence of or input by Hydrofera, LLC. Dr Lullove is a consultant and scientific advisor to Hydrofera LLC/Essity, Inc.

Correspondence: Eric Lullove, DPM; Chief Medical Officer, West Boca Center for Wound Healing, Clinical, 4855 W. Hillsboro Blvd., Ste B6, Coconut Creek, FL 33073; drlullove@drlullove.com

Manuscript Accepted: January 17, 2024