Mode of action of poloxamer‐based surfactants in wound care and efficacy on biofilms

Surfactants are widely used as detergents, emulsifiers, wetting agents, foaming agents, and dispersants in both the food and oil industry. Their use in a clinical setting is also common, particularly in wound care. Complicated or chronic wounds show clinical signs of delayed healing, persistent inflammation, and the production of non‐viable tissue. These types of wounds also present challenges such as infection and potentially house antimicrobial‐tolerant biofilms. The use of wound cleansers to aid cleaning and debridement of the wound is essential. A large proportion of skin and wound cleansers contain surfactants but there is only a small amount of data that shows the effectiveness of them in the enhancement of wound closure. This review paper aims to explore the available literature surrounding the use and mode of action of surfactants in wound healing, in particular Poloxamer 188 (Pluronic F‐68) and Poloxamer 407 (Pluronic F‐127), and also uncover the potential mechanisms behind the enhancement of wound healing and comparison to other surfactants used in wound care. Furthermore, the presence of a microbial biofilm in the wound is a significant factor in delayed wound healing. Therefore, the effect of clinically used surfactants on biofilms will be discussed, with emphasis on poloxamer‐based surfactants.     

Effectiveness of biofilm‐based wound care system on wound healing in chronic wounds

A biofilm plays a crucial role in delaying wound healing. Sharp debridement, a possible effective method for eliminating biofilms, can only be applied to the wound with visible necrotic tissue; thus, no option has been available for eliminating biofilms that are not accompanied by necrotic tissue. Wound blotting was recently developed to visualize biofilm noninvasively and quickly, and ultrasonic debridement is available for biofilm removal. Therefore, the purpose of this study was to investigate the efficacy of “biofilm‐based wound care system (BWCS),” a combination of wound blotting as a point‐of‐care testing and ultrasonic debridement, for promoting wound healing. Firstly, the cross‐sectional study was conducted to examine the proportion of biofilm removal by ultrasonic debridement in pressure ulcers [Study 1]. Subsequently, the retrospective cohort study was conducted to examine the effectiveness of BWCS for healing of chronic wounds [Study 2]. The proportions of wound healing between wounds treated with BWCS and those with standard care in the home‐visiting clinic were compared by Kaplan–Meier curve, and the Cox proportional hazard modeling was used to assess the effect of BWCS on wound healing. In Study 1, the median of biofilm removal proportion was 38.9% (interquartile range, 12.9–68.0%) for pressure ulcers treated with standard care and 65.2% (41.1–78.8%) for those treated with ultrasonic debridement (p = 0.009). In Study 2, the proportion of wound healing within 90 days was significantly higher in wounds treated with BWCS than in those treated with standard care (p = 0.001). The adjusted hazard ratio of BWCS for wound healing was 4.5 (95% confidence interval, 1.3–15.0; p = 0.015). In conclusion, we demonstrated that our novel approach, BWCS, can be a promising therapeutic strategy for visualizing biofilms that are not accompanied by necrotic tissue and promoting healing in chronic wounds.     

Time course study of delayed wound healing in a biofilm‐challenged diabetic mouse model

Bacterial biofilm has been shown to play a role in delaying wound healing of chronic wounds, a major medical problem that results in significant health care burden. A reproducible animal model could be very valuable for studying the mechanism and management of chronic wounds. Our previous work showed that Pseudomonas aeruginosa (PAO1) biofilm challenge on wounds in diabetic (db/db) mice significantly delayed wound healing. In this wound time course study, we further characterize the bacterial burden, delayed wound healing, and certain aspects of the host inflammatory response in the PAO1 biofilm‐challenged db/db mouse model. PAO1 biofilms were transferred onto 2‐day‐old wounds created on the dorsal surface of db/db mice. Control wounds without biofilm challenge healed by 4 weeks, consistent with previous studies; none of the biofilm‐challenged wounds healed by 4 weeks. Of the biofilm‐challenged wounds, 64% healed by 6 weeks, and all of the biofilm‐challenged wounds healed by 8 weeks. During the wound‐healing process, P. aeruginosa was gradually cleared from the wounds while the presence of Staphylococcus aureus (part of the normal mouse skin flora) increased. Scabs from all unhealed wounds contained 10⁷ P. aeruginosa, which was 100‐fold higher than the counts isolated from wound beds (i.e., 99% of the P. aeruginosa was in the scab). Histology and genetic analysis showed proliferative epidermis, deficient vascularization, and increased inflammatory cytokines. Hypoxia inducible factor expression increased threefold in 4‐week wounds. In summary, our study shows that biofilm‐challenged wounds typically heal in approximately 6 weeks, at least 2 weeks longer than nonbiofilm‐challenged normal wounds. These data suggest that this delayed wound healing model enables the in vivo study of bacterial biofilm responses to host defenses and the effects of biofilms on host wound healing pathways. It may also be used to test antibiofilm strategies for treating chronic wounds.     

The wound‐healing effects of a next‐generation anti‐biofilm silver Hydrofiber wound dressing on deep partial‐thickness wounds using a porcine model

Topical antimicrobials are widely used to control wound bioburden and facilitate wound healing; however, the fine balance between antimicrobial efficacy and non‐toxicity must be achieved. This study evaluated whether an anti‐biofilm silver‐containing wound dressing interfered with the normal healing process in non‐contaminated deep partial thickness wounds. In an in‐vivo porcine wound model using 2 pigs, 96 wounds were randomly assigned to 1 of 3 dressing groups: anti‐biofilm silver Hydrofiber dressing (test), silver Hydrofiber dressing (control), or polyurethane film dressing (control). Wounds were investigated for 8 days, and wound biopsies (n = 4) were taken from each dressing group, per animal, on days 2, 4, 6, and 8 after wounding and evaluated using light microscopy. No statistically significant differences were observed in the rate of reepithelialisation, white blood cell infiltration, angiogenesis, or granulation tissue formation following application of the anti‐biofilm silver Hydrofiber dressing versus the 2 control dressings. Overall, epithelial thickness was similar between groups. Some differences in infiltration of specific cell types were observed between groups. There were no signs of tissue necrosis, fibrosis, or fatty infiltration in any group. An anti‐biofilm silver Hydrofiber wound dressing did not cause any notable interference with normal healing processes.     

Increasing the presence of biofilm and healing delay in a porcine model of MRSA‐infected wounds

Data supporting the concept that microbial biofilms are a major cause of non‐healing ulcers remain limited. A porcine model was established where delayed healing resulted from methicillin‐resistant Staphylococcus aureus (MRSA) infection in full‐thickness wounds. At the end of one study a wound remaining open was sampled and a MRSA strain was isolated. This pig‐passaged strain was used as the inoculating strain in several subsequent studies. The resulting MRSA wound infections exhibited a greater, more stable tissue bioburden than seen in studies using the parent strain. Furthermore, wounds infected with the passaged strain experienced a greater delay in healing. To understand whether these changes corresponded to an increased biofilm character of the wound infection, wound biopsy samples from studies using either the parent or passaged MRSA strains were examined microscopically. Evidence of biofilm was observed for both strains, as most samples at a minimum had multiple isolated, dense microcolonies of bacteria. However, the passaged MRSA resulted in bacterial colonies of greater frequency and size that occurred more often in concatenated fashion to generate extended sections of biofilm. These results provide a model case in which increasing biofilm character of a wound infection corresponded with a greater delay in wound healing.     

Noncontact,low‐frequency ultrasound as an effective therapy against Pseudomonas aeruginosa–infected biofilm wounds

Bacterial biofilms, a critical chronic wound mediator, remain difficult to treat. Energy‐based devices may potentially improve healing, but with no evidence of efficacy against biofilms. This study evaluates noncontact, low‐frequency ultrasound (NLFU) in the treatment of biofilm‐infected wounds. Six‐millimeter dermal punch wounds in rabbit ears were inoculated with 10⁷ colony‐forming units of Pseudomonas aeruginosa or left as sterile controls. A biofilm was established in vivo using our published model. NLFU treatment was carried out every other day or every day, with contralateral ear wounds acting as internal, untreated controls. Wounds were harvested for several quantitative endpoints and scanning electron microscopy to evaluate the biofilm structure. The P. aeruginosa biofilm consistently impaired wound epithelialization and granulation. NLFU, both every other day and every day, improved healing and reduced bacterial counts relative to untreated controls (p < 0.05). Scanning electron microscopy confirmed a qualitative decrease in bacteria after both treatments. NLFU also reduced inflammatory cytokine expression (p < 0.05). Our study suggests that NLFU is an effective therapy against P. aeruginosa wound biofilm. This represents the first in vivo evidence of energy‐based modalities' impact on wound biofilm, setting the foundation for future mechanistic studies. Continued wound care technology research is essential to improving our understanding, and treatment, of biofilm‐infected chronic wounds.     

A prospective randomised open label study to evaluate the potential of a new silver alginate/carboxymethylcellulose antimicrobial wound dressing to promote wound healing

The aim of this study was to observe both the clinical signs and symptoms of wounds at risk of infection, that is critically colonised (biofilm infected) and antimicrobial‐performance of an ionic silver alginate/carboxymethylcellulose (SACMC) dressing, in comparison with a non silver calcium alginate fibre (AF) dressing, on chronic venous leg and pressure ulcers. Thirty‐six patients with venous or pressure ulcers, considered clinically to be critically colonised (biofilm infected), were randomly chosen to receive either an SACMC dressing or a non silver calcium AF dressing. The efficacy of each wound dressing was evaluated over a 4‐week period. The primary study endpoints were prevention of infection and progression to wound healing. The SACMC group showed a statistically significant (P = 0·017) improvement to healing as indicated by a reduction in the surface area of the wound, over the 4‐week study period, compared with AF controls. In conclusion, the SACMC dressing showed a greater ability to prevent wounds progressing to infection when compared with the AF control dressing. In addition, the results of this study also showed an improvement in wound healing for SACMC when compared with a non silver dressing.     

Surfactants: Role in biofilm management and cellular behaviour

Appropriate and effective wound cleaning represents an important process that is necessary for preparing the wound for improved wound healing and for helping to dislodge biofilms. Wound cleaning is of paramount importance to wound bed preparation for helping to enhance wound healing. Surfactant applications in wound care may represent an important area in the cleaning continuum. However, understanding of the role and significance of surfactants in wound cleansing, biofilm prevention and control, and enhancing cellular viability and proliferation is currently lacking. Despite this, some recent evidence on poloxamer‐based surfactants where the surfactants are present in high concentration have been shown to have an important role to play in biofilm management; matrix metalloproteinase modulation; reducing inflammation; and enhancing cellular proliferation, behaviour, and viability. Consequently, this review aims to discuss the role, mode of action, and clinical significance of the use of medically accepted surfactants, with a focus on concentrated poloxamer‐based surfactants, to wound healing but, more specifically, the role they may play in biofilm management and effects on cellular repair.     

Cadexomer iodine effectively reduces bacterial biofilm in porcine wounds ex vivo and in vivo

Biofilms are prevalent in non‐healing chronic wounds and implicated in delayed healing. Tolerance to antimicrobial treatments and the host's immune system leave clinicians with limited interventions against biofilm populations. It is therefore essential that effective treatments be rigorously tested and demonstrate an impact on biofilm across multiple experimental models to guide clinical investigations and protocols. Cadexomer iodine has previously been shown to be effective against biofilm in various in vitro models, against methicillin‐resistant Staphylococcus aureus biofilm in mouse wounds, and clinically in diabetic foot ulcers complicated by biofilm. Similarities between porcine and human skin make the pig a favoured model for cutaneous wound studies. Two antiseptic dressings and a gauze control were assessed against mature biofilm grown on ex vivo pig skin and in a pig wound model. Significant reductions in biofilm were observed following treatment with cadexomer iodine across both biofilm models. In contrast, silver carboxymethylcellulose dressings had minimal impact on biofilm in the models, with similar results to the control in the ex vivo model. Microscopy and histopathology indicate that the depth of organisms in wound tissue may impact treatment effectiveness. Further work on the promising biofilm efficacy of cadexomer iodine is needed to determine optimal treatment durations against biofilm.     

Assessment and documentation of non‐healing,chronic wounds in inpatient health care facilities in the Czech Republic: an evaluation study

The foundation of health care management of patients with non‐healing, chronic wounds needs accurate evaluation followed by the selection of an appropriate therapeutic strategy. Assessment of non‐healing, chronic wounds in clinical practice in the Czech Republic is not standardised. The aim of this study was to analyse the methods being used to assess non‐healing, chronic wounds in inpatient facilities in the Czech Republic. The research was carried out at 77 inpatient medical facilities (8 university/faculty hospitals, 63 hospitals and 6 long‐ term hospitals) across all regions of the Czech Republic. A mixed model was used for the research (participatory observation including creation of field notes and content analysis of documents for documentation and analysis of qualitative and quantitative data). The results of this research have corroborated the suspicion of inconsistencies in procedures used by general nurses for assessment of non‐healing, chronic wounds. However, the situation was found to be more positive with regard to evaluation of basic/fundamental parameters of a wound (e.g. size, depth and location of a wound) compared with the evaluation of more specific parameters (e.g. exudate or signs of infection). This included not only the number of observed variables, but also the action taken. Both were significantly improved when a consultant for wound healing was present (P = 0·047). The same applied to facilities possessing a certificate of quality issued by the Czech Wound Management Association (P = 0·010). In conclusion, an effective strategy for wound management depends on the method and scope of the assessment of non‐healing, chronic wounds in place in clinical practice in observed facilities; improvement may be expected following the general introduction of a ‘non‐healing, chronic wound assessment’ algorithm.     

Wound healing in US medical school curricula

Approximately 6.5 million Americans suffer from nonhealing wounds. As physicians are increasingly expected to manage chronic wounds, the degree to which formalized wound care education exists as a clinical rotation is unclear. For the first time, the prevalence and characteristics of formal wound electives offered by US medical schools are documented. Online surveys were distributed to 134 US medical schools and to the 74 medical students who completed the wound healing elective at the University of Miami regarding their experiences. School response rate was 41% (n = 55). We found that out of 55 schools, only 7 schools offered a formal wound healing elective. The University of Miami was the only school to include a surgical component. Students' response rate was 39% (n = 29). After completing the elective, 20 students (69%) felt confident in their knowledge of surgical and medical wound management. A majority of students (76%, n = 22) felt that the elective was an important part of the medical school curriculum. In conclusion, we found very few schools offer a formal wound elective and recommend medical schools in formalizing this education through clinical electives. Education should be team‐based and multidisciplinary; evidence exists that this is the best approach to managing chronic wounds. Basic tenets of wound care, both medical and surgical, should be emphasized.     

Bacterial chatter in chronic wound infections

One of the hallmark characteristics of chronic diabetic wounds is the presence of biofilm‐forming bacteria. Bacteria encapsulated in a biofilm may coexist as a polymicrobial community and communicate with each other through a phenomenon termed quorum sensing (QS). Here, we describe the QS circuits of bacterial species commonly found in chronic diabetic wounds. QS relies on diffusion of signaling molecules and the local concentration changes of these molecules that bacteria experience in wounds. These biochemical signaling pathways play a role not only in biofilm formation and virulence but also in wound healing. They are, therefore, key to understanding the distinctive nature of these infections. While several in vivo and in vitro models exist to study QS in wounds, there has been limited progress in understanding the interplay between QS molecules and host factors that contribute to wound healing. Lastly, we examine the potential of targeting QS for both diagnosis and therapeutic intervention purposes.     

Role of anaerobes in polymicrobial communities and biofilms complicating diabetic foot ulcers

Infected tissues in the feet of people with diabetes in the form of a diabetic foot ulcer (DFU) present a complex pathology for clinicians to manage. This is partly attributed to the multi‐factorial nature of the disease, which may include; altered foot architecture leading to excessive plantar pressures and frictional forces peripheral arterial disease and loss of protective sensation. In addition, to the above co‐morbid variables, it is understood that a delayed wound healing state may be perpetuated by the presence of microorganisms residing in the wound tissue. The microbiology of chronic DFUs has often been reported as being polymicrobial. Of growing interest is the presence and potential role of anaerobic microorganisms in the pathology of DFUs and how they may contribute to the infective process or delayed healing. The presence of anaerobes in DFUs has been greatly underestimated, largely due to the limitations of conventional culture methods in identifying them from samples. Advancements in molecular and microscopy techniques have extended our view of the wound microbiome in addition to observing the growth and behaviour (planktonic or biofilm) of microorganisms in situ. This review paper will reflect on the evidence for the role and significance of anaerobes in DFUs and infection. A focus of this review will be to explore recent advancements in molecular genomics and microscopy techniques in order to better assess the roles of anaerobic bacteria in chronic DFUs and in biofilm‐based wound care.     

Microscopy visualisation confirms multi‐species biofilms are ubiquitous in diabetic foot ulcers

Increasing evidence within the literature has identified the presence of biofilms in chronic wounds and proposed that they contribute to delayed wound healing. This research aimed to investigate the presence of biofilm in diabetic foot ulcers (DFUs) using microscopy and molecular approaches and define if these are predominantly mono‐ or multi‐species. Secondary objectives were to correlate wound observations against microscopy results in ascertaining if clinical cues are useful in detecting wound biofilm. DFU tissue specimens were obtained from 65 subjects. Scanning electron microscopy (SEM) and peptide nucleic acid fluorescent in situ hybridisation (PNA‐FISH) techniques with confocal laser scanning microscopy (CLSM) were used to visualise biofilm structures. Next‐generation DNA sequencing was performed to explore the microbial diversity. Clinical cues that included the presence of slough, excessive exudate, a gel material on the wound bed that reforms quickly following debridement, poor granulation and pyocyanin were correlated to microscopy results. Of the 65 DFU specimens evaluated by microscopy, all were characterised as containing biofilm (100%, P < 0·001). The presence of both mono‐species and multi‐species biofilms within the same tissue sections were detected, even when DNA sequencing analysis of DFU specimens revealed diverse polymicrobial communities. No clinical correlations were identified to aid clinicians in identifying wound biofilm. Microscopy visualisation, when combined with molecular approaches, confirms biofilms are ubiquitous in DFUs and form either mono‐ or multi‐species biofilms. Clinical cues to aid clinicians in detecting wound biofilm are not accurate for use in DFUs. A paradigm shift of managing DFUs needs to consider anti‐biofilm strategies.     

Non‐adherence to treatment of chronic wounds: patient versus professional perspectives

The reasons for the non‐adherence to treatment for wound healing are complex and fall into unintentional and intentional categories. This study explored intentional and unintentional non‐adherence to treatment from patient/carer and health care professional perspectives. Patients with wounds receiving ALLEVYN Life dressings (n = 20) and patients not receiving ALLEVYN Life dressings who were deemed to be non‐adherent to treatment regimes (n = 6) took part in semi‐structured interviews to explore their experiences of living with a wound, treatment and intentional and unintentional non‐adherence. Three focus groups of health care professionals explored issues surrounding non‐adherence to treatment regimes. Groups included nurses and doctors (n = 25). We found that relationships between participants and health care professionals varied in character across the groups. All participants expressed reasons for both intentional and unintentional adherence. Many reasons for intentional non‐adherence are related to comfort and working the regime around patients' lives. Health care professionals considered the most common form of non‐adherence to be unintentional. However, patients describe the most common form of non‐adherence as being intentional. The relationship between patients and health care professionals varied in character between the groups. Discrepancies between professional and patient perspectives need to be reconciled and addressed to improve adherence to treatment regimes.     

Response to White and Cutting critique

Response to White and Cutting critique In their letter, published in the March issue of JWC, White and Cutting raised concerns about clinical visualisation of wound biofilm in the absence of a definitive assay or validation of visual observations with microscopic confirmation. While I acknowledge that science plays a critical role in extending our knowledge of the role of biofilm in wound healing, clinicians cannot ignore patients' needs, or the patterns we observe as experts in our practice, while we await such scientific developments.     

Wound care evidence,knowledge and education amongst nurses: a semi‐systematic literature review

The aims of this study were to determine the knowledge and skills of nurses involved in wound care, to provide a critical overview of the current evidence base underpinning wound care and to determine the extent of utilisation of existing evidence by nurses involved in the management of wounds in practice. A semi‐systematic review of the literature was undertaken on Cinahl, Medline Science Direct and Cochrane using the search terms: wound, tissue viability, education, nurse, with limitations set for dates between 2009 and 2017 and English language. Shortfalls were found in the evidence base underpinning wound care and in links between evidence and practice, prevalence of ritualistic practice and in structured education at pre‐ and post‐registration levels. The evidence underpinning wound care practice should be further developed, including the conduction of independent studies and research of qualitative design to obtain rich data on both patient and clinician experiences of all aspects of wound management. More structured wound care education programmes, both at pre‐registration/undergraduate and professional development levels, should be established.     

Effect on total microbial load and community composition with two vs six‐week topical Cadexomer Iodine for treating chronic biofilm infections in diabetic foot ulcers

This study compares two vs six weeks of topical antimicrobial therapy with Cadexomer Iodine in patients with diabetic foot ulcers (DFUs) complicated by chronic biofilm infections. Patients with non‐healing DFUs with suspected chronic biofilm infections were eligible for enrolment. Patients were randomised to receive either two or six weeks of treatment with topical Cadexomer Iodine. Tissue biopsies from the ulcers were obtained pre‐and‐post treatment and underwent DNA sequencing and real‐time quantitative polymerase chain reaction (PCR) to determine the total microbial load, community composition, and diversity of bacteria. Scanning electron microscopy confirmed biofilm in all 18 ulcers with suspected chronic biofilm infections. Cadexomer Iodine resulted in 14 of 18 (78%) samples achieving a mean 0.5 log10 reduction in microbial load. Regardless of treatment duration, there was no statistical difference in the reduction of total microbial loads. No difference in the rate of wound healing in the two groups was seen at 6 weeks. Cadexomer Iodine reduces the total microbial load in DFUs with chronic biofilm infections and affects microbial community composition and diversity. All ulcers in both groups showed an initial reduction in wound size with application of Cadexomer Iodine, which might reflect its effect on biofilms.     

Defining success in clinical trials of diabetic foot wounds: the Los Angeles DFCon consensus

Regulatory requirements for new products should be guided by clinical trials that protect the public by a thorough evaluation of safety and efficacy, while not creating unnecessary barriers to their development and ultimate approval. While healing a wound is the ultimate goal of treating an individual with a diabetic foot ulcer, achieving this goal is physiologically complex requiring the initiation and interaction of many events and therefore unlikely to be achieved by one compound. We believe that developing new, more meaningful, study outcomes or end points in wound care trials would both aid in determining the true efficacy of wound management modalities and facilitate the product development cycle. The primary guidance from the US Food and Drug Administration to industry in this field was published in 2006. This document, while helpful and largely in concert with current knowledge of wound healing, needs to be substantially improved. We therefore convened an interdisciplinary task force comprising experts in various aspects of wound care to attempt to achieve consensus in defining primary outcomes and potential secondary endpoints for various classes of wound‐healing modalities.