Volume 33 Number 3

Introduction

Wound healing is a complex process to restore destroyed or damaged tissue, which includes multiple overlapping processes: hemostasis, inflammatory response, proliferation of connective tissues and its precursors (such as keratinocyte, fibroblast, macrophage, and endothelial cell migration), and tissue remodeling.^1,2 Disruption in any stage of wound healing may result in chronic, non-healing wounds, which may be attributable to multiple risk factors, such as advancing age, obesity, presence of comorbidity (for example diabetes mellitus, malignancy), repeated insults, and poor treatment choice and its adherence.^1,3 Treatment may also be more complicated in cases in which there is contamination of drug-resistant bacteria and biofilm formation, which may further hinder the process of wound healing.^4,5

Administration of topical disinfectants and wound dressing has been the choice of treatment in various wound types to replace the barrier function in intact skin, such as polyhexanide or polyhexamethylene biguanide (PHMB). Polyhexanide is a positively charged polymer with a hydrophobic backbone and cationic groups spaced by hexamethylene chains. This structure enables polyhexanide to attach to negatively charged molecules to bacterial surfaces, compromising the bacterial cell membrane and ultimately causing cell death.⁶ Polyhexanide has been widely used in wound care becuase of its effectiveness in reducing microbial loads and its high tolerability by cells and tissues and several other advantages, including a broad antimicrobial range, the capacity to bind to an organic matrix, and a positive impact on wound healing.^7,8 Previous study has reported the use of PHMB-containing dressings in various wound types, such as burn injury, pressure ulcers, and venous ulcers.^5,9,10 However, systematic evidence of polyhexanide use as main treatment in various wound types was still scarce. This study aimed to evaluate the efficacy and safety of polyhexanide for management of various wound types compared to other dressings.

Methods

Search strategy

This systematic review and meta-analysis followed the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A literature search was carried out in multiple journal databases, such as PubMed, Google Scholar, ScienceDirect, Cochrane, CENTRAL, and Clinicaltrials.gov until November 2024. The search was conducted independently by two authors to ensure thoroughness.

We included intervention studies (randomised controlled trials, non-randomised controlled trials, cohort studies) that evaluated the use of polyhexanide topical preparations in wound healing. We used Boolean operators with the following keywords: “wound”, “polyhexanide”, and outcomes with its synonyms. Outcomes of this study included efficacy and safety. Efficacy consisted of healing time, re-epithelialisation time and change in wound size, pain (by scores or overall quality of life assessment), antimicrobial effect (such as changes in bacterial load, infection rate, regression rate), and alterations of wound characteristics (including wound assessment scores, odor). Assessment of safety was evaluated with number of adverse events in included studies.

Data extraction

Four authors were involved in study selection and data extraction. Inclusion criteria of this study were:

• therapeutic study design evaluating the efficacy and/or safety of Polyhexanide Biguanide wound dressings;
• human-based studies involving patients with acute or chronic wounds; randomised controlled trials (RCTs) and cohort studies with a control group;
• studies comparing Polyhexanide Biguanide wound dressings to other standard wound dressings;
• studies reporting at least one quantitative clinical/microbiological outcomes;
• published in peer-reviewed journals with full-text availability;
• written in English (or with an available English translation).

We excluded studies with non-human subject research, case report or case series, review articles, meta-analyses, systematic reviews, narrative reviews, or expert opinions, evidence summaries (such as guideline summaries, clinical practice summaries, or consensus statements), and irretrievable full-text articles. Duplicate records were manually removed using Microsoft Excel. Data extraction was performed by Authors 1, 2, and 3 and included patient age, sample size, wound type, intervention details, and study outcomes (wound healing time, pain score, adverse reactions, antimicrobial effect, antiseptic effect, and alteration of wound characteristics). Any discrepancies in data extraction were resolved by Author 4.

Risk of bias assessment

Risk of bias in included studies was evaluated using Cochrane Risk of Bias (ROB) tool for randomised controlled-trials and ROBINS-I for non-randomised clinical trials.^11,12 Risk of bias was assessed independently by two authors, in which discrepancy between two authors were resolved by third author. Publication bias was assessed using a funnel plot for outcomes, with more than ten studies included for quantitative analysis.

Data synthesis and analysis

Data were presented in tables and figures. Meta-analysis was performed using Review Manager version 5.4 software. Outcomes were measured using mean difference (MD) for continuous variables and odds ratio (OR) for categorical variables, any study that did not report specific outcomes were not included in quantitative analysis. Random-effect meta-analysis model was used as we judged that each study may use different dosage and frequency of polyhexanide as treatment for wounds. Heterogeneity was assessed using chi-square analysis with I-squared statistics. A p value of less than 0.05 was considered as statistically significant. Synthesis and analysis was done by two authors and was further reviewed by a third and fourth author.

Results

Study characteristics

A total of 257 records were identified in the initial search (Figure 1). Removal of duplicates resulted in a total of 254 records, of which 194 records were excluded after title and abstract screening. Of 38 full-text articles, we excluded 20 articles due to difference in PICOs. A total of 18 included studies^{5,7–10,13–25} in this review can be seen in Table 1, which consisted of five studies for quantitative review. The included studies varied in design, with most being randomised controlled trials (RCTs), but also including cohort studies and non-randomised clinical trials. Sample sizes ranged from 12 to 146 participants, and study participants were generally adults with various wound types, including pressure ulcers, venous leg ulcers, burns and surgical wounds. Outcome measures included healing time, pain scores, bacterial load, odor, infection rates, wound size reduction, and quality of life assessments. A detailed breakdown of each study’s characteristics can be found in the table. Efficacy outcomes between studies can be seen in Table 2.

 

Figure 1. PRISMA flow diagram²⁶

 

Table 1. Study characteristics

 

Table 2. Efficacy outcomes in patients receiving polyhexanide

Table 2. Efficacy outcomes in patients receiving polyhexanide (cont)

Table 2. Efficacy outcomes in patients receiving polyhexanide (cont)

 

Risk of bias can be seen in Figure 2, in which 13 studies^{7,8,13–22,25} had moderate risk of bias due to bias arising from randomisation processes in RCT studies and bias due to confounding, missing data, and measurement outcomes in non-randomised clinical trials.

Figure 2. Risk of bias of included studies: (a) RoB 2.0 for RCT studies¹²; (b) ROBINS-I for cohort studies.¹¹

 

Healing time

A total of 4 studies^7,9,14,16 reported the outcome of healing time with a total sample of 248 patients (Figure 3). Mean difference of healing time was 14.84 days (95% CI 31.30, 1.62; p=0.08), and meta-analysis showed significantly faster healing time in polyhexanide compared to controls. However, Ceviker et al⁷ found no significant difference in wound healing time between polyhexanide (15±5 days) and Ringer’s Lactate Solution (RLS)  (16±3 days; p=0.462) groups.⁷ Heterogeneity was substantial in this outcome (I-squared=98%).

 

Figure 3. Pooled analysis of healing time

 

Bacterial load

Five studies^7–9,18,20 reported the outcome of bacterial load with a total sample of 140 patients (Figure 4). Meta-analysis of this outcome showed a non-significant difference in presence of bacterial load in PHMB treated wounds compared to controls (OR 0.76; 95%, CI 0.23, 2.48; p=0.65), although lower bacterial load was seen in patients receiving PHMB. Heterogeneity was substantial in this outcome (I-squared=75%). The timing of bacterial load assessment varied, with some studies measuring it at different follow-up intervals, which may influence pooled estimates.

 

Figure 4. Pooled analysis of bacterial load

 

Bacterial burden reduction rate

Three studies^8,21,23 reported bacterial burden reduction rates following polyhexanide administration. Eberlein et al⁸ found significantly higher bacterial clearance in polyhexanide treated wounds compared to silver (p=0.0009). Motta et al²¹ reported significant reductions in bacterial colony count (p<0.05), supporting the efficacy of polyhexanide in reducing bacterial burden. Sibbald et al²³ observed a decrease in bacterial burden in wounds treated with polyhexanide dressings. Pooled analysis of this outcome showed a non-significant difference between polyhexanide and controls (OR 1.44; 95% CI 0.17, 12.45; p=0.74), with substantial heterogeneity (I-squared=78%) (Figure 5). The follow-up duration for bacterial burden reduction varied between studies, ranging from days to weeks: Eberlein et al⁸ measured outcomes at seven days, Motta et al²¹ at 14 days, and Sibbald et al²³ at 21 days, which may impact the observed effects.

 

Figure 5. Pooled analysis of bacterial burden reduction rate

 

Time to re-epithelialisation

Two studies^13,17 reported time to re-epithelialisation in which Kiefer et al¹³ reported time to re-epithelialisation of 7.1±0.2 days in deep partial or full-thickness burn injury requiring split thgickness skin graft (STSG) in adult subjects, while Lorincz et al¹⁷ reported longer time (8.78±2.64 days) in pediatric burn injury patients.

Wound size

Two studies^14,25 reported final wound size following polyhexanide administration. Lenselink et al²⁵ reported smaller wound size in week 24 after patients received polyhexanide-containing dressings. Borges et al¹⁴ compared polyhexanide to normal saline for wound dressings, which showed smaller wound size (17.68±4.48 vs 22.95±4.69cm-squared; p=0.882) in polyhexanide group, although the difference were not statistically significant. The follow-up duration in these studies differed, with Lenselink et al²⁵ assessing outcomes at 24 weeks and Borges et al¹⁴ at 12 weeks.

Wound closure rate

Two studies^7,21 reported the rate of wound closure following polyhexanide treatment. Ceviker et al⁷ found improved epithelialised scar tissue length in polyhexanide-treated wounds (10.4±4.09mm) compared to RLS (4.22±2.81mm; p=0.015). Motta et al²¹ also observed improved wound closure in polyhexanide-treated wounds.Pooled analysis of these studies found a non-significant improvement in wound closure rate with polyhexanide (OR 2.47; 95% CI 0.70, 8.78; p=0.16), with no heterogeneity (I-squared=0%) (Figure 6). Follow-up periods in these studies ranged from weeks to months, with Ceviker et al⁷ assessing outcomes at four weeks and Motta et al²¹ at 12 weeks, potentially influencing the comparability of findings.

 

Figure 6. Pooled analysis of wound closure rate

 

Pain score

Six studies^{5,8–10,24,25} reported pain scores on a VAS scale. Lenselink et al²⁵ reported decreases on a pain scale in week 24 in patients receiving polyhexanide-containing dressings (7.4 vs 3.2). Romanelli et al⁵ reported significantly lower pain score in polyhexanide group (p<0.05) compared to normal saline, while Bellingeri et al¹⁰ reported a non-significant difference in final pain scores. Eberlein et al⁸ found that pain reduction before dressing change was significantly better in polyhexanide (p=0.03).Villela-Castro et al²⁴ also reported a significant reduction in pain scores following polyhexanide treatment.²⁴ The timing of pain assessment varied across studies, with Romanelli et al⁵ assessing at 4 weeks, Villela-Castro et al²⁴ at 8 weeks, and Lenselink et al²⁵ at 24 weeks.

Two studies^8,9 compared polyhexanide (either used as wound dressing solution or gel) with silver sulfadiazine. Wattanaploy et al⁹ showed significantly lower pain scores in patients treated with polyhexanide gel (p=0.0472). However, Eberlein et al⁸ reported higher pain score in polyhexanide-containing biocellulose dressings compared to silver sulfadiazine (6.13±1.43 vs 5.42±1.43), although both showed significantly decreased pain following treatment (p<0.001 in both groups). Pooled analysis of pain scores showed a mean difference of 1.36 (95%, CI 0.28, 2.43; p=0.01), with low heterogeneity (I-squared = 0%) (Figure 7).

 

Figure 7. Pooled analysis of pain score

 

BWAT score

Bates-Jensen Wound Assessment Tool (BWAT) score was used as outcome in one study.¹⁰ BWAT score consisted of several items: wound size, depth, edges, type of exudate, amount of exudate, skin color surrounding wound, peripheral tissue edema and induration, and granulation tissue; in which higher value indicated more severe wounds. Wound dressing using polyhexanide solution was associated with significantly lower total BWAT score and inflammatory signs characterised with BWAT scoring tools compared to normal saline (p=0.0248 and p=0.03 respectively).

Infection rate

Four studies^7,9,15,18 reported infection rates in wounds. Wattanaploy et al⁹ reported no infection in patients receiving either polyhexanide gel or silver sulfadiazine for burn injury treatment. However, Saleh et al¹⁵ reported significantly higher infection rate in patients treated with dressings soaked with polyhexanide compared to normal saline. Ceviker et al reported fluctuating infection rates over four weeks with no significant differences.⁷ Lee et al found that polyhexanide significantly reduced overall infection rate (p<0.001) compared to the control group.¹⁸ Follow-up durations for infection rates varied, with Wattanaploy et al⁹ assessing at two weeks, Saleh et al¹⁵ at six weeks, Ceviker et al⁷ at four weeks, and Lee et al¹⁸ at 12 weeks, which could influence variability in results.

Alteration of wound characteristics

One study²⁵ reported alteration of wound characteristics, which were reported as presence of granulation tissue in wound bed. Polyhexanide-containing biocellulose dressings resulted in significantly higher granulation tissue on Day four compared to initial assessment (77.4±36 vs 38.2±34.6; p<0.04).

Human Papilloma Virus (HPV)  regression rate

One study, by Gentile et al,¹⁹ assessed HPV regression rate following polyhexanide administration. The study found a notable reduction in HPV-related lesions, suggesting that polyhexanide may contribute to improved viral clearance in affected patients.¹⁹

Odor control

One study, by Villela-Castro et al,²⁴ evaluated the effect of polyhexanide on odor control in wound care. The study reported a significant reduction in wound-related odor in patients treated with polyhexanide dressings, contributing to improved patient comfort and overall wound management.

HRQOL & HRQOL subscale improvement

The study by Villela-Castro et al²⁴ also assessed health-related quality of life (HRQOL) and its subscales in patients receiving polyhexanide treatment. The study found significant improvements in overall HRQOL, with notable enhancements in pain relief, mobility, and emotional well-being subscales, indicating a positive impact of polyhexanide on patient outcomes.

Adverse events

Five studies^7,8,10,13,20 evaluated adverse events in patients receiving polyhexanide. Kiefer et al¹³ reported that 12 patients (23.5%) had one to four adverse events following administration of gel containing polyhexanide and betaine, which include tachycardia, eye irritation, gastrointestinal symptoms (constipation, abdominal pain, nausea), postprocedural hemorrhage and transplant failure, hyperglycemia, musculoskeletal symptoms (arthralgia, back pain, pain in extremity), dizziness, anxiety disorder, anuria, pneumonia, hypertension, and others. Mild to moderate pruritus was seen in two patients. Bellingeri et al¹⁰ reported no adverse events following polyhexanide in propylbetaine 0.1% and polihexanide 0.1% as wound cleansing solution. Ceviker et al⁷ reported two cases of pruritus and erythema in the polyhexanide group and one death (stroke). Eberlein et al⁸ found no serious adverse events but reported slightly higher periwound maceration in the polyhexanide group (p<0.0001). Findlay et al²⁰ reported cardiovascular and rheumatological adverse events as well as transient skin erythema in polyhexanide-treated patients.

Discussion

This study aims to evaluate the efficacy and safety of polyhexanide for management of various wound types compared to other dressings. We found significantly faster healing time in patients receiving polyhexanide compared to controls in the treatment of wounds. However, substantial heterogeneity (I-squared = 98%) among studies suggests that differences in study design, wound types, and treatment protocols may influence the observed effects, warranting further investigation into the optimal application of PHMB for different wound types. Lower risk of bacterial load was also seen, although not statistically significant, which may be attributed to the range of variability of bacterial species and differences in the bacterial load assessment methods. Multiple adverse events (mild to moderate) were reported in five studies with ranging adverse effects, although other study reported no adverse events.

Treatment using simple solution (i.e., normal saline, RLS) may remove necrotic tissues and destroy adhesion bridges between biofilm formed by bacteria and wound bed to aid wound healing, although it may be less efficacious as there was no active agent in simple isotonic solution. In our findings, the administration of polyhexanide reduced healing time, wound size, BWAT score, and resulted in higher granulation tissue in the wound bed. The mechanism of action of polyhexanide may be attributable to its antimicrobial properties. Polyhexanide has been shown effective to both Gram-negative and Gram-positive bacteria, such as strains of Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and fungi such as Candida albicans.^1,27,28 In vitro study conducted by Zhang et al²⁹ reported sensitivity of 60%, 45%, and 80% to Staphylococcus aureus, Acinetobacter baumannii, and Klebsiella pneumoniae, and its cytotoxicity increased with increasing exposure time and drug concentration. The mechanism of action involved disruption of cell membranes and inhibition of internal metabolic process of pathogens.³⁰ Polyhexanide also has antibiofilm property, in which a previous study reported good efficacy against biofilm in 63% patients treated with polyhexanide-containing dressing for non-healing wounds.²⁵ Improvement in wound healing processes was also suitable in pediatric populations, as shown in Lorincz et al¹⁷, in which there was rapid wound closure and time to re-epithelialisation following administration of lower concentration of polyhexanide gel (0.04%) betaine in burn injuries.

The effects of polyhexanide on bacterial load may also be explained by reduction in in inflammatory markers (such as CRP and leukocyte counts) reported by Ceviker et al,⁷ which may indicate reduce in inflammatory and infection processes involved in wounds. An in vitro study³¹ also suggested the role of polyhexanide in inhibiting the formation of reactive oxygen species (ROS) and reactive nitrogen species responsible for inflammation. Polyhexanide treatment has also been associated with improved HRQOL, including better mobility and emotional well-being, underscoring its holistic benefits in wound management beyond physical healing.²⁴

It is also important to assess patient-reported outcomes, such as pain scores. Use of polyhexanide, either in gel or solution in wound dressings, resulted in decreased in pain scores.^8,9,25 Pain scores were reported to be significantly lower compared to other agents, such as normal saline and silver sulfadiazine.^5,9 Eberlein et al⁸ highlighted that the use of polyhexanide was associated with significantly reduced pain scores from baseline while also it promoted faster and better removal of bacterial load compared to silver sulfadiazine. The use of biocellulose dressings in the study may exert a physical cooling effect and help lower pain scores.⁸

The use of polyhexanide also exhibits other advantages compared to other active agents. For instance, silver sulfadiazine has been associated with delayed healing, tissue irritation caused by nitrate, and the formation of pseudo-eschar.³² Use of polyhexanide may also cause less mechanical stimuli resulting in pain perception in burn wounds compared to silver sulfadiazine.This was attributed to its moist properties and non-toxic main ingredients to human cells; thus resulting in faster healing time and lower pain scores.^9,30 Also, the transparency of polyhexanide (particularly gel preparations) was beneficial as it may facilitate direct wound assessment, which ensures effective wound management and handling.¹⁶ Polyhexanide treatment was also found to significantly reduce wound-related odor, enhancing patient comfort and quality of life, particularly in chronic wounds prone to malodor.²⁴

In a study conducted by Saleh et al¹⁵ higher infection rate with no effect on bacterial load was reported in wound dressings soaked with polyhexanide solution compared to silver sulfadiazine. The study highlighted that use of polyhexanide may possibly reduce some specific commensal flora, and potentially led to colonization of pathogenic bacteria (such as S. aureus). For instance, specific bacteria such as S. epidermidis has been reported to produce antimicrobials that inhibit growth of other pathogenic bacteria,³³ and the absence of S. epidermidis was associated with higher spread of bacterial levels and detection of Gram-negative bacteria.¹⁵ Further studyies with larger populations are needed to evaluate the association of bacterial species present in patients’ wounds and polyhexanide efficacy.

However, routine administration of antiseptics as cleansing solution for wounds may result in potential toxicity to adjacent cells with the risk of inactivation of essential organic material.¹⁴ Although, an in vivo study reported that following polyhexanide administration, there was no significantly different level in erythema and melanin with absence of edema, papule, and vesicle/bullae with no toxic effect to adjacent cells in in vitro study; which suggested that polyhexanide was non-irritant and safe to use as routine dressings.³⁴ Despite these findings, concerns remain regarding potential adverse events, such as pruritus and erythema in some patients, highlighting the need for further safety evaluations.

There were some limitations in our review. Firstly, quantitative analysis to perform comprehensive statistical comparisons was limited due to variability in the parameters reported across included studies following polyhexanide treatment. Also, the studies included in the review used different control groups, which potentially affects outcome interpretation and comparability of results. There was also no data regarding long-term safety and potential cytotoxic effect. Future studies should focus on standardising protocols and assessing the long-term benefits and risks of polyhexanide use in wound management. Furthermore, the follow-up duration varied across studies, with some studies measuring outcomes at different time points, which may impact comparability. Clarification on when specific variables, such as pain scores, were measured is necessary to ensure consistency in evaluating polyhexanide efficacy over time.

Conclusions

Polyhexanide demonstrated significantly faster healing time in treatment of various types of wounds. It also possessed multiple advantages, such as its transparent properties, antimicrobial activity, and reduced pain compared to other treatments. Further studies may be needed to assess long-term efficacy and safety of polyhexanide in various wound types.

Conflict of interest

None.

Ethics statement

An ethics statement is not applicable.

Funding

The authors received no funding for this study.

Author contribution

All authors made substantial contributions regarding literature searching, data extraction, statistical analysis, interpretation, drafting and final approval of the manuscript.

Author(s)

Vannia Christianto Teng¹*, Asnawi Madjid¹, Widya Widita¹, Khairuddin Djawad^1
1Department of Dermatology and Venereology, Faculty of Medicine, University of Hasanuddin, Makassar, Indonesia

*Corresponding author email vanniacteng@gmail.com

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