From Lab to Clinic: The Necessity of Realistic Testing Conditions in Evaluating Wound Dressing Performance
Editorial Summary
This editorial highlights the critical importance of employing clinically relevant testing conditions in the evaluation of wound dressings. Case examples from the published literature demonstrate potential pitfalls in the material design of wound dressings when clinically relevant testing is not undertaken. Specifcally, the focus is on non-medicated wound dressings, which are claimed to have antimicrobial properties, and advanced foam products, for which superior exudate management is claimed.
Introduction
Wound dressings have become an integral component in the management of open wounds. Further, there is an expanse of choices with regards to the types of materials, formulations (biological and non-biological) and carriers, all designed with specific functions of relevance to the management of wounds. The primary goal of a dressing is to have the highest performance when used clinically on individuals with wounds, however, how is this achieved when virtually all the design features of a wound dressing are developed in the laboratory? To achieve this goal, developers must employ validated laboratory test methods during the design stages of a wound dressing to ensure that the laboratory testing mimics what occurs in real life conditions, thus maximizing the chances of the dressing performing well in the clinical setting.
Unfortunately, a large percentage of dressing development, and performance evaluation, is undertaken using oversimplified and clinically irrelevant test conditions, such as the utilization of salt solutions which are supposed to mimic (but do not) wound exudate. In this review, we highlight the need for more clinically realistic testing conditions and hope to raise awareness of the necessity of adopting testing methodologies that accurately reflect realworld clinical scenarios, ultimately enhancing the reliability and relevance of wound dressing assessments.
What Is the Impact of Using Test Solutions to Mimic Wound Exudate That Are Not Clinically Relevant?
Wound care is a pivotal but often overlooked aspect of healthcare, yet this area has seen significant advancements with the development of innovative advanced wound dressings. Two of the most significant functions provided by advanced wound dressings are the management of exudate and/or the provision of an antimicrobial effect to manage bioburden. Despite being seen as a trivial matter by some, the absence of a material to manage wound exudate would result in the leakage of exudate onto the surrounding skin (causing maceration), clothes and linen, leading to distress and a reduced quality of life for patients.1–3 Additionally, leaving a wound open to the environment increases the risk of contamination by microorganisms or foreign material like dirt, which can negatively impact the wound. Many clinicians have thus adopted the adjunctive use of topical antimicrobial wound dressings to provide local infection management, aiming for better source control of infected tissues and, consequently, improved infection outcomes.
Whether a wound dressing is optimized for fluid handling or to provide an antimicrobial action, both have the commonality of being exposed to wound exudate (often referred to as ‘wound fluid’ or ‘wound drainage’).3 So, what is human wound exudate? Is its presence a physiologic or pathologic response in open wounds? The World Union of Wound Healing Societies (WUWHS) consensus document on Wound Exudate,3 along with the recent review
Assoc Prof Matthew Malone
Dr Erik Nygren
From Lab to Clinic: The Necessity of Realistic Testing Conditions
“Standardization is aimed at increasing the trueness, reliability, repeatability, and replicability of measured values. To achieve this, numerous variables must be controlled for, and this does not necessarily ft the heterogenous nature we see clinically.”
by Cullen and Gefen,4 offers a succinct overview of this question. However the short answer to this is that wound exudate serves as both a physiological response to aid wound healing, but also has a pathological role which negatively impacts wound healing. Additionally, we have a limited understanding of the biological profile of wound exudate and, adding to the complexity, is that it likely changes under different environmental or physiological conditions.
In extrapolating the work that has been undertaken to explore the composition of wound exudate, herein are some (but not limited to) generalized constituents: waterserum containing bulk proteins [albumin, fibrinogen, globulins] and electrolytes, growth factors, proteases, immunity-related cells and mediators [white blood cells, inflammatory chemokines], tissues [fibrin, slough, platelets, cellular debris], metabolic waste products and microorganisms.4–8 Analyses of typical wound exudate samples have indicated an approximate 50% total protein concentration of that observed in human serum, with albumin identified as the predominant protein type.9–14 At a clinical level, the differences in composition can also affect the viscosity of the exudate, with the consistency varying from thin and watery to thick and viscous.
But what does all this mean from a clinical perspective regarding how a wound dressing performs? The answer is that it has the potential to negatively impact performance. A wound dressing may function entirely differently than expected, based on oversimplified laboratory testing, leading to poor clinical performance and outcomes. We need not look further than the EN 13726 standard (revised, renamed, and made available in September 2023 as EN 13726:2023 Test methods for wound dressings - Aspects of absorption, moisture vapor transmission, waterproofness and extensibility). This standard, which uses a water solution of sodium chloride and calcium chloride, completely disregards the complex fluid chemistry, physics, and mechanics of wound exudates.16–18 So, what are the advantages of using such simple salt solutions in the standardized testing of medical devices, and who is benefiting?
Standardization is aimed at increasing the trueness, reliability, repeatability, and replicability of measured values. To achieve this, numerous variables must be controlled for, and this does not necessarily fit the heterogenous nature we see clinically. However, considering the broad influence of test fluid composition in relation to wound dressing performance evaluations, illustrated here for antimicrobial properties and microbial binding, as well as fluid handling capacity testing, it is critical to consider the composition and properties of wound exudate and their simulations.
Several publications have explored the use of simulated wound fluids in laboratory evaluations of wound care materials and products. These studies are based on an understanding of the physiological origin and composition of wound exudates, which derive from serum. Collectively, these studies highlight the crucial role of proteins and other serum components in affecting material and wound dressing surface interactions (including fouling) which in turn impacts performance evaluation outcomes. 6,18–24
Figure 1: Identifying wound exudate
“Importantly, including a single protein source, such as bovine serum albumin, in a test solution for fuid handling performance evaluation aligns with existing research on biological fuid-solid interactions, particularly protein-surface interactions.”
Thus, incorporating serum as a protein source in test fluids for laboratory evaluations has emerged as a clinically relevant approach, given its reflection of the physiological origin and composition of wound exudates.
Regarding the composition of proteins in non-healing wound exudates, Trengove et. al. reported total protein concentrations in fluids from non-healing wounds in the range of 26 to 46 mg/mL, with a median value of 34 mg/mL.9 Despite differences in sampling techniques, Severing et al. later observed similar results with a mean concentration of 42.9 ± 4.9 mg/mL (Mean ± SD).13 Thamm et al. reported a range of 31.3 to 38.3 mg/mL, with a median of 34.3 mg/mL. 14 James et al. found a range of 20 to 42 mg/mL, with a median of 29.7 mg/mL. Normal serum total protein concentrations are typically cited in the range of 60 to 80 mg/mL.
For antimicrobial testing of wound dressings and related products, the practice of incorporating serum as a protein source is well established, as illustrated by the application of 50% Fetal Calf Serum and 50% Maximum Recovery Diluent (Peptone Saline Diluent) in several scientific publications,19,20,22,24–26 and in standard EN 17854:2024 Antimicrobial wound dressings — Requirements and test method.27 Correspondingly, a test solution composed of 50% horse serum and 50% Solution A have emerged as reasonable representation of wound exudates in fluid handling performance evaluation of wound dressings.1,6 More intricate simulations of wound exudates have been investigated,5,18 exemplified by Kadam et al., who delineated a protocol involving the integration of fetal bovine serum with additional host matrix components and biochemical factors,5 encompassing collagen, fibrinogen, fibronectin, lactoferrin, and lactic acid.
Similarly, the development of simulated wound fluid (SWF) based on serum albumin has been proposed and implemented for fluid handling performance evaluations.4,6,28–30
This approach improves standardization and ease of use, as demonstrated by Svensby et. al. For example, it enhances reproducibility, increases availability, and reduces the risk of microbial contamination. The proposed new test fluid for application in the EN 13726 standard, named SWF A by Svensby et al., is specifically designed to mimic the composition of chronic wound exudate.6 It contains bovine serum albumin (BSA) as the primary protein component. In addition to BSA, SWF A contains a balanced mix of salts and buffers. These are included to replicate the physicochemical properties of wound exudates. Although the exact balance of these components can vary,9,31 the goal was to create an improved SWF for standard testing that closely resembles the fluid found in chronic wounds.
Including a single protein source, such as bovine serum albumin, in a test solution for fluid handling performance evaluation aligns with existing research on biological fluid-solid interactions, particularly proteinsurface interactions. It is however crucial to consider the argumentation made by Svensby et al. They point out that differences in salt composition and pH in Solution A, compared to exudate, can significantly affect proteinsurface interactions.32 These differences make the simple addition of albumin to Solution A inadequate for generating a test liquid with
Figure 2: Simulated Wound Fluid A (SWF A) components and functions. A detailed description of the rational and development of SWF A is provided in Svensby et al., 2024
From
“Several studies demonstrate the capacity of DACC dressings to bind wound-associated bacteria or fungi, including Staphylococcusaureus, methicillin-resistant S. aureus (MRSA), and Pseudomonasaeruginosa, or endotoxin.”
Figure 3: Reduction in Fluid Handling Capacity (FHC) of wound dressings was observed when Simulated Wound Fluid A (SWF A), which contains serum albumin, was used in standard EN 13726 testing instead of Solution A (Sol A). This reduction was noted in four out of eight dressings tested. Results adapted from Svensby et al., 2024
clinical relevance for fluid handling capacity (FHC) testing.6
Case 1: The Influence of Different Test Solutions on the Performance of Nonmedicated Dressings
Akin to the development of materials to manage wound exudate, there has been radical developments in the field of materials for the management of local wound infection. Much of this has been in the form of active antimicrobial compounds, polymers, and peptides. There has also been development and exploration of materials that do not possess traditional antimicrobial mechanisms but offer a more passive approach such as microbial sequestering by non-medicated materials.33 These include activated charcoal cloth,34,35 ceramic wound dressing36 and dialkylcarbamoyl chloride (DACC)-coated dressings.19,37
DACC-coated wound care products (Sorbact®, Essity) are designed to primarily exploit non-specific hydrophobic interactions to physically adsorb/sequester microorganisms
and macromolecules of microbial origin onto their surface, potentially reducing bioburden and promoting healing in complex wound scenarios. A multitude of in vitro investigations have explored the mechanisms and microbial adsorption properties of DACCcoated dressings.19,20,37–40 These investigations typically leveraged the affinity of hydrophobic microorganisms for the hydrophobic DACC material, elucidating the binding interactions that underpin the efficacy of these dressings. Consequently, DACC serves as an exemplary model for enhancing the understanding of nonmedicated wound dressings and their laboratory evaluation.
Several studies demonstrate the capacity of DACC dressings to bind wound-associated bacteria or fungi, including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa, or endotoxin.19,33,37 However, the clinical relevance of this in vitro microbial adsorption capacity by DACC-coated dressing materials necessitates further investigation. Critical considerations described in the scientific literature include limitations such as the focus on bound bacteria rather than those remaining in the simulated wound environment,19,26 natural or induced variations in microbial hydrophobicity,38,39 and the potential detachment of bound microorganisms over time.20 In addition to their hydrophobic properties, it is crucial to recognize that various factors, such as surface topography and inherent wound characteristics, can significantly impact the physiological performance of wound dressing materials. Even materials with strong hydrophobicity may exhibit diverse performance in bacterial attachment and biofilm formation due to the complex interplay of these factors, as discussed in previous studies.20,41
As interest in non-medicated wound dressings for infection control grows, the assessment of microbial attachment/sequestration, and
“Recent scientifc work by Husmark et al. and Malone et al., simulating the impact of non-medicated wound dressings on infected wounds, provide valuable insights into the complexity and physiochemical and biological parameters that govern their performance efcacy.”
retention by these dressings and innovative materials has become a pivotal aspect of dressing evaluation. In the laboratory evaluation of both antimicrobial wound dressing textile products and disinfectants/antiseptics, it is recognized - and reflected in standards such as EN 17854:202427, EN ISO 20743:202142 and EN 13727:2012+A2:201513 - that the choice of test solution significantly influences the reliability of these evaluations. Similarly, using solutions that do not contain the organic content found in wound exudate could lead to a misrepresentation of a dressing’s performance in a clinical setting. This discrepancy could result in an overestimation of a dressing’s ability to inhibit microbial growth, which could potentially lead to suboptimal treatment outcomes. Therefore, it is crucial to consider the organic content of test solutions to ensure accurate and reliable evaluations.
Recent scientific work by Husmark et al. and Malone et al., simulating the impact of non-medicated wound dressings on infected wounds, provide valuable insights into the complexity and physiochemical and biological parameters that govern their performance.19,20 These investigations underscore the importance of testing methods that mimic realworld scenarios, including the use of simulated wound fluids that contain not only salts but also increased levels of biological components found in wound exudate. These studies demonstrated that when the bacteria, either S. aureus or P. aeruginosa, was administered in biologically relevant simulated wound fluid containing fetal calf serum, there was a significant reduction in bacterial attachment to the DACC-coated wound dressings as compared to when the bacteria were administered in Maximum Recovery Dilutent (MRD) or Phosphatebuffered saline (PBS).19,20 For example, in the Husmark study, augmentation of the simulated wound fluid with 10% or 50% serum resulted in reduced P. aeruginosa attachment by approximately 7 log units.
These observations are in agreement with the understanding that hydrophobic surfaces tend to have high affinity for proteins, which are also largely hydrophobic.43
In addition to analyzing attached bacteria, Malone et al. also enumerated the remaining bacteria after dressing removal, i.e. the number of P. aeruginosa left in the inoculation media containing 50% serum. When DACC coated dressings were tested under these conditions, the dressing performance was greatly affected.20 The maximum reduction observed was 0.1 log CFU for the DACC-coated dressing; contrasting the widely accepted definition of bactericidal efficacy, which is a 3 log viable bacterial counts reduction.
These observations are consistent with the study of Brauwarth and Brill,38 evaluating a range of wound dressings, some with a DACC coating and others without, assessing both their hydrophobic characteristics and their quantitative capacity to remove S. aureus and P. aeruginosa in an in vitro model using agar surfaces. Both categories of dressings - those coated with DACC and those uncoateddisplayed hydrophobic properties. However, no direct correlation was established between the hydrophobicity of the dressings and their bactericidal efficacy. Moreover, this study provides context to the antimicrobial efficacy of non-medicated wound dressings in comparison to silver dressings. Drawing parallels to the research conducted by Larkö,40 which employed a 3D synthetic soft tissue model to evaluate performance against P. aeruginosa biofilm, the results of both studies demonstrated that the silver dressings, but not the DACC-coated dressings, reduced the bacterial load by more than 3 log CFU.38,40
Together, these observations suggest that, while surface hydrophobicity may play a role in bacterial adsorption, it does not necessarily
From Lab to Clinic: The Necessity of Realistic Testing Conditions in
translate into effective bacterial elimination. These findings also underscore the need to assess dressing efficacy in vitro beyond traditional antimicrobial effects and consider factors such as fouling (i.e. slough, bulk tissue and proteins), which can significantly impact clinical outcomes. Fouling of medical devices such as implants or in-dwelling devices is well studied, but there is very limited previous context or discussion on how fouling could negatively impact wound dressings. In two published studies including clinical samples from chronic wounds, Malone et al identified and raised the potential problems associated with fouling.20,44 Their research used scanning electron microscopy to image DACC-coated wound dressings after 3 days of wear by patients with chronic wounds. The authors observed that host fouling coated the DACC fibers, creating a dense cover that facilitated direct bacterial attachment to the host material, thus circumventing attachment to actual dressing material. Also, the authors used a molecular approach to analyze the total bacterial load in wounds (using qPCR) and the microbiome (using 16S sequencing) following treatment with DACC-coated dressings. The results demonstrated no reductions in the number of bacteria pre- and post-study, nor did the treatment with DACC destabilize or shift the microbiome.
In the context of both in vivo and in vitro observations related to DACC- and siliconebased dressings,19,20,38,44 as outlined previously by Malone et al., the following scenarios are probable under in vivo conditions after the application of non-medicated wound dressings: Biopolymers (present in wound exudate), and slough adsorb onto the dressings, thereby forming a conditioning layer. This layer alters the physiochemical properties of the hydrophobic wound contact material. Microorganisms, either as individual entities or as aggregates, typically adhere to this layer rather than directly to the dressing surface, a phenomenon known as polymer bridging.45 It is recognized that host fouling from polymer-rich nutrients in bodily fluids, such as the serum proteins found in wound exudate, influence bacterial cell surface properties, promoting aggregate formation and providing a nutrient-rich niche for microbial proliferation on surfaces.41 Further, host fouling is a rapid process, especially in relation to the wear time commonly observed with wound dressings. Consequently, the processes of
microbial attachment to DACC (and other hydrophobic surfaces) and the subsequent biofilm formation do not fundamentally differ from those occurring in wounds. Furthermore, in accordance with the present understanding of biofilm organization and life cycles in vitro, in situ, and in vivo,45 the aggregation and attachment of microorganisms, as well as their disaggregation and detachment, are continuous dynamic processes, i.e., they are characterized by their open system nature. Arguably, the notion of irreversible microbial attachment to wound dressings over time in clinical settings, exemplified by DACC- and siliconecoated dressings, is neither in alignment with current scientific microbiological theory or with the available clinically relevant evidence.
Further, incorporating biologically relevant Simulated Wound Fluids (sometimes termed Increased Protein Content, IPC) into the invitro models offers a more realistic representation of clinical wound conditions, facilitating more accurate assessments of non-medicated as well as antimicrobial dressing performance, i.e., the efficacy to curtail aggregation, attachment and growth.
Case 2: Fluid Handling Capacity Principles in the Context of Exudate Management
Exudate secretion is a normal and integral part of the wound healing process, requiring effective management to maintain a moist wound environment essential for healing.1,3,46 Failure in exudate management may result in delayed healing and increased risk of infection, impacting both physical and psychosocial well-being. Wound dressings utilized across a range of exuding wound types, such as surgical incisions, DFUs, and venous leg ulcers (VLUs), have been designed to help regulate moisture levels across a wide spectrum of exudate levels.
Assessing wound dressings under standard conditions to determine whether they provide favorable moisture balanced conditions, poses a significant challenge.1,47 The European standard EN 13726, sets benchmarks for wound dressings, focusing on fluid absorption and moisture control under standard conditions. Annex E of the standard details the measurement of FHC of dressings tested, a basic indicative of their ability to consistently manage exudate by absorption and evaporation.16,17 Evaporation (through the semipermeable backing film) is
quantified as the moisture vapor loss (MVL), or as water vapor transmission rate (WVTR). For a detailed description of FHC testing and discussion on the caveats of the different fluid handling measurements included in the latest revision of this standard, EN 13726:2023, the author refers to the recent paper by Nygren and Gefen.16 Notably, the scientific arguments provided in Case 2 regarding EN 13726 also apply to standard ASTM E96/E96M-24, based on the significant similarities in the methodologies used to determine evaporation through a dressing.48
FHC and WVTR outcomes hold significant value, as these data are extensively utilized to guide decision-making among clinicians, health care administrators, and industry professionals involved in wound care.1,49 These decisions may directly influence procurement strategies and dressing design, or indirectly shape package iconography regarding fluid handling, among other things.48,50 However, it is essential to approach FHC outcomes with a critical eye, as they are frequently overinterpreted. The translation of superior FHC (or WVTR) results to superior clinical efficacy is a contentious issue.1,6,28,48,49,51 Further, this ongoing debate casts doubt on the effectiveness of some of the more recent innovative dressings under clinically relevant conditions. It is crucial to ensure that the perceived effectiveness of these dressings is not merely a result of optimistic laboratory testing, but is backed by more substantial and relevant evidence.
In this context, the employment of Solution A, the test fluid described in EN 13726 for FHC determination, is of significant importance. This test liquid is well recognized to fall short in biological relevance due to its simplistic composition, which completely lacks proteins and other macromolecules found in wound exudate.4,6,8–10,12,16 Moreover, the overall salt composition and physicochemical parameters of Solution A deviate from those observed in wound fluids,9,10 as detailed in Svensby et al.6
Empirical evidence supporting the influence of test fluid composition on the fluid handling performance of wound dressings in laboratory testing is abundant.6,15,21,23,52 For example, Sprung et al. demonstrated in immersion tests that the choice of test fluid can influence absorption characteristics for certain wound dressings.21 Similarly, Mennini et al. observed
substantial differences in FHC when using variable test liquids.23 Further, recent investigations by Svensby et al. into biologically relevant simulated wound fluids analyzing FHC across a spectrum of wound dressings and test fluids, statistically show that the employment of Solution A can lead to significantly inflated estimations of a dressing’s FHC, with biased results being observed for half of the dressings being evaluated.6 This phenomenon has notable implications, potentially skewing procurement and clinical decisions in favor of dressings that excel in standardized laboratory tests but may underperform in real-world clinical scenarios. Gefen et.al. recently published a comprehensive paper detailing the contemporary bioengineering theory and practice of evaluating fluid handling performance of foam-based wound dressings.1 It is argued that, while EN 13726 FHC testing using Solution A provides a foundational framework, it has significant limitations. Therefore, it is essential to complement such testing with performance evaluations that incorporate up-to-date evidence, scientifically robust experimental metrics, and clinically relevant benchmarks. Importantly, Annex L of EN 13726:2023 acknowledges the limitations of Solution A,17 by stating that laboratories may opt to use alternative test fluids simulating wound exudate; offering industry and wound care institutions the possibility to request FHC evidence obtained using clinically relevant test fluids.6
Concluding Remarks
Assessing and comparing fluid handling capabilities or antimicrobial properties of wound dressings in clinical settings are inherently challenging, due to the absence of standardized evaluation methods and the inherent variability arising from diverse patient populations, wound types, and care protocols. Consequently, industry, academia and health care institutions resort to employing controlled laboratory tests to evaluate dressing performance in fluid handling as well as microbial control.2,19,23,26,38,50,53 In this context it is important to observe that manufacturers are responsible for ensuring that their product claims are accurate, requiring well-defined and validated testing methods to facilitate fair comparisons by end-users. Therefore, the findings discussed here, concerning the influence of the composition and properties of simulated wound fluids on
From Lab to Clinic: The Necessity of Realistic Testing Conditions in Evaluating Wound Dressing
“In summary, testing wound dressings under stringent clinically relevant conditions ensures their validity, efectiveness, and safety in wound management, ultimately enhancing patient outcomes and optimizing wound care delivery.”
outcomes, highlight ethical considerations.
It is sometimes argued that stringent laboratory testing might not fully replicate real-world conditions. However, rigorous and scientifically sound laboratory testing is essential for enhancing dressing performance in real-world scenarios, promoting healing and preventing complications such as infections or exudate leakage. Effective wound dressings may also contribute to improved patient outcomes by promoting quality of life.1–3
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In summary, testing wound dressings under stringent clinically relevant conditions ensures their validity, effectiveness, and safety in wound management, ultimately enhancing patient outcomes and optimizing wound care delivery.
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