Challenges with Wound Infection Models in Drug Development

Abstract

: Wound research is an evolving science trying to unfold the complex untold mechanisms behind the wound healing cascade. In particular, interest is growing regarding the role of microorganisms in both acute and chronic wound healing. Microbial burden plays an important role in the persistence of chronic wound, ultimately resulting in delayed wound healing. It is therefore important for clinicians to understand the evolution of infection science and its various etiologies. Therefore, to understand the role of bacterial biofilm in chronic wound pathogenesis various in- vitro and in-vivo models are required to investigate biofilms in wound-like settings. Infection models should be refined comprising important signet of biofilms. These models are eminent for translational research to obtain data for designing an improved wound care formulation. However, all the existing models possess limitations and do not fit properly in the model frame for developing wound care agents. Among various impediments, one of the major drawbacks of such models is that the wound they possess does not mimic the wound human develops. Therefore, a novel wound infection model is required which can imitate the human wounds. This review article mainly discusses various in-vitro and in-vivo models showing microbial colonization, their advantages and challenges. Apart from these models there are also present ex -vivo wound infection models, but this review mainly focused on various in-vitro and in-vivo models available for studying wound infection in controlled conditions. This information might be useful in designing an ideal wound infection model for developing an effective wound healing formulation.

Antimicrobial Hypochlorous Wound Irrigation Solutions Demonstrate Lower Anti-biofilm Efficacy Against Bacterial Biofilm in a Complex in-vitro Human Plasma Biofilm Model (hpBIOM) Than Common Wound Antimicrobials

“…Another major concern is the sometimes liberal extrapolation of results in basic “non-challenging” test scenarios (e.g., antimicrobial efficacy in planktonic assays or biofilms grown on plastic surfaces without introduction of organic load) to clinical “real-world” situations. The significant differences in efficacy between a standard planktonic (DIN EN 13727; DIN, 2013 ) and in-vitro biofilm assay as well as between different forms of biofilm assays have been demonstrated before ( Brackman and Coenye, 2016 ; Johani et al, 2018 ; Shukla et al, 2020 ) and could be reproduced in this study ( Figures 2A – C ) when comparing reduction rates of QSM to hpBIOM. Where bacteria in a planktonic state are easily eradicated by the antiseptic OCT/PE and the PHMB-based antimicrobial irrigation solution within 30 min, reduction rates are significantly reduced in the more complex hpBIOM ( Figures 2A – C ) which introduces organic challenge faced by antimicrobial agents in human biofilm-burdened chronic wounds (higher protein load, hard-to-penetrate EPS structure, immune cells, dormant bacteria, etc.).…”

“…Several in-vitro models have been applied for this purpose, growing wound biofilms on plastic or metal surfaces, in many cases without additional organic and/or human material ( Brackman and Coenye, 2016 ; Schultz et al, 2017 ; Shukla et al, 2020 ). Such approaches are feasible for evaluating biocides and disinfectants for (surface) decontamination, but in case of wound antimicrobials, the more complex composition of the wound microenvironment (cytokines, proteases, fibrin, cells, etc.)…”

Composition of Challenge Substance in Standardized Antimicrobial Efficacy Testing of Wound Antimicrobials Is Essential to Correctly Simulate Efficacy in the Human Wound Micro-Environment

“…Dubbed the “protein error” or “dirty conditions”, the standard attempts to address the matter using bovine albumin and/or sheep erythrocytes in varying combinations and concentrations to simulate conditions in real life. As correct in itself to use challenges for estimating the agent’s performance in a real-world scenario, recent publications have demonstrated significant and relevant variations between standard conditions, challenged conditions, artificially constructed wound conditions, and conditions using human material to simulate the acute/chronic wound micro-environment [ 3 , 4 , 5 , 6 , 7 ]. This leads to incoherent reports and unclear efficacy profiles regarding antimicrobial agents intended for wound irrigation or antisepsis and false translation into subsequent steps of evidence-building for clinical recommendations.…”

In vitro Activity of Antimicrobial Wound Dressings on P. aeruginosa Wound Biofilm

“…Mostly, in vitro evaluation of anti-biofilm activity is performed in models and settings less suited to sufficiently mimic a wound biofilm and the interactions with the human wound microenvironment. Such models and settings include simple single-species-biofilms, lower protein challenge than in clinical wounds, non-human matrix material (e.g., plastic or stainless steel surface) and one-dimensional biofilm structures (Brackman and Coenye, 2016;Shukla et al, 2020). In addition, most studies are not performed with dressings, but with antimicrobial solutions to prove the efficacy of a compound.…”