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Biofilms and Impaired Wound Healing … 217
The feasibility of some of the detection methods presented here might prove
impractical as they require large and expensive equipment, which can only be
operated by specially trained personnel. To expect this to occur at any common
hospital is unrealistic, so using detection methods which utilize equipment that is
already present, such as ultrasound devices or PET imagers, is more likely to
become widespread.
Alternatively, cheap and easily created equipment such as
paper-based sensors might be more viable for use everywhere. Simple diagnostic
tools such as thermometers and litmus paper for measuring wound temperature and
alkalinity should also be encouraged as these might help to show early signs of
infection.
Many sensor-based detection methods including several imaging techniques
have limitations with respect to detecting very small biofilms. Yet this is an
important feature, as wound aggregates may only be a few micrometres across in
diameter (Bjarnsholt et al. 2013). The volume-sensitivity of detection techniques
and the spatial resolution of imaging techniques limits their use to detect small
aggregat
es. T
his issue extends into our next discussion point: even small amounts
of bacteria can lead to an infection. This is particularly true in patients who are
already immunocompromised or suffer from poor vascularisation and therefore,
tissue oxygenation, as is often the case of chronic wound patients (Sen 2019).
D
n methods that rely on large quantities of bacteria, or the by-product of
etectio
large microbial masses, including QS controlled secretions, might fail to diagnose
infections in their early stages. Many detection methods rely on the EPS products of
biofilms, yet actual investigations of EPS components in vivo are incredibly scarce.
Some studies have used imaging techniques to show the presence of EPS and
certain EPS compounds in wound samples, but no large studies have been performed which have analysed the EPS components of chronic wound biofilms
(Johani et al. 2017; Neut et al. 2011; Oates et al. 2014). Hence, we need to be
careful when making assumptions about chronic wounds based on data obtained
from in vitro experiments. EPS components produced in abundance in vitro might
not be found to the same extent in vivo. There is an ongoing search for universal
biofilm markers, yet such markers might not exist, as we have modestly suggested
here.
It is often cited that only chronic wounds contain biofilms while acute wounds
do not (Attinger and Wolcott 2012)
et, newer studies show that this assumption
. Y
might not be true. In 2018, Bay et al. found biofilm formations in 67% of acute
wounds (Bay et al. 2018), while Schaber et al. (2007) found biofilm formations in
91% of acute wounds in an animal model, and a recent study by Kolpen et al., that
compared
single cells in all samples (Kolpen et al. 2022
chronic and acute lung infections, found both biofilm aggregates and
Based on their finding, Kolpen et al.
).
analysed the growth rates of the aggregates and found that the aggregates isolated
from acute lung infections had a higher metabolism than the ones from chronic
infections. This finding may cultivate speculations about whether it is not the
presence of a biofilm, but rather the growth rate of the bacteria in the biofilm, which
causes the main differences between acute and chronic infections. If this is the case,
detection methods that infer details in regards to the metabolic status of the
218 I. C. Thaarup and T. Bjarnsholt
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surveyed microbes might prove more valuable than initially thought. Further
speculations can be made in regards to the microenvironment of the wound
infection, as it is not yet known whether the presence of a biofilm leads to an
unfavourable wound microenvironment or if the unfavourable wound microenvironment promotes the establishment of said biofilm. Hence, detection methods that
continuously survey the microenvironmental conditions of the wound, (e.g. tem-
ure, oxygenation and pH) could help prevent the early establishment of an
t
pera
infection, if these conditions are corrected in a timely manner.
Several of the detection methods presented here specializes in the detection of a
single species. Pyocyanin and pyoverdine, which are detected in the methods
presented by Simoska et al. (2020)
, Jarosova et al. (2019) and Raizman et al.
(2021), are only produced by P. aeruginosa. The detection method presented by
Gao et al. (2021) contained an aptamer specifictoS. aureus and the method in Roy
et al. (2021) used an S. a
ureus specific DNA probe. Arguments can be made that
the detection of these two species is highly relevant, as their presence in chronic
wounds has previously been linked to a worse healing outcome and even wound
enlargement (Madsen et al. 1996;Gjødsbøl et al. 2006; Kalan et al. in press). Yet,
their absence does not automatically result in a positive healing outcome, as other
species have been found to dominate in some chronic ulcers (Redkar et al. 2000).
Hence, detection met hods which solely look for a single species, or a certain range
of species, must be supplemented with a different detection method in case of a
negative result. Yet, specific pathogen identification has its value, especially when a
medical physician needs to choose a suitable antibiotic for treatment. The identification of certain resistance genes is also very relevant in this regard, and consequently, molecular techniques, which are already used today, are still incredibly
valuable. The same holds true for transcriptional profiles, as they might make
implications in regards to the metabolic status of the infectious pathogens. It has
previously been shown how certain antibiotics may have a limited effect on
metabolically inactive microbes, thus knowing the activity status of the infectious
microbes might be equally relevant to the treating physician (Liu et al. 2020). Some
studies make distinctions between commensals and pathogens, yet this distinction
seems dangerous when it is known that commensals in a new environment may act
unpredictably (Otto 2009). This is particularly important to consider when using
detection methods that rely on the production of toxins, as toxin production is not a
guarantee in all infections.
In conclusion, when a patient develops a chronic wound it should be investigated
using a well-rounded, holistic approach which includes immune cell signals,
microenvironmental factors such as pH, temperature and oxygenation, but also
various microbial factors such as species, microbial amount, EPS components,
metabolic rates, toxins, transcriptomes and resistance profiles. A single detection
method can not be expected to fulfil all these requirements, hence the development
of a range of different detection methods with different angles, based on a variety of
biological markers is likely to be highly beneficial, though it may be costly and
complicated. More importantly, before we continue the development of different
detection methods, it would be more useful to first expand on our knowledge in
Biofilms and Impaired Wound Healing … 219
regards to the chronic wound microbiome. Once we understand the role of both
biofilms and single cells in the wound, and once we have established the presence
and function of various EPS components, and determined how and if these components affect the healing process, we can then turn to develop adequate methods to
help us detect the most important factors for woun d healing. Improved understanding of microbial infections in chronic wounds is essential.
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