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Oral mucositis is the most common and severe non-hematological complication associated with cancer radiotherapy, chemotherapy, or their combination. Treatment of oral mucositis focuses on pain management and the use of natural anti-inflammatory, sometimes weakly antiseptic mouth rinses in combination with optimal oral cavity hygiene. To prevent negative effects of rinsing, accurate testing of oral care products is necessary. Due to their ability to mimic realistic in-vivo conditions, 3D models may be an appropriate option in compatibility testing of anti-inflammatory and antiseptically effective mouth rinses. We present a 3D model of oral mucosa based on the cell line TR-146 with a physical barrier, characterized by high transepithelial electrical resistance (TEER) and confirmed cell integrity. Histological characterization of the 3D mucosa model showed a stratified, non-keratinized multilayer of epithelial cells similar to that of human oral mucosa. By means of immuno-staining, tissue-specific expression of cytokeratin 13 and 14 was shown. Incubation of the 3D mucosa model with the rinses had no effects on cell viability, but TEER decreased 24h after incubation in all solutions except ProntOral®. Analogous to skin models, the established 3D model meets the quality control criteria of OECD guidelines and may therefore be suitable for comparing the cytocompatibility of oral rinses.
Hair follicles constitute important drug delivery targets for skin antisepsis since they contain ≈25% of the skin microbiome. Nanoparticles are known to penetrate deeply into hair follicles. By massaging the skin, the follicular penetration process is enhanced based on a ratchet effect. Subsequently, an intrafollicular drug release can be initiated by various trigger mechanisms. Here, we present novel ultraviolet A (UVA)-responsive nanocapsules (NCs) with a size between 400 and 600 nm containing hydroxyethyl starch (HES) functionalized by an o-nitrobenzyl linker. A phase transfer into phosphate-buffered saline (PBS) and ethanol was carried out, during which an aggregation of the particles was observed by means of dynamic light scattering (DLS). The highest stabilization for the target medium ethanol as well as UVA-dependent release of ethanol from the HES-NCs was achieved by adding 0.1% betaine monohydrate. Furthermore, sufficient cytocompatibility of the HES-NCs was demonstrated. On ex vivo porcine ear skin, a strong UVA-induced release of the model drug sulforhodamine 101 (SR101) could be demonstrated after application of the NCs in cyclohexane using laser scanning microscopy. In a final experiment, a microbial reduction comparable to that of an ethanol control was demonstrated on ex vivo porcine ear skin using a novel UVA-LED lamp for triggering the release of ethanol from HES-NCs. Our study provides first indications that an advanced skin antisepsis based on the eradication of intrafollicular microorganisms could be achieved by the topical application of UVA-responsive NCs.
Aim: The efficacy of antimicrobial compounds included in wound dressings has been determined using the quantitative suspension test according to EN 13727 before. However, as suspension tests are not an accurate reflection of the conditions under which wound antiseptics are used, it was investigated if a disc carrier test would yield results simulating practical conditions on wound surfaces. A silver-leaching foam wound dressing was used for evaluation of the disc carrier test method. Method: The disc carriers consisted of circular stainless-steel discs measuring 2 cm in diameter and 1.5 mm in thickness, complying with the requirements of EN 10088-2. Carriers were contaminated with Staphylococcus aureus, methicillin-resistant S. aureus or Pseudomonas aeruginosa, respectively, together with an artificial wound secretion and left to dry at room temperature for 30 min. The wound dressings being tested were placed on the discs for the length of the exposure time, and after neutralization by thioglycolate in phosphate-buffered saline the number of surviving test organisms was then counted. The logarithmic reduction factor was calculated from the difference between the initial inoculum and the number of recovered test organisms. Results: The disc carrier test allowed determination of an antimicrobial efficacy in a realistic setting. It also imposed more stringent requirements on efficacy over time than the quantitative suspension test. The silver foam wound dressing showed a time-dependent antimicrobial efficacy. After 24-hour application time, the reduction factors against S. aureus, P. aeruginosa and the methicillin-resistant S. aureus were 1.9 ± 0.15, 2.1 ± 0.14 and 3.1 ± 0.18, respectively. Conclusion: The disc carrier test was a useful method for testing the antimicrobial efficacy of a foam silver dressing. The antimicrobial dressing exhibited an antimicrobial effect after 3 h and achieved a reduction >2 log against the tested bacterial strains in the presence of a simulated wound secretion after 24 h.
Objectives
Oral mucositis caused by intensive cancer chemotherapy or radiotherapy frequently results in pronounced damage of the oral mucosa leading to painful oral hygiene. To support oral care, antimicrobial effective mouth rinses may be used. Thus, the efficacy of a hypochlorite-based mouth rinse (Granudacyn®), assumed to be highly biocompatible because of the compounds being part of the natural pathogen defense, as possible antiseptic agent in case of oral mucositis was compared to that of an octenidine based antiseptic mouth rinse (Octenidol® md).
Materials and methods
The study was conducted as monocentric, controlled, randomized, blind cross over comparative study on 20 volunteers. As a proof of principle, we performed the study on orally healthy subjects and not cancer patients. The efficacy was determined as reduction of colony forming units (cfu) on buccal mucosa as well as in saliva. After mouth rinsing for 30 s, samples were taken after 1 min, 15 min, 30 and 60 min. The lg-reduction was calculated as difference between lg-values of cfu pre- and post-treatment.
Results
Both antiseptic mouth rinses induced a significant reduction of cfu on buccal mucosa and in saliva 1 min after mouth rinsing. The effect persisted up to 60 min. The octenidine based rinse was significantly superior to the hypochlorite-based rinse up to the last sample 60 min after rinsing. However, the known cytotoxicity of octenidine argues against its application.
Conclusion
Within the limits of this study, due to its antiseptic efficacy, the hypochlorite-based rinse Granudacyn® can be regarded appropriate to support the oral hygiene in patients with a sensitive oral mucosa during an aggressive cancer chemotherapy and radiation treatment in case of oral mucositis.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen
species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and
recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with
an immunological dimension, successful antigen presentation and inflammation modulation is a
key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However,
the inflammatory consequences of DCs following plasma exposure are unknown. To this end,
human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes;
exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles
were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used.
Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable
increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell
costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether,
this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in
human moDCs, which might exert beneficial effects in the tumor microenvironment.
Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species
(2018)
Background: Annual transfusion rates in many European countries range between 25 and 35 red blood cell concentrates (RBCs)/1,000 population.It is unclear why transfusion rates in Germany are considerably higher (approx. 50–55 RBCs/1,000 population). Methods: We assessed the characteristics of transfusion recipients at all hospitals of the German federal state Mecklenburg-Western Pomerania during a 10-year longitudinal study. Results: Although 75% of patients received ≤4 RBCs/patient in 2015 (1 RBC: 11.3%; 2 RBCs: 42.6%; 3 RBCs: 6.3%; 4 RBCs: 15.0%), the mean transfusion index was 4.6 RBCs due to a minority of patients with a high transfusion demand. Two thirds of all RBCs were transfused to only 25% of RBC recipients. Consistently, male patients received a higher number of RBCs (2005: 54.2%; 2015: 56.8%) and had a higher mean transfusion index than female patients (mean 5.1 ± 7.2; median 2; inter-quartile range [IQR] 2–4 vs. mean 4.0 ± 5.8; median 2; IQR 2–4). The absolute transfusion demand decreased between 2005 and 2015 by 13.5% due to a composite of active reduction (clinical practice change) and population decline in the 65- to 75-year age group (lower birth rate cohort 1940–1950); however, with major differences between hospitals (range from –61.0 to +41.4%). Conclusion: Transfusion demand in a population could largely be driven by patients with high transfusion demand. Different treatment practices in this group of patients probably add to the major differences in transfusion demand per 1,000 individuals between countries. The available data cannot prove this hypothesis. Implementation of a diagnosis-related group-based monitoring system is urgently needed to allow informative monitoring on the population level and meaningful comparisons between transfusion practices.
Currently, there are no generally accepted definitions for wounds at risk of infection. In clinical practice, too many chronic wounds are regarded as being at risk of infection, and therefore many topical antimicrobials – in terms of frequency and duration of use – are applied to wounds. Based on expert discussion and current knowledge, a clinical assessment score was developed. The objective of this wounds at risk (W.A.R.) score is to allow decision-making on the indication for the use of antiseptics on the basis of polihexanide. The proposed clinical classification of W.A.R. shall facilitate the decision for wound antisepsis and allow an appropriate general treatment regimen with the focus on the prevention of wound infection. The W.A.R. score is based on a clinically oriented risk assessment using concrete patient circumstances. The indication for the use of antiseptics results from the addition of differently weighted risk causes, for which points are assigned. Antimicrobial treatment is justified in the case of 3 or more points.
Background: In clinical practice, treatment of genital tract infections is based on administration of either antibiotics or antiseptics. While antibiotics may be applied systemically or topically, antiseptics may be applied only topically. In case of bacterial vaginosis (BV), antibiotic therapy may often be limited and side effects due to systemic administration may develop. Polihexanide (PHMB) is a promising option for the topical treatment of genital tract infections, in particular BV and vaginitis. Method: A systematic search for publications on the use of PHMB for the treatment of genital infections in two electronic databases was performed. Titles, abstracts and citations were imported into a reference database. Duplicates were removed and two reviewers assessed each identified publication separately. Results: Among a total of 204 references, 3 prospective randomized trials were identified. Two trials treated BV infections with PHMB in comparison to clindamycin as antibiotic standard therapy with no significant differences either in safety or in efficacy. The third controlled trial investigated the clinical efficacy of PHMB compared to placebo in the treatment of human papilloma virus. Patients treated with PHMB daily for up to 16-weeks showed significantly higher (52%) clearance of genital warts as compared to patients treated with placebo (4%). Conclusion: PHMB may be a clinically effective alternative for the treatment of BV and human papilloma virus. Although PHMB-based antiseptics are available since the late 90s, controlled trials to investigate its clinical potential for antiseptic treatment are scant. Clinical use of antiseptics for the treatment of infectious diseases should be explored and supported further.
There has been a substantial evolution of anti-cancer therapies in the last decade, leading
to improved prognosis and disease-free survival of patients with melanoma. Due to the
number of patients that still develop resistance or to the high systemic toxicity and side
effects, new treatment options are still needed. Regardless of the type of therapeutic
interventions (except surgery), the reactive oxygen species (ROS) are a by-product or
contribute to the action mechanism of many successful therapies. In this context, medical
cold atmospheric plasma (CAP) arises as a promising tool, and studies are important to
prove the effectiveness of this new device.
Since combination therapies are the current standard way to treat melanoma, we explored
candidates to be combined with cold atmospheric plasma, with potential to become a
therapeutic option in the combination. Here, we tested the radiotherapy and clinically safe
mitochondrial inhibitor drugs. In the end of the study, both, ionizing radiation and four
mitochondrial-targeted-drugs showed to be promising candidates for the combination with
CAP. These combinations induced increased cytotoxicity and modulated the immune
system improving the anti-tumor immune response. Mitochondrial damage seems to be
the first stage to induce cellular deficiency and culminate in apoptotic cell death.
Furthermore the release of GM-CSF contribute to a pro inflammatory state and immune
system activation.
This dissertation showed that CAP serves as an excellent tool to boost melanoma cell
death and induce anti-tumor response. In addition, in our proposed therapeutic
combination, the intensity of plasma treatment could be decreased possibly resulting in
less systemic toxicity. Our results serves as model to be studied in other tumor entities.
Colonization and infection of wounds represent a major reason for the impairment of tissue repair. Recently, it has been reported that tissue-tolerable plasma (TTP) is highly efficient in the reduction of the bacterial load of the skin. In the present study, the antiseptic efficacy of TTP was compared to that of octenidine hydrochloride with 2-phenoxyethanol. Both antiseptic methods proved to be highly efficient. Cutaneous treatment of the skin with octenidine hydrochloride and 2-phenoxyethanol leads to a 99% elimination of the bacteria, and 74% elimination is achieved by TTP treatment. Technical challenges with an early prototype TTP device could be held responsible for the slightly reduced antiseptic properties of TTP, compared to a standard antiseptic solution, since the manual treatment of the skin surface with a small beam of the TTP device might have led to an incomplete coverage of the treated area.
Introduction: Antiseptics are used for the prophylaxis of infections of acute wounds and for the treatment of critically colonized chronic wounds as well as localized infections of acute and chronic wounds. If an antiseptic with too much tissue toxicity and/or too little efficacy is used, the wound healing can be delayed.
Objective: The aim was to compare the irritation potency of frequently used wound antiseptics by using the hen's egg test on the chorioallantoic membrane (HET-CAM). Additionally, the influence of antiphlogistic active additives which might increase the tolerability was examined. To allow a more extensive comparison, antiseptics classified as obsolete such as hydrogen peroxide, creams on PVP- iodine base, silver sulfadiazine, chlorhexidine and nitrofural as well as the non-antiseptic wound treatment agents dexpanthenol and hemoglobin spray were also examined.
Method: The HET-CAM was used as a semi-in-vivo method to test the tolerability of wound antiseptics to tissues by observing the reactions that occur in the blood vessels of the highly vascularized CAM such as hemorrhage, lysis and coagulation. The irritation score (IS) was calculated and differentiated in 4 ranges according to Spielmann (1991).
Results: The vascular injuries of the CAM were considered as an indirect indicator of the tolerability. It is accepted that agents with no or low irritation potential on the CAM are to be preferred in the clinical practice if they are clinically effective.
Severe CAM reaction was observed after short-term application of octenidine based wound gel (active ingredient octenidine 0.05%) (IS: 10.3) and chlorhexidine digluconate 0.5% solution (IS: 9.5). Moderate reaction was observed for the combination of octenidine 0.05% in aqueous solution with panthenol 1.34% and allantoin 0.2% (IS: 8.7), hydrogen peroxide 1.5% in aqueous solution (IS: 6.1) and hydrogen peroxide 0.5% solution (IS: 5.5). Slight reaction was observed for hydrogen peroxide 1.5% solution in combination with sodium thiocyanate 0.698% (IS: 2.6), sodium thiocyanate 0.698% solution (IS: 2.1) and Dermacyn® (active ingredient NaOCl/HOCl each 0.004) (IS: 1.2). Polihexanide 0.04% in Ringer solution (IS: 0.9), Polihexanide 0.05% in Lipofundin, Granulox® (active agent hemoglobin 10%) (IS: 0) and dexpanthenol 5% solution (IS: 0) showed no reaction. In the long-term observation (24 hours after application), Dermacyn® showed the best results (59% of irritation remained alive after 24 hours). The addition of dexpanthenol and allantoin reduced the irritability only slightly, whereas the decrease of IS of hydrogen peroxide by addition of sodium thiocyanate was almost significant (p 0.0596).
Conclusion: It is suggested that agents with no or low irritation potential on the CAM are to be preferred in the clinical practice if they are clinically effective. It is suggested that further in vivo and in vitro studies are to be undertaken with these agents.
Solely regarding local tolerability, polihexanide and hypochlorite are the antiseptic agents of choice of the tested preparations. The wound oxygenizer hemoglobin spray is tolerated without irritation as well as the negative control 0.9% NaCl solution. Because of their other disadvantages in conjunction with their irritability, the outdated cream formulations on basis of silver sulfadiazine, PVP- iodine, chlorhexidine and nitrofural cannot be recommended for wound antisepsis.
The exact qualitative and quantitative analysis of wound healing processes is a decisive prerequisite for optimizing wound care and for therapy control. Transepidermal water loss (TEWL) measurements are considered to be the standard procedure for assessing the progress of epidermal wound healing. The damage to the stratum corneum correlates with an increased loss of water through the skin barrier. This method is highly susceptible to failure by environmental factors, in particular by temperature and moisture. This study was aimed at comparing TEWL measurements and in vivo laser scanning microscopy (LSM) for the characterization of the epidermal wound healing process. LSM is a high-resolution in vivo method permitting to analyze the kinetics and dynamics of wound healing at a cellular level. While the TEWL values for the individual volunteers showed a wide scattering, LSM permitted the wound healing process to be clearly characterized at the cellular level. However, a comparison between the two methods was very difficult, because the results provided by LSM were images and not numerical. Therefore, a scoring system was set up which evaluates the stages of wound healing. Thus, the healing process could be numerically described. This method is independent of any environmental factors. Providing morphologically qualitative and numerically quantitative analyses of the wound healing process and being far less vulnerable to failure, LSM is advantageous over TEWL.
COVID-19 Vaccinated Individuals Can Be a Source of SARS-CoV-2 Transmission—A Systematic Review
(2021)
Fundamental rights are probably given back earlier to COVID-19 vaccinated individuals
assuming that they cannot spread SARS-CoV-2 anymore. The objective of the study was to determine
if COVID-19 vaccinated individuals can still be the source of SARS-CoV-2 transmission. PubMed
was searched for studies on 4 April 2021. All studies with original data on COVID-19 cases among
vaccinated individuals (phase III RCTs) and on viral load in the upper respiratory tract of vaccinated
macaques after a SARS-CoV-2 challenge were included. Symptomatic COVID-19 cases were found
in four trials among vaccinated participants although less frequently than among control subjects.
One study revealed asymptomatic COVID-19 cases in a similar frequency among 2.168 AZD1222-
vaccinated subjects (1.0%) compared to 2.223 control subjects (1.0%). In 15 studies with vaccinated
macaques, it was found that the load of SARS-CoV-2 RNA, subgenomic RNA and infectious virus
in the upper respiratory tract is variable. Sterilizing immunity was found in none of the animal
studies. Major limitations of the animal studies are that the SARS-CoV-2 challenge took place within
a few weeks of the final or only vaccine dose, that the viral challenge was often high and, in some
studies, administered by up to four routes. Based on current knowledge it seems clear that COVID-19
vaccinated individuals can still be the source of SARS-CoV-2 transmission.
Because of its antimicrobial properties, nonthermal plasma could serve as an alternative to chemical antisepsis in wound treatment. Therefore, this study investigated the inactivation of biofilm-embedded Pseudomonas aeruginosa SG81 by a surface barrier-discharged (SBD) plasma for 30, 60, 150 and 300 s. In order to optimize the efficacy of the plasma, different carrier gases (argon, argon admixed with 1% oxygen, and argon with increased humidity up to approx. 80%) were tested and compared against 0.1% chlorhexidine digluconate (CHG) exposure for 600 s. The antimicrobial efficacy was determined by calculating the difference between the numbers of colony-forming units (CFU) of treated and untreated biofilms. Living bacteria were distinguished from dead by fluorescent staining and confocal laser scanning microscopy. Both SBD plasmas and CHG showed significant antimicrobial effects compared to the untreated control. However, plasma treatment led to a higher antimicrobial reduction (argon plasma 4.9 log<sub>10</sub> CFU/cm<sup>2</sup>, argon with admixed oxygen 3 log<sub>10</sub> CFU/cm<sup>2</sup>, and with increased gas humidity 2.7 log<sub>10</sub> CFU/cm<sup>2</sup> after 300 s) compared to CHG. In conclusion, SBD plasma is suitable as an alternative to CHG for inactivation of Pseudomonas aeruginosa embedded in biofilm. Further development of SBD plasma sources and research on the role of carrier gases and humidity may allow their clinical application for wound management in the future.
Background
The approval of ethanol by the Biocidal Products Regulation has been under evaluation since 2007. This follows concern over alcohol uptake from ethanol-based hand rubs (EBHR). If ethanol is classified as carcinogenic, mutagenic, or reprotoxic by the European Chemicals Agency (ECHA), then this would affect infection prevention and control practices.
Aim
A review was performed to prove that ethanol is toxicological uncritical and indispensable for hand antisepsis because of its unique activity against non-enveloped viruses and thus the resulting lack of alternatives. Therefore, the following main points are analyzed: The effectiveness of ethanol in hand hygiene, the evidence of ethanol at blood/tissue levels through hand hygiene in healthcare, and the evidence of toxicity of different blood/tissue ethanol levels and the non-comparability with alcoholic consumption and industrial exposure.
Results
EBHR are essential for preventing infections caused by non-enveloped viruses, especially in healthcare, nursing homes, food industry and other areas. Propanols are effective against enveloped viruses as opposed to non-enveloped viruses but there are no other alternatives for virucidal hand antisepsis. Long-term ingestion of ethanol in the form of alcoholic beverages can cause tumours. However, lifetime exposure to ethanol from occupational exposure < 500 ppm does not significantly contribute to the cancer risk. Mutagenic effects were observed only at doses within the toxic range in animal studies. While reprotoxicity is linked with abuse of alcoholic beverages, there is no epidemiological evidence for this from EBHR use in healthcare facilities or from products containing ethanol in non-healthcare settings.
Conclusion
The body of evidence shows EBHRs have strong efficacy in killing non-enveloped viruses, whereas 1-propanol and 2-propanol do not kill non-enveloped viruses, that pose significant risk of infection. Ethanol absorbed through the skin during hand hygiene is similar to consumption of beverages with hidden ethanol content (< 0.5% v/v), such as apple juice or kefir. There is no risk of carcinogenicity, mutagenicity or reprotoxicity from repeated use of EBHR. Hence, the WHO Task Force strongly recommend retaining ethanol as an essential constituent in hand rubs for healthcare.
Background: Due to the high number of immunosuppressed and other predisposed patients hospitals have to control and ensure the microbiological water quality. The origin for the occurrence of pathogenic microorganisms in water pipes is the formation of biofilm. Methods: For the permanent control of water safety a water safety plan (WSP) was realized as recommended by the WHO following the principle "search and destroy". The WSP is based on an established HACCP concept due to the special focus. The most important measures include the concept for sample taking depending on patient risk. 3 different categories) are distinguished: risk area1 (high infection risk), risk 2 (moderate infection risk), and risk area 3 (not increased infection risk). Additionally to the threshold value of the German law for the quality of drinking water (TrinkwV) three more limiting values were defined (warning, alert, and worst case) for immediate risk adapted reaction. Additional attention has to be focussed on lavatory sinks, which are an open bacterial reservoir. Therefore continuous disinfecting siphons were installed as part of the WSP in high risk areas. If extended technical equipment is not available, especially for immunocompromised patients the following measures are easy to realize: boiled (or sun exposed) water for nursing procedures as well alimentary use, no showering. Results: Comparing data over 3 years the microbial water quality was significantly improved resulting in no new case of nosocomial Legionella pneumoniae and decrease in neonatal sepsis. Conclusion: According to average situations with highly contaminated water system the management must be defined with implementation of water task force, immediate providing of special equipment, information of patients and staff and control of the water quality, an example for successful decontamination of the hospital within 24 hours is given.
AbstractPlasma medicine refers to the application of nonequilibrium plasmas at approximately body temperature, for therapeutic purposes. Nonequilibrium plasmas are weakly ionized gases which contain charged and neutral species and electric fields, and emit radiation, particularly in the visible and ultraviolet range. Medically-relevant cold atmospheric pressure plasma (CAP) sources and devices are usually dielectric barrier discharges and nonequilibrium atmospheric pressure plasma jets. Plasma diagnostic methods and modelling approaches are used to characterize the densities and fluxes of active plasma species and their interaction with surrounding matter. In addition to the direct application of plasma onto living tissue, the treatment of liquids like water or physiological saline by a CAP source is performed in order to study specific biological activities. A basic understanding of the interaction between plasma and liquids and bio-interfaces is essential to follow biological plasma effects. Charged species, metastable species, and other atomic and molecular reactive species first produced in the main plasma ignition are transported to the discharge afterglow to finally be exposed to the biological targets. Contact with these liquid-dominated bio-interfaces generates other secondary reactive oxygen and nitrogen species (ROS, RNS). Both ROS and RNS possess strong oxidative properties and can trigger redox-related signalling pathways in cells and tissue, leading to various impacts of therapeutic relevance. Dependent on the intensity of plasma exposure, redox balance in cells can be influenced in a way that oxidative eustress leads to stimulation of cellular processes or oxidative distress leads to cell death. Currently, clinical CAP application is realized mainly in wound healing. The use of plasma in cancer treatment (i.e. plasma oncology) is a currently emerging field of research. Future perspectives and challenges in plasma medicine are mainly directed towards the control and optimization of CAP devices, to broaden and establish its medical applications, and to open up new plasma-based therapies in medicine.
The loss of skin integrity is inevitable in life. Wound healing is a necessary sequence of events to reconstitute the body’s integrity against potentially harmful environmental agents and restore homeostasis. Attempts to improve cutaneous wound healing are therefore as old as humanity itself. Furthermore, nowadays, targeting defective wound healing is of utmost importance in an aging society with underlying diseases such as diabetes and vascular insufficiencies being on the rise. Because chronic wounds’ etiology and specific traits differ, there is widespread polypragmasia in targeting non-healing conditions. Reactive oxygen and nitrogen species (ROS/RNS) are an overarching theme accompanying wound healing and its biological stages. ROS are signaling agents generated by phagocytes to inactivate pathogens. Although ROS/RNS’s central role in the biology of wound healing has long been appreciated, it was only until the recent decade that these agents were explicitly used to target defective wound healing using gas plasma technology. Gas plasma is a physical state of matter and is a partially ionized gas operated at body temperature which generates a plethora of ROS/RNS simultaneously in a spatiotemporally controlled manner. Animal models of wound healing have been vital in driving the development of these wound healing-promoting technologies, and this review summarizes the current knowledge and identifies open ends derived from in vivo wound models under gas plasma therapy. While gas plasma-assisted wound healing in humans has become well established in Europe, veterinary medicine is an emerging field with great potential to improve the lives of suffering animals.
Unlike the native surface of the implant material (Ti6Al4V), oxidation with H2O2 leads to increased binding of the effective antimicrobial agent poly(hexamethylene) biguanide [PHMB]. However, treating with NaOH instead results in an even higher PHMB mass coverage. After oxidation with H2O2, strong differences in the PHMB adsorption capability between polished and corundum-blasted surfaces appear, indicating a roughness dependence. After NaOH treatment, no such effect was observed. The wetting properties of specimens treated with either H2O2 or NaOH prior to PHMB exposure clearly varied. To unravel the nature of this interaction, widespread in silico and in vitro experiments were performed. Methods: By X-ray photoelectron spectroscopy, scanning electron microscopy, water contact angle measurements and MD simulations, we characterized the interplay between the polycationic antimicrobial agent and the implant surface. A theoretical model for PHMB micelles is tested for its wetting properties and compared to carbon contaminated TiO2. In addition, quantitation of anionic functional group equivalents, the binding properties of PHMB with blocked amino end-group, and the ability to bind chlorhexidine digluconate (CHG) were investigated. Ultimately, the capability of osteoblasts to build calcium apatite, and the activity of alkaline phosphatase on PHMB coated specimens, were determined. Results: Simulated water contact angles on carbon contaminated TiO2 surfaces and PHMB micelle models reveal little influence of PHMB on the wetting properties and point out the major influence of remaining and recovering contamination from ambient air. Testing PHMB adsorption beyond the critical micelle concentration and subsequent staining reveals an island-like pattern with H2O2 as compared to an evenly modified surface with NaOH. Both CHG and PHMB, with blocked amino end groups, were adsorbed on the treated surfaces, thus negating the significant influence of PHMB’s terminal groups. The ability of osteoblasts to produce calcium apatite and alkaline phosphatase is not negatively impaired for PHMB mass coverages up to 8 μg/specimen. Conclusion: Differences in PHMB adsorption are triggered by the number of anionic groups and carbon contaminants, both of which depend on the specimen pre-treatment. With more PHMB covering, the implant surface is protected against the capture of new contamination from the ambient air, thus building a robust antimicrobial and biocompatible surface coating.
Aim
Periprosthetic joint infections are a devastating complication after arthroplasty, leading to rejection of the prosthesis. The prevention of septic loosening may be possible by an antimicrobial coating of the implant surface. Poly (hexamethylene) biguanide hydrochloride [PHMB] seems to be a suitable antiseptic agent for this purpose since previous studies revealed a low cytotoxicity and a long-lasting microbicidal effect of Ti6Al4V alloy coated with PHMB. To preclude an excessive activation of the immune system, possible inflammatory effects on macrophages upon contact with PHMB-coated surfaces alone and after killing of S. epidermidis and P. aeruginosa are analyzed.
Methods
THP-1 monocytes were differentiated to M0 macrophages by phorbol 12-myristate 13-acetate and seeded onto Ti6Al4V surfaces coated with various amounts of PHMB. Next to microscopic immunofluorescence analysis of labeled macrophages after adhesion on the coated surface, measurement of intracellular reactive oxygen species and analysis of cytokine secretion at different time points without and with previous bacterial contamination were conducted.
Results
No influence on morphology of macrophages and only slight increases in iROS generation were detected. The cytokine secretion pattern depends on the surface treatment procedure and the amount of adsorbed PHMB. The PHMB coating resulted in a high reduction of viable bacteria, resulting in no significant differences in cytokine secretion as reaction to coated surfaces with and without bacterial burden.
Conclusion
Ti6Al4V specimens after alkaline treatment followed by coating with 5–7 μg PHMB and specimens treated with H2O2 before PHMB-coating (4 μg) had the smallest influence on the macrophage phienotype and thus are considered as the surface with the best cytocompatibility to macrophages tested in the present study.
The effect of water-filtered infrared-A radiation (wIRA) on normal skin flora was investigated by generating experimental wounds on the forearms of volunteers utilizing the suction blister technique. Over 7 days, recolonization was monitored parallel to wound healing. Four groups of treatment were compared: no therapy (A), dexpanthenol cream once daily (B), 20 min wIRA irradiation at 30 cm distance (C), and wIRA irradiation for 30 min once daily together with dexpanthenol cream once daily (D). All treatments strongly inhibited the recolonization of the wounds. Whereas dexpanthenol completely suppressed recolonization over the test period, recolonization after wIRA without (C) and in combination with dexpanthenol (D) was suppressed, but started on day 5 with considerably higher amounts after the combination treatment (D). Whereas the consequence without treatment (A) was an increasing amount of physiological skin flora including coagulase-negative staphylococci, all treatments (B–D) led to a reduction in physiological skin flora, including coagulase-negative staphylococci. In healthy volunteers, wIRA alone and in combination with dexpanthenol strongly inhibited bacterial recolonization with physiological skin flora after artificial wound setting using a suction-blister wound model. This could support the beneficial effects of wIRA in the promotion of wound healing.
Multiple evidence in animal models and in humans suggest a beneficial role of cold physical
plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic
advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the long-term
side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear
wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood,
systemic changes of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α
were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged.
Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver,
lung, and skin were found to be similar in the control and treatment group as well. Likewise,
histological and immunohistochemical analysis failed to detect abnormal morphological changes
and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor
of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as
anatomical magnetic resonance imaging and positron emission tomography-computed tomography.
Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent
side effects including tumor formation or chronic inflammation.
Abstract
Antimicrobial coating of implant material with poly(hexamethylene biguanide) hydrochloride (PHMB) may be an eligible method for preventing implant‐associated infections. In the present study, an antibacterial effective amount of PHMB is adsorbed on the surface of titanium alloy after simple chemical pretreatment. Either oxidation with 5% H2O2 for 24 hr or processing for 2 hr in 5 M NaOH provides the base for the subsequent formation of a relatively stable self‐assembled PHMB layer. Compared with an untreated control group, adsorbed PHMB produces no adverse effects on SaOs‐2 cells within 48 hr cell culture, but promotes the initial attachment and spreading of the osteoblasts within 15 min. Specimens were inoculated with slime‐producing bacteria to simulate a perioperative infection. Adsorbed PHMB reacts bactericidally against Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa after surface contact. Adhered SaOs‐2 cells differentiate and produce alkaline phosphatase and deposit calcium within 4 days in a mineralization medium on PHMB‐coated Ti6Al4V surfaces, which have been precontaminated with S. epidermidis. The presented procedures provide a simple method for generating biocompatibly and antimicrobially effective implant surfaces that may be clinically important.
Cold physical plasmas, especially noble gas driven plasma jets, emit considerable amounts of ultraviolet radiation (UV). Given that a noble gas channel is present, even the energetic vacuum UV can reach the treated target. The relevance of UV radiation for antimicrobial effects is generally accepted. It remains to be clarified if this radiation is relevant for other biomedical application of plasmas, e.g., in wound care or cancer remediation. In this work, the role of (vacuum) ultraviolet radiation generated by the argon plasma jet kINPen for cysteine modifications was investigated in aqueous solutions and porcine skin. To differentiate the effects of photons of different wavelength and complete plasma discharge, a micro chamber equipped with a MgF2, Suprasil, or Borosilicate glass window was used. In liquid phase, plasma-derived VUV radiation was effective and led to the formation of cysteine oxidation products and molecule breakdown products, yielding sulfite, sulfate, and hydrogen sulfide. At the boundary layer, the impact of VUV photons led to water molecule photolysis and formation of hydroxyl radicals and hydrogen peroxide. In addition, photolytic cleavage of the weak carbon-sulfur bond initiated the formation of sulfur oxy ions. In the intact skin model, protein thiol modification was rare even if a VUV transparent MgF2 window was used. Presumably, the plasma-derived VUV radiation played a limited role since reactions at the boundary layer are less frequent and the dense biomolecules layers block it effectively, inhibiting significant penetration. This result further emphasizes the safety of physical plasmas in biomedical applications.
The objective of the present investigation was to examine the residual antimicrobial activity after a topical exposure of reconstructed human epidermis (RHE) to equimolar solutions of either chlorhexidine digluconate (CHG, 0.144% w/v) or octenidine dihydrochloride (OCT, 0.1% w/v) for 15 min. RHE-associated antiseptic agents were more effective on Staphylococcus aureus than on Pseudomonas aeruginosa. S. aureus was not detected after 24 h of contact, which demonstrated a microbicidal efficacy of greater than 5-log<sub>10</sub> reduction. In contrast, P. aeruginosa was reduced by approximately 2 log<sub>10</sub> at the same incubation time, which parallels the growth of the initial inoculum. This result could be interpreted either as a microbiostatic effect or as an adherence of P. aeruginosa to a low positively charged surface. Small amounts of CHG and OCT can penetrate the stratum corneum. Using these antiseptic agents, the viability of keratinocytes was reduced to 65-75% of that of the untreated RHE control following 24 h incubation in the presence of test microorganisms. With consideration of antimicrobial activity and cytotoxic effect, OCT corresponds better to a biocompatible antiseptic agent than CHG.
Contaminated surfaces have been discussed as a possible source of severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2). Under experimental conditions, SARS-CoV-2 can remain
infectious on surfaces for several days. However, the frequency of SARS-CoV-2 detection on surfaces
in healthcare settings and the public is currently not known. A systematic literature review was
performed. On surfaces around COVID-19 cases in healthcare settings (42 studies), the SARS-CoV2 RNA detection rates mostly were between 0% and 27% (Ct values mostly > 30). Detection of
infectious SARS-CoV-2 was only successful in one of seven studies in 9.2% of 76 samples. Most of the
positive samples were obtained next to a patient with frequent sputum spitting during sampling.
Eight studies were found with data from public surfaces and RNA detection rates between 0% and
22.1% (Ct values mostly > 30). Detection of infectious virus was not attempted. Similar results
were found in samples from surfaces around confirmed COVID-19 cases in non-healthcare settings
(7 studies) and from personal protective equipment (10 studies). Therefore, it seems plausible to
assume that inanimate surfaces are not a relevant source for transmission of SARS-CoV-2. In public
settings, the associated risks of regular surface disinfection probably outweigh the expectable health
benefit
Wound healing disorders frequently occur due to biofilm formation on wound surfaces requiring conscientious wound hygiene. Often, the application of conventional liquid antiseptics is not sufficient and sustainable as (1) the borders and the surrounding of chronic wounds frequently consist of sclerotic skin, impeding an effectual penetration of these products, and (2) the hair follicles representing the reservoir for bacterial recolonization of skin surfaces are not affected. Recently, it has been reported that tissue-tolerable plasma (TTP), which is used at a temperature range between 35 and 45°C, likewise has disinfecting properties. In the present study, the effectivity of TTP and a standard liquid antiseptic was compared in vitro on porcine skin. The results revealed that TTP was able to reduce the bacterial load by 94%, although the application of the liquid antiseptic remained superior as it reduced the bacteria by almost 99%. For in vivo application, however, TTP offers several advantages. On the one hand, TTP enables the treatment of sclerotic skin as well, and on the other hand, a sustainable disinfection can be realized as, obviously, also the follicular reservoir is affected by TTP.