Application of UV-radiation and UV-responsive nanocapsules for skin antisepsis
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Philipps-Universität Marburg
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Based on the global health care burden caused by surgical site infections (SSI) as well as the rising prevalence of multi-drug resistant bacteria this dissertation suggests the implementation of two novel and innovative approaches for an advanced skin antisepsis. Hair follicles are known to represent a densely colonized reservoir of pathogens. During prolonged surgical procedures, recolonization of the skin surface can therefore occur from this reservoir transmitting pathogens into the surgical field. It is known that SSI are caused by endogenous germs in 90% of all cases. This leads to two possible approaches for improved skin antisepsis: targeted decontamination of deep sections of hair follicles and repetitive intraoperative decontamination of the skin. The first part of this dissertation addresses the application of a pharmaceutical-based approach for enhanced skin antisepsis. Based on the so-called ratchet effect, nanoparticles penetrate into hair follicles when external forces are applied. Thus, it is known that a significantly deeper follicular penetration of therapeutics can be achieved using nano-delivery systems as compared to the application of free active ingredient solutions. A targeted eradication could therefore be induced by a controlled release of antiseptics in the deeper segments of the hair follicles, whereas these segments are inaccessible to non-particulate substances. For a targeted and rapid release of the antiseptic contained in nanocapsules (NCs), ultraviolet A light (UVA) was utilized due to its accessibility to the dermal portions of the skin. This approach was pursued using UVA light emitting diode (LED) systems as well as biocompatible photo-responsive NCs. The first of two studies focused on principal experiments to evidence the possibility of follicular penetration and intrafollicular UV-triggered drug release using biocompatible polyurethane (PU)-NCs. Using an ex vivo porcine skin model, UVA-responsive degradation of the NCs at a mean follicular penetration depth of approximately 500 µm was obtained tracking the model drug sulforhodamine 101 (SR101) in cryohistological slices with confocal laser scanning microscopy (CLSM). In a follow-up approach hydroxyethyl starch (HES)-NCs based on the same technology were utilized. With these, a comparable follicular penetration depth could be achieved. In a final microbiological experiment utilizing HES-NCs with encapsulated ethanol, no significant difference to a particle-free control (80% ethanol) could be observed on ex vivo porcine ear skin showing that the choice of nanocarrier materials should always be based on the field of application and compatibility with the continuous phase.
Complementary to this, far-UVC light (UVC < 240 nm) represents the second approach for improved skin surface decontamination as it is very easy to apply consecutively and can therefore quickly disinfect recolonized surfaces to prevent SSI. Based on its high energy, far-UVC radiation has the advantage of inactivating pathogens through the immediate generation of DNA lesions without provoking bacterial resistance. Unlike UVC radiation of 254 nm, which is mostly applied for the disinfection of water and surfaces, it is absorbed strongly in the non-nucleated stratum corneum limiting the penetration of far-UVC photons into the viable epidermis. In this thesis, a novel LED emitting far-UVC light of 233 nm was comprehensively assessed for its skin compatibility evaluating the formation of DNA damage and free radicals on various skin models. Microbiocidal doses as previously determined by project partners of the University Medicine Greifswald were applied. At an application dose from 40 to 60 mJ/cm2, a complete eradication of methicillin-resistant Staphylococcus aureus (MRSA) on agar plates and germ carriers was observed. Irradiation with microbiocidal 233 nm far-UVC led to a minor development of DNA damage in intact ex vivo human skin compared to 10% of a minimal erythema dose (MED) of UVB radiation. Moreover, the formation of free radicals was lower than for visible and near-infrared (VIS–NIR) irradiation equivalent to 20 min solar exposure in reconstructed human epidermal models. To investigate whether 233 nm far-UVC radiation can also be applied to wounds during surgical procedures, an ex vivo wound model was assessed in the follow-up study. An increase and relocation of DNA lesions to deeper areas of wounded skin was observed after irradiation with 233 nm far-UVC. Interestingly, applying artificial wound exudate to the exposed viable epidermis before irradiation led to reconstruction of the photoprotective function of an intact stratum corneum. Furthermore, it was found that a certain amount of free radicals is generated in wounded skin, which is an interesting subject for future studies on possible wound healing processes. To determine the influence of the melanin concentration, human skin of different skin types was irradiated ex vivo with 222 nm, 233 far-UVC light and with broadband UVB light. In this study it was revealed that the formation of DNA lesions was lower in dark skin types than in fair skin types after irradiation at 233 nm. However, 222 nm radiation caused no skin type-dependent differences due to its limited penetration depth while UVB caused a strong divergence between light and dark skin types when applying 10% of a MED. The melanin concentration differs less between light and dark skin types in the upper epidermal fraction than in the deep layers of the epidermis. This leads to skin type-dependent deviations in tolerability due to the maximum penetration depth of the respective wavelength.
In summary, the nanoparticle-based approach for skin decolonization is usefully complemented by the far-UVC light-based approach, and both bear potential for a preoperative and intraoperative skin antisepsis. Nevertheless, the pharmaceutical side requires significant optimization before it can be finally implemented. The use of far-UVC LEDs for skin surface decontamination has been comprehensively addressed for the first time but still further risk assessment studies need to be performed for the final implementation of this approach.
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Created: 2023Issued: 2024-02-15Updated: 2024-02-15
Faculty
Fachbereich Pharmazie
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
DFG-subjects
HaarfollikelUVAHautantisepsisWundenNanokapselnDNA SchädenStratum corneumMelaninUVCLEDHauttypKontrollierte Wirkstofffreisetzung
DDC-Numbers
615
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Busch, Loris (0000-0002-2671-2028): Application of UV-radiation and UV-responsive nanocapsules for skin antisepsis. : Philipps-Universität Marburg 2024-02-15. DOI: https://doi.org/10.17192/z2024.0047.
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