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Hydrogels and Cubic Liquid Crystals for Non-Invasive Sampling of Low-Molecular-Weight Biomarkers-An Explorative In Vivo Study
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.ORCID iD: 0000-0001-8720-3705
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
Malmö University, Biofilms Research Center for Biointerfaces. Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).ORCID iD: 0000-0003-0304-7528
Linkoping Univ, Fac Hlth Sci, Dept Biomed & Clin Sci, Div Clin Chem & Pharmacol, S-58183 Linkoping, Sweden.;Local Hlth Care Serv Cent Ostergotland, Dept Emergency Med, S-58185 Linkoping, Sweden..
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2022 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, no 2, article id 313Article in journal (Refereed) Published
Abstract [en]

The molecular composition of human skin is altered due to diseases, which can be utilized for non-invasive sampling of biomarkers and disease diagnostics. For this to succeed, it is crucial to identify a sampling formulation with high extraction efficiency and reproducibility. Highly hydrated skin is expected to be optimal for increased diffusion of low-molecular-weight biomarkers, enabling efficient extraction as well as enhanced reproducibility as full hydration represents a well-defined endpoint. Here, the aim was to explore water-based formulations with high water activities, ensuring satisfactory skin hydration, for non-invasive sampling of four analytes that may serve as potential biomarkers, namely tryptophan, tyrosine, phenylalanine, and kynurenine. The included formulations consisted of two hydrogels (chitosan and agarose) and two different liquid crystalline cubic phases based on the polar lipid glycerol monooleate, which were all topically applied for 2 h on 35 healthy subjects in vivo. The skin status of all sampling sites was assessed by electrical impedance spectroscopy and transepidermal water loss, enabling explorative correlations between biophysical properties and analyte abundancies. Taken together, all formulations resulted in the successful and reproducible collection of the investigated biomarkers. Still, the cubic phases had an extraction capacity that was approximately two times higher compared to the hydrogels.

Place, publisher, year, edition, pages
MDPI, 2022. Vol. 14, no 2, article id 313
Keywords [en]
low-molecular-weight biomarker, tryptophan, kynurenine, tyrosine, phenylalanine, tryptophan-to-kynurenine ratio, skin barrier integrity, stratum corneum, natural moisturizing factor, electrical impedance spectroscopy, transepidermal water loss
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:mau:diva-50952DOI: 10.3390/pharmaceutics14020313ISI: 000765124800001PubMedID: 35214046Scopus ID: 2-s2.0-85124460011OAI: oai:DiVA.org:mau-50952DiVA, id: diva2:1650271
Available from: 2022-04-06 Created: 2022-04-06 Last updated: 2024-02-05Bibliographically approved
In thesis
1. Non-invasive monitoring of low molecular weight biomarkers relevant to skin inflammation and cancer
Open this publication in new window or tab >>Non-invasive monitoring of low molecular weight biomarkers relevant to skin inflammation and cancer
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Development of skin inflammation and cancer in viable epidermis and dermis involve slow molecular weight (LMW) metabolites. We hypothesize that these LMW compounds can be collected on the surface of the skin and used for non-invasive diagnostics of skin disorders. Keeping in mind that substantial transdermal penetrationis achieved only for molecules of < 500 Da, we focused on topical monitoring of LMW biomarkers. In this thesis we investigated non-invasive, topical methods for monitoring LMW biomarkers by relevant in vitro and in vivo experiments. The LMW biomarkers were:

- reactive oxygen species (ROS), specifically, hydrogen peroxide, H2O2

- amino acids and their derivatives, i.e., tryptophan (Trp), kynurenine (Kyn; a Trpderivative), phenylalanine (Phe), and tyrosine (Tyr; a Phe derivative).

Initially, we have carried out in vitro experiments using dermatomed porcine skin and cell cultures. We characterized permeability of the biomarkers through skin and assessed methods of their monitoring. By using Prussian white particles, deposited on porcine skin, we demonstrated that hydrophilic biomarkers, such as H2O2, permeate the skin mainly through hair follicle pathways (Paper I). In paper II, we have showed that the enzymes transforming Trp to the inflammation and cancer biomarker Kyn, are expressed in the basal layer of epidermis. The magnitude of changes of the Trp/Kyn ratio in the cell culture model was assessed. In paper III, we have characterized Trp and Kyn permeability through skin in vitro, concluding that their permeabilities through stratum corneum are comparable. By in vivo experiments outlined in Paper IV, we have demonstrated the feasibility of topical, non-invasive sampling of Trp and Kyn, in relation to other amino acids. Kyn detection was compromised by its low abundance on the skin. In paper V, we performed a proof-of-concept study in vivo and confirmed that non-invasive sampling of Trp and amino acids of similar abundance, such as Phe and Tyr, is more robust. We concluded that Phe/Trp ratio might be equally good biomarker of skin disorders as a predicted Trp/Kyn ratio. Summarizing, the results of this thesis provide basic knowledge for deeper clinical studies of non-invasive, topical sampling of hydrophilic LMW biomarkers of skin inflammation and cancer.

Place, publisher, year, edition, pages
Malmö: Malmö universitet, 2021. p. 66
Series
Malmö University Health and Society Dissertations, ISSN 1653-5383 ; 2021:9
Keywords
Tryptophan, Kynurenine, Phenylalanine, Tyrosine, Low molecular Weight Biomarkers, Non-Invasive, Skin Surface Sampling, Skin Permeability, Hydrogels, Prussian White
National Category
Health Sciences
Research subject
Health and society
Identifiers
urn:nbn:se:mau:diva-46859 (URN)10.24834/isbn.9789178772230 (DOI)978-91-7877-222-3 (ISBN)978-91-7877-223-0 (ISBN)
Public defence
2021-11-29, Live stream and on location at HS assembly hall, Jan Waldenströms gata 25, ö, 09:00
Opponent
Supervisors
Note

Paper III published in dissertation as manuscript with title Non-invasive, Topical Sampling of Potential Skin Cancer Biomarkers,Kynurenine and Tryptophan: Study on Healthy Volunteers

Available from: 2021-11-15 Created: 2021-11-15 Last updated: 2022-11-09Bibliographically approved
2. Biophysical aspects of the skin barrier: towards increased non-invasive extraction and optimized biomarker sampling
Open this publication in new window or tab >>Biophysical aspects of the skin barrier: towards increased non-invasive extraction and optimized biomarker sampling
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The skin provides a link to the body’s health via its rich variety of high and low molecular weight biomarkers, reflecting both systemic diseases (e.g., cancer, diabetes) and local skin disorders (e.g., atopic dermatitis, psoriasis). Non-invasive monitoring of disease-specific biomarkers on the skin surface provides a highly attractive diagnostic procedure as alternative to current practices that normally are biopsy-based and invasive. In order to succeed with non-invasive topical diagnostics, the sampling of biomarkers should proceed in a highly accurate and reproducible manner. Further, a major challenge to achieve this goal is to overcome the outermost skin layer (the stratum corneum, SC) that acts as a remarkable permeability barrier, restricting molecular diffusion in and out of our body, including diffusion of potential biomarkers.

The primary aim of this thesis is to achieve an optimized and reproducible noninvasive sampling of endogenous biomarkers from the skin surface. Here, water plays a crucial role as the hydration degree of the SC has a strong influence on the diffusion of molecules across the skin barrier. In particular, fully hydrated skin is expected to be optimal for increased diffusion of biomarkers in the skin tissue, favoring efficient extraction.

Considering this, to develop a suitable sampling matrix for non-invasive extraction, it is very important to optimize the matrix so that it has a good ability to hydrate the skin as well as a high capacity to absorb the biomarker and finally allow for analytic quantification. The main questions in this thesis are as follows. (i) How long time does it take to reach a stable level of skin hydration? (ii) How do the intrinsic properties of sampling matrices influence the extraction of biomarkers? (iii) What are the effects of the sampling matrices on the biophysical properties of the skin barrier?(iv) Are hydrogels and bicontinuous cubic liquid crystals suitable matrices for noninvasive sampling of endogenous biomarkers? (v) Is reverse iontophoresis a suitable technique to further enhance the extraction endogenous biomarkers?

The hydration of the skin is investigated in vivo and in vitro in order to estimate the time to reach stable hydration level. We show that skin hydration proceeds in two distinct stages with different rates of change of the electrical impedance response and conclude that stable conditions are obtained approximately after 60 min of hydration. We explore the novel approach of using lipid-based bicontinuous cubic liquid crystalline phases as matrices for non-invasive sampling of biomarkers in vivo and invitro and compare them with hydrogel-based materials.

From these investigations, we conclude that both kind of materials show promising capacity of hydrating the skin and collect skin-derived biomarkers. However, the cubic phases are shown to havea bout twice as high extraction capacity, as compared to hydrogels. Further, we show that reverse iontophoresis enhances extraction of a potential cancer biomarker in vitro by at least an order of magnitude, as compared to passive diffusion. Taken together, the results obtained in this thesis can serve as a point-of-departure for future applications based on non-invasive sampling of disease-related biomarkers from skinin clinical diagnostics.

Place, publisher, year, edition, pages
Malmö: Malmö universitet, 2021. p. 70
Series
Malmö University Health and Society Dissertations, ISSN 1653-5383 ; 2021:10
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:mau:diva-48311 (URN)10.24834/isbn.9789178772254 (DOI)9789178772247 (ISBN)9789178772254 (ISBN)
Opponent
Supervisors
Note

Paper II published in dissertation as manuscript.

Paper IV published in dissertation as manuscript with title Non-invasive, Topical Sampling of Potential Skin Cancer Biomarkers,Kynurenine and Tryptophan: Study on Healthy Volunteer

Available from: 2021-12-21 Created: 2021-12-21 Last updated: 2023-10-19Bibliographically approved

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Morin, MaximJankovskaja, SkaidreRuzgas, TautgirdasEngblom, JohanBjörklund, Sebastian

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