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Biophysical aspects of the skin barrier: towards increased non-invasive extraction and optimized biomarker sampling
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
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: urn:nbn:se:mau:diva-48311DOI: 10.24834/isbn.9789178772254ISBN: 9789178772247 (print)ISBN: 9789178772254 (electronic)OAI: oai:DiVA.org:mau-48311DiVA, id: diva2:1622018
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
List of papers
1. Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro.
Open this publication in new window or tab >>Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro.
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 17218Article in journal (Refereed) Published
Abstract [en]

Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.

Place, publisher, year, edition, pages
Springer, 2020
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-18777 (URN)10.1038/s41598-020-73684-y (DOI)000582678700012 ()33057021 (PubMedID)2-s2.0-85092579040 (Scopus ID)
Available from: 2020-10-23 Created: 2020-10-23 Last updated: 2024-02-05Bibliographically approved
2. Bicontinuous Cubic Liquid Crystals as Potential Matrices for Non-Invasive Topical Sampling of Low-Molecular-Weight Biomarkers
Open this publication in new window or tab >>Bicontinuous Cubic Liquid Crystals as Potential Matrices for Non-Invasive Topical Sampling of Low-Molecular-Weight Biomarkers
2023 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 8, article id 2031Article in journal (Refereed) Published
Abstract [en]

Many skin disorders, including cancer, have inflammatory components. The non-invasive detection of related biomarkers could therefore be highly valuable for both diagnosis and follow up on the effect of treatment. This study targets the extraction of tryptophan (Trp) and its metabolite kynurenine (Kyn), two compounds associated with several inflammatory skin disorders. We furthermore hypothesize that lipid-based bicontinuous cubic liquid crystals could be efficient extraction matrices. They comprise a large interfacial area separating interconnected polar and apolar domains, allowing them to accommodate solutes with various properties. We concluded, using the extensively studied GMO-water system as test-platform, that the hydrophilic Kyn and Trp favored the cubic phase over water and revealed a preference for locating at the lipid-water interface. The interfacial area per unit volume of the matrix, as well as the incorporation of ionic molecules at the lipid-water interface, can be used to optimize the extraction of solutes with specific physicochemical characteristics. We also observed that the cubic phases formed at rather extreme water activities (>0.9) and that wearing them resulted in efficient hydration and increased permeability of the skin. Evidently, bicontinuous cubic liquid crystals constitute a promising and versatile platform for non-invasive extraction of biomarkers through skin, as well as for transdermal drug delivery.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
tryptophan, kynurenine, tryptophan-to-kynurenine ratio, cancer-related biomarkers, non-invasive extraction, bicontinuous cubic liquid crystal, bilayer partitioning, glycerol monooleate, DOTAP, X-ray diffraction, humidity scanning (HS) QCM-D
National Category
Pharmaceutical Chemistry
Identifiers
urn:nbn:se:mau:diva-62643 (URN)10.3390/pharmaceutics15082031 (DOI)001055274500001 ()37631245 (PubMedID)2-s2.0-85168893889 (Scopus ID)
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2023-10-19Bibliographically approved
3. Reverse Iontophoretic Extraction of Skin Cancer-Related Biomarkers
Open this publication in new window or tab >>Reverse Iontophoretic Extraction of Skin Cancer-Related Biomarkers
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2022 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, no 1, article id 79Article in journal (Refereed) Published
Abstract [en]

Non-invasive methods for early diagnosis of skin cancer are highly valued. One possible approach is to monitor relevant biomarkers such as tryptophan (Trp) and kynurenine (Kyn), on the skin surface. The primary aim of this in vitro investigation was, therefore, to examine whether reverse iontophoresis (RI) can enhance the extraction of Trp and Kyn, and to demonstrate how the Trp/Kyn ratio acquired from the skin surface reflects that in the epidermal tissue. The study also explored whether the pH of the receiver medium impacted on extraction efficiency, and assessed the suitability of a bicontinuous cubic liquid crystal as an alternative to a simple buffer solution for this purpose. RI substantially enhanced the extraction of Trp and Kyn, in particular towards the cathode. The Trp/Kyn ratio obtained on the surface matched that in the viable skin. Increasing the receiver solution pH from 4 to 9 improved extraction of both analytes, but did not significantly change the Trp/Kyn ratio. RI extraction of Trp and Kyn into the cubic liquid crystal was comparable to that achieved with simple aqueous receiver solutions. We conclude that RI offers a potential for non-invasive sampling of low-molecular weight biomarkers and further investigations in vivo are therefore warranted.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
tryptophan, kynurenine, tryptophan-to-kynurenine ratio, cancer-related biomarkers, non-invasive extraction, bicontinuous cubic liquid crystals
National Category
Pharmaceutical Chemistry
Identifiers
urn:nbn:se:mau:diva-50524 (URN)10.3390/pharmaceutics14010079 (DOI)000758502900001 ()35056976 (PubMedID)2-s2.0-85122161916 (Scopus ID)
Available from: 2022-03-09 Created: 2022-03-09 Last updated: 2024-02-05Bibliographically approved
4. Non-Invasive, Topical Sampling of Potential, Low-Molecular Weight, Skin Cancer Biomarkers: A Study on Healthy Volunteers.
Open this publication in new window or tab >>Non-Invasive, Topical Sampling of Potential, Low-Molecular Weight, Skin Cancer Biomarkers: A Study on Healthy Volunteers.
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2022 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 94, no 15, p. 5856-5865Article in journal (Refereed) Published
Abstract [en]

Monitoring of low-molecular weight cancer biomarkers, such as tryptophan (Trp) and its derivative kynurenine (Kyn), might be advantageous to non-invasive skin cancer detection. Thus, we assessed several approaches of topical sampling of Trp and Kyn, in relation to phenylalanine (Phe) and tyrosine (Tyr), on the volar forearm of six healthy volunteers. The sampling was performed with three hydrogels (made of agarose or/and chitosan), hydrated starch films, cotton swabs, and tape stripping. The biomarkers were successfully sampled by all approaches, but the amount of collected Kyn was low, 20 ± 10 pmol/cm2. Kyn quantification was below LOQ, and thus, it was detected only in 20% of topical samples. To mitigate variability problems of absolute amounts of sampled amino acids, Tyr/Trp, Phe/Trp, and Phe/Tyr ratios were assessed, proving reduced inter-individual variation from 79 to 45% and intra-individual variation from 42 to 21%. Strong positive correlation was found between Phe and Trp, pointing to the Phe/Trp ratio (being in the 1.0–2.0 range, at 95% confidence) being least dependent on sampling materials, approaches, and sweating. This study leads to conclusion that due to the difficulty in quantifying less abundant Kyn, and thus the Trp/Kyn ratio, the Phe/Trp ratio might be a possible, alternative biomarker for detecting skin cancers.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:mau:diva-51301 (URN)10.1021/acs.analchem.1c05470 (DOI)000792814500018 ()35394278 (PubMedID)2-s2.0-85128387453 (Scopus ID)
Available from: 2022-05-04 Created: 2022-05-04 Last updated: 2023-11-29Bibliographically approved
5. Hydrogels and Cubic Liquid Crystals for Non-Invasive Sampling of Low-Molecular-Weight Biomarkers-An Explorative In Vivo Study
Open this publication in new window or tab >>Hydrogels and Cubic Liquid Crystals for Non-Invasive Sampling of Low-Molecular-Weight Biomarkers-An Explorative In Vivo Study
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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
Keywords
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:nbn:se:mau:diva-50952 (URN)10.3390/pharmaceutics14020313 (DOI)000765124800001 ()35214046 (PubMedID)2-s2.0-85124460011 (Scopus ID)
Available from: 2022-04-06 Created: 2022-04-06 Last updated: 2024-02-05Bibliographically approved

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