| 1. |
- Jankovskaja, Skaidre, et al.
(författare)
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Non-Invasive, Topical Sampling of Potential, Low-Molecular Weight, Skin Cancer Biomarkers : A Study on Healthy Volunteers
- 2022
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:15, s. 5856-5865
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Tidskriftsartikel (refereegranskat)abstract
- Monitoring of low-molecular weight cancer biomarkers, suchas tryptophan (Trp) and its derivative kynurenine (Kyn), might beadvantageous to non-invasive skin cancer detection. Thus, we assessedseveral approaches of topical sampling of Trp and Kyn, in relation tophenylalanine (Phe) and tyrosine (Tyr), on the volar forearm of six healthyvolunteers. The sampling was performed with three hydrogels (made ofagarose or/and chitosan), hydrated starchfilms, cotton swabs, and tapestripping. The biomarkers were successfully sampled by all approaches, butthe amount of collected Kyn was low, 20 +/- 10 pmol/cm2.Kynquantification was below LOQ, and thus, it was detected only in 20% oftopical samples. To mitigate variability problems of absolute amounts ofsampled 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 foundbetween Phe and Trp, pointing to the Phe/Trp ratio (being in the 1.0-2.0 range, at 95% confidence) being least dependent onsampling materials, approaches, and sweating. This study leads to conclusion that due to the difficulty in quantifying less abundantKyn, and thus the Trp/Kyn ratio, the Phe/Trp ratio might be a possible, alternative biomarker for detecting skin cancers.
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| 2. |
- Li, Weimin, et al.
(författare)
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Charge-Induced Patchy Attractions between Proteins
- 2015
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 119:2, s. 503-508
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Tidskriftsartikel (refereegranskat)abstract
- Static light scattering (SLS) combined with structure-based Monte Carlo (MC) simulations provide new insights into mechanisms behind anisotropic, attractive protein interactions. A nonmonotonic behavior of the osmotic second virial coefficient as a function of ionic strength is here shown to originate from a few charged amino acids forming an electrostatic attractive patch, highly directional and complementary. Together with Coulombic repulsion, this attractive patch results in two counteracting electrostatic contributions to the interaction free energy which, by operating over different length scales, is manifested in a subtle, salt-induced minimum in the second virial coefficient as observed in both experiment and simulations.
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| 3. |
- Li, Weimin, et al.
(författare)
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Strings and stripes formed by a protein system interacting via a single-patch attraction
- 2016
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 12:46, s. 9330-9333
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Tidskriftsartikel (refereegranskat)abstract
- The phase behavior of lactoferrin has been studied as a function of concentration at a pH and ionic strength where lactoferrin is known to interact effectively via a patch-patch attraction. In contrast to isotropic attractive potentials, the directional attraction gives rise to a different phase or solution behavior. At low concentrations, the protein dimerizes. As the concentration is increased, the protein self-assembles into elongated, stripe-like structures at intermediate protein concentrations, a behavior which has been predicted for the case of attractive one-patch colloids. The stripe phase is surprisingly difficult to detect using conventional techniques, i.e. small-angle X-ray scattering, since only a small fraction of the proteins participate in the stripes combined with sedimentation due to micron-sized entities. This is circumvented by monitoring the change in the overall protein concentration by static light scattering and the stripe formation can be followed. For visualization of the structures cryo-TEM is used.
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| 4. |
- Lind, Tania K., et al.
(författare)
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Effects of ethylene oxide chain length on crystallization of polysorbate 80 and its related compounds
- 2021
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier. - 0021-9797 .- 1095-7103. ; 592, s. 468-484
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Tidskriftsartikel (refereegranskat)abstract
- As a result of the synthesis protocol polyoxyethylene sorbitan monooleate (polysorbate 80, PS80) is a highly complex mixture of compounds. PS80 was therefore separated into its main constituents, e.g. polyoxyethylene isosorbide esters and polyoxyethylene esters, as well as mono- di- and polyesters using preparative high-performance liquid chromatography. In this comprehensive study the individual components and their ethoxylation level were verified by matrix assisted laser desorption/ionization time-of-flight and their thermotropic behavior was analyzed using differential scanning calorimetry and X-ray diffraction. A distinct correlation was found between the average length of the ethylene oxide (EO) chains in the headgroup and the individual compounds' ability to crystallize. Importantly, a critical number of EO units required for crystallization of the headgroup was determined (6 EO units per chain or 24 per molecule). The investigation also revealed that the hydrocarbon tails only crystallize for polyoxyethylene sorbitan esters if saturated. PS80 is synthesized by reacting with approximately 20 mol of EO per mole of sorbitol, however, the number of EO units in the sorbitan ester in commercial PS80 products is higher than the expected 20 (5 EO units per chain). The complex behavior of all tested compounds revealed that if the amount of several of the linear by-products is reduced, the number of EO units in the chains will stay below the critical number and the product will not be able to crystallize by the EO chains.
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| 5. |
- Morin, Maxim, et al.
(författare)
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Bicontinuous Cubic Liquid Crystals as Potential Matrices for Non-Invasive Topical Sampling of Low-Molecular-Weight Biomarkers
- 2023
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 15:8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Morin, Maxim
(författare)
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Biophysical aspects of the skin barrier : towards increased non-invasive extraction and optimized biomarker sampling
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 7. |
- Morin, Maxim, et al.
(författare)
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Effects of storage conditions on permeability and electrical impedance properties of the skin barrier.
- 2023
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 637, s. 122891-
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the effect of various skin preservation protocols on in vitro drug permeation, epidermal-dermal drug distribution, and electrical impedance properties of skin membranes. Acyclovir (AC) and methyl salicylate (MS) were selected as model drugs due to their different physicochemical properties and skin metabolic profiles. In particular, AC is relatively hydrophilic (logP -1.8) and not expected to be affected by skin metabolism, while MS is relatively lipophilic (logP 2.5) and susceptible to metabolism, being a substrate for esterase residing in skin. Skin from pig ears was used and freshly excised into split-thickness membranes, which were divided and immediately stored at five different storage conditions: a) 4 °C overnight (fresh control), b) 4 °C for 4 days, c) and d) -20 °C for 6 weeks and one year, respectively, and e) -80 °C for 6 weeks. Based on the combined results, general trends are observed showing that fresh skin is associated with lower permeation of both model drugs and higher skin membrane electrical resistance, as compared to the other storage conditions. Interestingly, in the case of fresh skin, significantly lower amounts of MS are detected in the epidermis and dermis compartments, implying higher levels of ester hydrolysis of MS (i.e., higher esterase activity). In line with this, the concentration of salicylic acid (SA) extracted from the dermis is significantly higher for fresh skin, as compared to the other storage conditions. Nevertheless, for all storage conditions, substantial amounts of SA are detected in the receptor medium, as well as in the epidermis and dermis, implying that esterase activity is maintained to some extent in all cases. For AC, which is not expected to be affected by skin metabolism, freeze storage (protocols c-e) is observed to result in higher accumulation of AC in the epidermis, as compared to the case of fresh skin, while the AC concentration in dermis is unaffected. These observations can be rationalized primarily by the observed lower permeability of fresh skin towards this hydrophilic substance. Finally, a strong correlation between AC permeation and electrical skin resistance is shown for individual skin membranes irrespective of storage condition, while the corresponding correlation for MS is inferior. On the other hand, a strong correlation is shown for individual membranes between MS permeation and electrical skin capacitance, while a similar correlation for AC is lower. The observed correlations between drug permeability and electrical impedance open up for standardizing in vitro data for improved analysis and comparisons between permeability results obtained with skin stored at different conditions.
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| 8. |
- Morin, Maxim, et al.
(författare)
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Hydrogels and Cubic Liquid Crystals for Non-Invasive Sampling of Low-Molecular-Weight Biomarkers-An Explorative In Vivo Study
- 2022
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Morin, Maxim, et al.
(författare)
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Reverse Iontophoretic Extraction of Skin Cancer-Related Biomarkers
- 2022
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Morin, Maxim, et al.
(författare)
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Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 17218-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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