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| 2. |
- Kaesdorf, Benjamin T., et al.
(författare)
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Mucin-Inspired Lubrication on Hydrophobic Surfaces
- 2017
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Ingår i: Biomacromolecules. - : AMER CHEMICAL SOC. - 1525-7797 .- 1526-4602. ; 18:8, s. 2454-2462
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Tidskriftsartikel (refereegranskat)abstract
- In the human body, high-molecular-weight glycoproteins called mucins play a key role in protecting epithelial surfaces against pathogenic attack, controlling the passage of molecules toward the tissue and enabling boundary lubrication with very low friction coefficients. However, neither the molecular mechanisms nor the chemical motifs of those biomacromolecules involved in these fundamental processes are fully understood. Thus, identifying the key features that render biomacromolecules such as mucins outstanding boundary lubricants could set the stage for creating versatile artificial superlubricants. We here demonstrate the importance of the hydrophobic terminal peptide domains of porcine gastric mucin (MUCSAC) and human salivary mucin (MUCSB) in the processes of adsorbing to and lubricating a hydrophobic PDMS surface. Tryptic digestion of those mucins results in removal of those terminal domains, which is accompanied by a loss of lubricity as well as surface adsorption. We show that this loss can in part be compensated by attaching hydrophobic phenyl groups to the glycosylated central part of the mucin macromolecule. Furthermore, we demonstrate that the simple biopolysaccharide dextran can be functionalized with hydrophobic groups which confers efficient surface adsorption and good lubricity on PDMS to the polysaccharide.
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| 3. |
- Kimna, Ceren, et al.
(författare)
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DNA Strands Trigger the Intracellular Release of Drugs from Mucin-Based Nanocarriers
- 2021
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Ingår i: ACS Nano. - : AMER CHEMICAL SOC. - 1936-0851 .- 1936-086X. ; 15:2, s. 2350-2362
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Tidskriftsartikel (refereegranskat)abstract
- Gaining control over the delivery of therapeutics to a specific disease site is still very challenging. However, especially when cytotoxic drugs such as chemotherapeutics are used, the importance of a control mechanism that can differentiate "sick" target cells from the surrounding healthy tissue is pivotal. Here, we designed a nanoparticle-based drug delivery process, which releases an active agent only in the presence of a specific trigger DNA sequence. With this strategy, we are able to initiate the release of therapeutics into the cytosol with high efficiency. Furthermore, we demonstrate how an endogenous marker (e.g., a specific miRNA sequence) that is overexpressed in the initial phases of certain cancer types can be used as a stimulus to autonomously initiate intracellular drug release-and only in cells where this pathophysiological marker is present. We expect that this precisely controlled delivery mechanism can facilitate the design of site-specific treatments for such diseases, where an overexpression of signature oligonucleotide sequences has been identified.
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| 4. |
- Marczynski, Matthias, et al.
(författare)
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Structural Alterations of Mucins Are Associated with Losses in Functionality
- 2021
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Ingår i: Biomacromolecules. - : AMER CHEMICAL SOC. - 1525-7797 .- 1526-4602. ; 22:4, s. 1600-1613
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Tidskriftsartikel (refereegranskat)abstract
- Commercial mucin glycoproteins are routinely used as a model to investigate the broad range of important functions mucins fulfill in our bodies, including lubrication, protection against hostile germs, and the accommodation of a healthy microbiome. Moreover, purified mucins are increasingly selected as building blocks for multifunctional materials, i.e., as components of hydrogels or coatings. By performing a detailed side-by-side comparison of commercially available and lab-purified variants of porcine gastric mucins, we decipher key molecular motifs that are crucial for mucin functionality. As two main structural features, we identify the hydrophobic termini and the hydrophilic glycosylation pattern of the mucin glycoprotein; moreover, we describe how alterations in those structural motifs affect the different properties of mucins-on both microscopic and macroscopic levels. This study provides a detailed understanding of how distinct functionalities of gastric mucins are established, and it highlights the need for high-quality mucins-for both basic research and the development of mucin-based medical products.
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| 5. |
- Yan, Hongji, et al.
(författare)
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Glyco-Modification of Mucin Hydrogels to Investigate Their Immune Activity
- 2020
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 12:17, s. 19324-19336
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Tidskriftsartikel (refereegranskat)abstract
- Mucins are multifunctional glycosylated proteins that are increasingly investigated as building blocks of novel biomaterials. An attractive feature is their ability to modulate the immune response, in part by engaging with sialic acid binding receptors on immune cells. Once assembled into hydrogels, bovine submaxillary mucins (Muc gels) were shown to modulate the recruitment and activation of immune cells and avoid fibrous encapsulation in vivo. However, nothing is known about the early immune response to Muc gels. This study characterizes the response of macrophages, important orchestrators of the material-mediated immune response, over the first 7 days in contact with Muc gels. The role of mucin-bound sialic acid sugar residues was investigated by first enzymatically cleaving the sugar and then assembling the mucin variants into covalently cross-linked hydrogels with rheological and surface nanomechanical properties similar to nonmodified Muc gels. Results with THP-1 and human primary peripheral blood monocytes derived macrophages showed that Muc gels transiently activate the expression of both pro-inflammatory and anti-inflammatory cytokines and cell surface markers, for most makers with a maximum on the first day and loss of the effect after 7 days. The activation was sialic acid-dependent for a majority of the markers followed. The pattern of gene expression, protein expression, and functional measurements did not strictly correspond to M1 or M2 macrophage phenotypes. This study highlights the complex early events in macrophage activation in contact with mucin materials and the importance of sialic acid residues in such a response. The enzymatic glyco-modulation of Muc gels appears as a useful tool to help understand the biological functions of specific glycans on mucins which can further inform on their use in various biomedical applications.
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| 6. |
- Yan, Hongji, et al.
(författare)
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Immune-Informed Mucin Hydrogels Evade Fibrotic Foreign Body Response In Vivo
- 2019
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Ingår i: Advanced Functional Materials. - : WILEY-V C H VERLAG GMBH. - 1616-301X .- 1616-3028.
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Tidskriftsartikel (refereegranskat)abstract
- The immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia, is leveraged. By using a bioorthogonal inverse electron demand Diels-Alder reaction, mucins are crosslinked into implantable hydrogels. It is shown that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels do not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels are covered by fibrous tissues. Further, Muc-gels dampen the recruitment of innate and adaptive immune cells to the gel and trigger a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating transforming growth factor beta 1 cytokine. Macrophages recruited to Muc-gels upregulate the gene expression of the protein inhibitor of activated STAT 1 (PIAS1) and SH2-containing phosphatase 1 (SHP-1) cytokine regulatory proteins, which likely contributes to their low cytokine expression profiles. With this advance in mucin materials, an essential tool is provided to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired "immune-informed" materials for implantable devices subject to fibrotic encapsulation.
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| 7. |
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| 8. |
- Yan, Hongji, et al.
(författare)
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Reversible Condensation of Mucins into Nanoparticles
- 2018
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Ingår i: Langmuir. - : AMER CHEMICAL SOC. - 0743-7463 .- 1520-5827. ; 34:45, s. 13615-13625
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Tidskriftsartikel (refereegranskat)abstract
- Mucins are high molar mass glycoproteins that assume an extended conformation and can assemble into mucus hydrogels that protect our mucosal epithelium. In nature, the challenging task of generating a mucus layer, several hundreds of micrometers in thickness, from micrometer-sized cells is elegantly solved by the condensation of mucins inside vesicles and their on-demand release from the cells where they suddenly expand to form the extracellular mucus hydrogel. We aimed to recreate and control the process of compaction for mucins, the first step toward a better understanding of the process and creating biomimetic in vivo delivery strategies of macromolecules. We found that by adding glycerol to the aqueous solvent, we could induce drastic condensation of purified mucin molecules, reducing their size by an order of magnitude down to tens of nanometers in diameter. The condensation effect of glycerol was fully reversible and could be further enhanced and partially stabilized by cationic cross-linkers such as calcium and polylysine. The change of structure of mucins from extended molecules to nano-sized particles in the presence of glycerol translated into macroscopic rheological changes, as illustrated by a dampened shear-thinning effect with increasing glycerol concentration. This work provides new insight into mucin condensation, which could lead to new delivery strategies mimicking cell release of macromolecules condensed in vesicles such as mucins and heparin.
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