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Responsive Hyaluronic Acid-Ethylacrylamide Microgels Fabricated Using Microfluidics Technique
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Farmaceutisk fysikalisk kemi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.ORCID iD: 0000-0001-9102-956x
AstraZeneca, Innovat Strategies & External Liaison, Pharmaceut Technol & Dev, Operat, SE-43183 Gothenburg, Sweden..
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2022 (English)In: Gels, E-ISSN 2310-2861, Vol. 8, no 9, article id 588Article in journal (Refereed) Published
Abstract [en]

Volume changes of responsive microgels can probe interactions between polyelectrolytes and species of opposite charges such as peptides and proteins. We have investigated a microfluidics method to synthesize highly responsive, covalently crosslinked, hyaluronic acid microgels for such purposes. Sodium hyaluronate (HA), pre-modified with ethylacrylamide functionalities, was crosslinked in aqueous droplets created with a microfluidic technique. We varied the microgel properties by changing the degree of modification and concentration of HA in the reaction mixture. The degree of modification was determined by H-1 NMR. Light microscopy was used to investigate the responsiveness of the microgels to osmotic stress in aqueous saline solutions by simultaneously monitoring individual microgel species in hydrodynamic traps. The permeability of the microgels to FITC-dextrans of molecular weights between 4 and 250 kDa was investigated using confocal laser scanning microscopy. The results show that the microgels were spherical with diameters between 100 and 500 mu m and the responsivity tunable by changing the degree of modification and the HA concentration. Microgels were fully permeable to all investigated FITC-dextran probes. The partitioning to the microgel from an aqueous solution decreased with the increasing molecular weight of the probe, which is in qualitative agreement with theories of homogeneous gel networks.

Place, publisher, year, edition, pages
MDPI, 2022. Vol. 8, no 9, article id 588
Keywords [en]
microsphere, microgel, synthesis, microfluidics, hyaluronic acid, responsiveness, swelling, permeability, partition coefficient, dextran, confocal microscopy
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-486403DOI: 10.3390/gels8090588ISI: 000857519900001PubMedID: 36135299OAI: oai:DiVA.org:uu-486403DiVA, id: diva2:1701938
Funder
Vinnova, 2019-00048Available from: 2022-10-07 Created: 2022-10-07 Last updated: 2023-09-01Bibliographically approved
In thesis
1. Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
Open this publication in new window or tab >>Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polymers are a group of macromolecules used in formulations of pharmaceuticals, one example being the delivery system DC Bead™. Further, some of the most abundant and for drug delivery important constituents of the subcutaneous tissue are charged polymers (polyelectrolytes), e.g. collagen, hyaluronic acid, and chondroitin sulfate. The interactions between these subcutaneous polyelectrolytes and drug molecules are believed to heavily affect the transport and absorption of subcutaneously injected drugs. To increase the understanding of how the interactions between subcutaneous polymers and drug molecules affect the pharmaceutical behavior in subcutaneous tissue, we developed a new microfluidic-based platform. The platform is used to study interactions between polyelectrolytes and drug molecules, and can beyond the investigation of subcutaneous interactions be used to develop polyelectrolyte-based microgel formulations. In this thesis, the microfluidic method denoted “Microfluidic chip for interactions studies” (MIS) is presented, and the design, validation, and several examples of usage are described. The method which is based on microfluidic instrumentation, utilizes spherical microgels created using different types of polymers/polyelectrolytes. These hydrogels collapse when experiencing attractive interactions with drug molecules making it possible to investigate drug binding by studying the volume change of the microgels. We prove that the interactions are strongly affected by charges both on the gel networks and the drug molecules. Further, the aggregation behavior of drugs in a polyelectrolyte-rich environment is studied in detail. Results show that both a strong aggregation behavior and a high charge on the drugs may affect the transport through a network of polyelectrolytes. The behavior of drugs in subcutaneous polyelectrolyte-rich environments such as hyaluronic acid networks, can partly explain bioavailability and absorption rates of the drugs in vivo. Several potential drug delivery systems in the form of microgels were investigated together with both small amphiphilic molecules and larger peptides exhibiting a wide range of physicochemical properties. The results indicate a possibility of delivering large amounts of drug in low volumes of microgel suspensions but with varying release times, ranging from seconds to days. The MIS was able to provide information about the interactions in a large number of polyelectrolyte-drug systems. The studies were performed in a highly efficient and cost-effective way, with experiments being mostly automated. This makes it a suitable method for rapid screening experiments in the development of new microgel formulations, and as part of larger studies utilizing several different methods to better understand and predict the behavior and absorption profiles of potential subcutaneously administrated drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2023. p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 338
Keywords
Microgels, Subcutaneous administration, Drug delivery, Microfluidics, In vitro methodology, Method development, Biopharmaceuticals, Amphiphilic drugs, Polyelectrolytes, Hyaluronic acid, Peptides
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-509384 (URN)978-91-513-1888-2 (ISBN)
Public defence
2023-10-20, Room A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2023-09-28 Created: 2023-09-01 Last updated: 2023-09-28

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Wanselius, MarcusRodler, AgnesSearle, SeanHansson, Per

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