Thermosensitive display of ligand molecules on microgel scaffolds to facilitate switchable bioadhe-sion

• Applicant: Professor Dr. Stephan Schmidt
• Subject Area: Polymer Materials ; Biomaterials ; Preparatory and Physical Chemistry of Polymers ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397673471

• Final Report Year: 2022

Final Report Abstract

In this project, ligand decorated thermoresponsive microgels were used to facilitate switchable biomolecular interactions. Small temperature changes that lead to polymer phase transitions, i.e. either collapse or swelling of the microgel network, were sufficient to switch “on” and “off” the attachment of receptors to the ligands in the microgel network. Overall, the results of this project confirmed the original hypothesis that for weak binding carbohydrate ligands, a change in ligand density, triggered by switchable swelling, leads to changes in multivalent binding and avidity. This was successfully shown by the triggered capture of E. coli binding to mannose units and certain cancer cell lines binding to hyaluronic acid. The quantification of the attachment forces to the sugar units by means of AFM confirmed the shift in affinity when crossing the VPTT of the microgels, as well as statistical multivalency effects due to the change of the overall ligand density. In addition, the accessibility of ligand units can be controlled by the swelling state of the microgels and also used for switching biomolecular interactions. For example, when using hydrophobic biotin ligands, the interactions were reduced in the collapsed state of the microgel. This is because the hydrophobic ligands are depleted from the microgel-water interface when the network becomes also hydrophobic above the VPTT. Furthermore, smaller receptor species with molecular sizes often show reduced binding to collapsed microgels when compared with swollen microgels. This is because in the swollen state, the small receptors could diffuse into the open network below the VPTT and access more ligand units. These functional behaviors, the temperature-controlled binding and the size-dependent binding, could also be transferred to microgel coatings on solid supports. Here we focused on realizing capture release devices for hyaluronic acid binding cancer cells, but also E. coli bacteria could be captured and released using mannose presenting microgels with a high swelling degree. Overall, given their straightforward synthesis and strong temperature response enabling capture and release of cells and pathogens, microgels may become suitable for applications in biomedicine or biotechnology. Furthermore, the guiding principles for switchable biomolecular interactions worked out in this project, i.e. statistical multivalency effects and ligand accessibility, could be adapted to other switchable polymer systems, such as macroscopic scaffold or pH, ionic strength or light-switchable systems.

Publications

• Thermosensitive Display of Carbohydrate Ligands on Microgels for Switchable Binding of Proteins and Bacteria. ACS Appl Mater Interfaces 2019, 11 (30), 26674-26683
  Paul, T. J.; Rubel, S.; Hildebrandt, M.; Strzelczyk, A. K.; Spormann, C.; Lindhorst, T. K.; Schmidt, S.
  
• Quantifying Thermoswitchable Carbohydrate-Mediated Interactions via Soft Colloidal Probe Adhesion Studies. Macromolecular Bioscience 2020, 2000186
  Strzelczyk, A. K.; Paul, T. J.; Schmidt, S.
  
• Switchable Adhesion of E. coli to Thermosensitive Carbohydrate-Presenting Microgel Layers: A Single-Cell Force Spectroscopy Study. Langmuir 2020, 36 (42), 12555-12562
  Wilms, D.; Schroer, F.; Paul, T. J.; Schmidt, S.
  
• Temperature-Switchable Glycopolymers and Their Conformation-Dependent Binding to Receptor Targets. Biomacromolecules 2020, 21 (7), 2913-2921
  Paul, T. J.; Strzelczyk, A. K.; Feldhof, M. I.; Schmidt, S.
  
• Elastic modulus distribution in poly(N- isopopylacrylamide) and oligo(ethylene glycol methacrylate)-based microgels studied by AFM. Soft Matter 2021
  Wilms, D.; Adler, Y.; Schröer, F.; Bunnemann, L.; Schmidt, S.
  
• Lectin and E. coli Binding to Carbohydrate-Functionalized Oligo(ethylene glycol)-Based Microgels: Effect of Elastic Modulus, Crosslinker and Carbohydrate Density. Molecules 2021, 26 (2)
  Schroer, F.; Paul, T. J.; Wilms, D.; Saatkamp, T. H.; Jack, N.; Muller, J.; Strzelczyk, A. K.; Schmidt, S.
  
• Selective Adhesion and Switchable Release of Breast Cancer Cells via Hyaluronic Acid Functionalized Dual Stimuli-Responsive Microgel Films. Acs Applied Bio Materials 2021, 4 (8), 6371-6380
  Schmidt, M.; Franken, A.; Wilms, D.; Fehm, T.; Neubauer, H. J.; Schmidt, S.