Forschung im Bereich Pharmazeutische Technologie

Die Pharmazeutische Technologie fokussiert sich auf Biomaterialforschung und die Entwicklung von Controlled Release Systemen von Nukleinsäurewirkstoffen.

Wir danken folgenden Drittmittelförderern: DFG (SFB TRR67), SAB, ZIM, SMWK.

Beispiele unserer Forschung anhand von Kurzfassungen ausgewählter Publikationen:

Extracellular Vesicles

A focus on critical aspects of uptage and transport of milk-derived extracellular vesicles across the Caco-2 intestinal barrier model
European Journal of Pharmaceutics and Biopharmaceutics 166 (2021) 61-74
Josepha Roerig, Laura Schiller, Hermann Kalwa, Gerd Hase, Cica Vissiennon, Michael C. Hacker, Christian Wölk, Michaela Schulz-Siegmund
https://doi.org/10.1016/j.ejpb.2021.05.026 
In recent years, extracellular vesicles (EVs), long considered as membrane-enclosed cellular waste, have been discovered to play an important role in cell communication over short and long distances in the body [1]. EVs are small vesicles carrying microRNA that are secreted by cells and carry specific marker proteins on their surface, that help to classify them.
These vesicles provide a negative zeta potential but are still well taken up by other cells. We and others therefore consider Evs as interesting shuttle systems for therapeutic RNAs, such as siRNA [2]. We currently concentrate on bovine milk derived Evs as they are available in large amounts. In this first study, Josepha Rörig could show their uptake and transcytosis by polarized Caco-2 cell layers. We could also show that cellular uptake is mediated by neonatal Fc receptors on the cell surface. Further studies currently deal with the loading of siRNA into these Evs.
[1] R. Kalluri, V.S. LeBleu, The biology, function, and biomedical applications of exosomes, Science 367 (2020)
[2] Schulz-Siegmund M, Aigner A. Nucleic acid delivery with extracellular vesicles. Adv Drug Deliv Rev. 2021 Jun;173:89-111. doi: 10.1016/j.addr.2021.03.005

Nucleic acid delivery with extracellular vesicles
Advanced Drug Delivery Reviews 173 (2021) 89-111
Michaela Schulz-Siegmund, Achim Aigner
https://doi.org/10.1016/j.addr.2021.03.005

Oberflächenmodifikationen von Biomaterialien zur Knochenregeneration

Biodegradable macromers for implant bulk and surface engineering
Biological Chemistry, Band 402, Heft 11
Jan Krieghoff, Mathis Gronbach,  Michaela Schulz-Siegmund, Michael C. Hacker
https://doi.org/10.1515/hsz-2021-0161
This review summarizes our work in the SFB Transregio 67 that was funded from 2009 to the end of 2021 with a focus on the theses of Jan Krieghoff and Mathis Gronbach. Aim of the SFB TRR67 was to elucidate the mechanisms of sulfated glycosaminoglycans (GAGs) in bone regeneration and wound healing.
Our part within this project was to develop biomaterials to present the GAGs on and in biomaterials for in vitro and in vivo testing. In the 12 year funding period, we created a platform of macromer-based biodegradable materials for scaffold film and scaffold fabrication. Our materials allowed to control scaffold mechanics via crosslinking degree as well as degradation time over a period of up months to years. In contrast to pure poly-α-hydroxyesters (e.g. polylactids (PLA) and polyglycolids (PGA)), our biomaterials degraded more regularly avoiding the typical bulk degradation related burst release of acidic products well known from PLAs:

Composition-controlled degradation behavior of macroporous scaffolds from three-armed biodegradable macromers
Polymer Degradatio and Stability 195 (2022) 109775
Jan Krieghoff, Christian Kascholke, Rudi Loth, Annett Starke, Andreas Koenig, Michaela Schulz-Siegmund, Michael C. Hacker
https://doi.org/10.1016/j.polymdegradstab.2021.109775
Moreover, we processed the macromers into films as model surfaces for scaffolds. In contrast to 3D scaffolds, defined and smooth film surfaces allow for sophisticated characterization. For covalent binding of GAGs, we integrated a small anchor molecule, glycidylmethacrylate (GMA) in the macromer films, bound polyetheramines and decorated them with GAGs. These GAG decorated films were characterized for their interaction with wnt-antagonists, known to negatively impact bone regeneration e.g. in osteoporosis. We could show that highly sulfated hyaluronan (sHA3) was able to tightly bind and inactivate sclerostin and dickkopf-1 (Dkk-11). In the Acta Biomaterialia paper, Mathis Gronbach showed the effects of the GAG modifications on scavenging of Dkk-1 and osteogenic differentiation of mesenchymal stem cells, key players in bone regeneration.

Scavenging of Dickkopf-1 by macromer-based biomaterials covalently decorated with sulfated hyaluronan displays pro-osteogenic effects
Acta Biomaterialia 114 (2020) 76-89​
M. Gronbach, F. Mitrach, V. Lidzba, B. Müller, S. Möller, S. Rother, J.Salbach-Hirsch, L.C. Hofbauer, M. Schnabelrauch, V. Hintze, M.C. Hacker, M. Schulz-Siegmund
https://doi.org/10.1016/j.actbio.2020.07.017
Effects of processing parameters for film production and polyetheramine length on the efficiency of surface modification were shown in a second paper by Mathis Gronbach. Here, we also showed that sclerostin was scavenged in addition to Dkk-1 which required an increased stability of the macromer films. In contrast to the wnt-antagonists, we showed that wnt-3a, a wnt-agonist remained unbound in presence of surface immobilized sHA3.

A Versatile Macromer-Based Glycosaminoglycan (sHA3) Decorated Biomaterial for Pro-Ostegenic Scavenging of Wnt Antagonists
Pharmaceutics 2020 (12)11
Mathis Gronbach, Franziska Mitrach, Stephanie Möller, Sandra Rother, Sabrina Friebe, Stefan G. Mayr, Matthias Schnebelrauch, Vera Hintze, Michael C. Hacker, Michaela Schulz-Siegmund
https://doi.org/10.3390/pharmaceutics12111037
ACS Appl. Mater. Interfaces 2020, 12, 8, 8963–8977

G​ene activated matrices for regenerative medicines 

Contact-Triggered Lipofection from Multilayer Films Designed as Surfaces for in Situ Transfection Strategies in Tissue Engineering
Catharina Husterden, Falko Doberenz, Nathalie Goergen, Shashank Reddy Pinnapireddy, Christopher Janich, Andreas Langner, Frank Syrowakta, Alexandros Repanas, Frank Erdmann, Jarmila Jedelská, Udo Bakowsky, Thomas Groth, Christian Wölk
https://doi.org/10.1021/acsami.9b18968​
We also try to develop gene activated matrices for regenerative medicines which can functionalize surfaces.

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