Functional fibrin-based hydrogels for the direction of cell/biomaterial interactions in biohybrid cardiovascular Implants.

• Applicants: Professorin Dr. Sabine Neuss-Stein; Professor Dr. Andrij Pich
• Subject Area: Biomaterials ; Medical Physics, Biomedical Technology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402991504

• Final Report Year: 2024

Final Report Abstract

For the design of biohybrid cardiovascular implants, a biomaterial is required that can provide an environment for cell growth and differentiation. Fibrin, a biopolymer that is formed during blood coagulation, is an interesting material that can be used as a scaffolds in Tissue Engineering. Due to its natural abundancy in the body, fibrin based hydrogels possess excellent biocompatibility, biodegradability and nonlinear elastic behaviour that can withstand large deformations common for biological tissues. Furthermore, fibrin can act as provisional matrix during tissue repair that support the growth of cells to form a new extracellular matrix. However, non-modified fibrin hydrogels have low mechanical properties and fast degradation behaviour. Approaches to overcome these issues include the incorporation of additives, e.g. tranexamic acid or polymers. Al Enezy-Ulbrich et al. used reactive amphiphilic copolymers to reinforce fibrin-based hydrogels, influencing the mechanical properties and decreasing the degradation time. Alternatively, biodegradable polymers such as collagen or polysaccharides (hyaluronic acid or alginate) are of interest in combination with fibrin, as they can form interpenetrating polymer networks (IPNs) with improved mechanical properties. In this project, functional fibrin/polysaccharide hydrogels and beaded hydrogels (microbeads) with adjustable mechanical and structural properties are fabricated as functional elements for cardiovascular implants. These gels can be loaded with signalling molecules, e.g. hepatocyte growth factors. For the synthesis, polysaccharides, e.g. dextran or pectin are modified to contain functional groups and combined with fibrinogen to form either covalently crosslinked hydrogels or double network hydrogel systems. While covalently crosslinked fibrin/polysaccharide hydrogels did not show significant influence on the mechanical properties, fibrin/polysaccharide IPNs possess higher mechanical stiffness compared to the single hydrogel networks (fibrin hydrogel or dextran hydrogel). In addition, porosity, degradation behaviour and structural properties can be influenced depending on the concentration of dextran-methacrylate. To enhance nutrient and oxygen transport, beaded hydrogels (microgels) based on fibrin/polysaccharide double networks are fabricated using microfluidic synthesis. During the microfluidic synthesis, hepatocyte growth factors are incorporated into the microgels and the degradation profile analysed to examine the release profile. Furthermore, fibrin/dextran bulk hydrogels and microgels were printed successfully. For fibrin/dextran bulk hydrogels, a gelatine support bath is used to ensure the structural position, while for microgels this is not required. Printing of fibrin/dextran bulk hydrogels provided stable structures. Microgels were printed with high fidelity, showing cell growth around the microgels creating 3D structures. In general, printing of fibrin/dextran gels allows for precise control over the hierarchical structures to create intricately complex functional tissues suitable for cardiovascular implants.

Publications

• Impact of Reactive Amphiphilic Copolymers on Mechanical Properties and Cell Responses of Fibrin‐Based Hydrogels. Advanced Functional Materials, 30(38).
  Al Enezy‐Ulbrich, Miriam Aischa; Malyaran, Hanna; de Lange, Robert Dirk; Labude, Norina; Plum, René; Rütten, Stephan; Terefenko, Nicole; Wein, Svenja; Neuss, Sabine & Pich, Andrij
  
• From In Vitro to Perioperative Vascular Tissue Engineering: Shortening Production Time by Traceable Textile-Reinforcement. Tissue Engineering and Regenerative Medicine, 19(6), 1169-1184.
  Mohapatra, Saurav Ranjan; Rama, Elena; Melcher, Christoph; Call, Tobias; Al Enezy-Ulbrich, Miriam Aischa; Pich, Andrij; Apel, Christian; Kiessling, Fabian & Jockenhoevel, Stefan
  
• Assessment of Fibrin‐Based Hydrogels Containing a Fibrin‐Binding Peptide to Tune Mechanical Properties and Cell Responses. Macromolecular Materials and Engineering, 308(7).
  Brinkmann, Jannika; Malyaran, Hanna; Al Enezy‐Ulbrich, Miriam Aischa; Jung, Shannon; Radermacher, Chloé; Buhl, Eva Miriam; Pich, Andrij & Neuss, Sabine
  
• Fibrin–Dextran Hydrogels with Tunable Porosity and Mechanical Properties. Biomacromolecules, 24(9), 3972–3984.
  Jung, Shannon Anna; Malyaran, Hanna; Demco, Dan Eugen; Manukanc, Anna; Häser, Leonie Sophie; Kučikas, Vytautas; van Zandvoort, Marc; Neuss, Sabine & Pich, Andrij
  
• Enhancing Adhesion of Fibrin-Based Hydrogel to Polythioether Polymer Surfaces. ACS Applied Materials & Interfaces, 16(11), 14371–14381.
  Al Enezy-Ulbrich, Miriam Aischa; Kreuels, Klaus; Simonis, Marc; Milvydaitė, Indrė; Reineke, Anna Theresa; Schemmer, Carina; Gillner, Arnold & Pich, Andrij
  
• Fibrin-Based Hydrogels with Reactive Amphiphilic Copolymers for Mechanical Adjustments Allow for Capillary Formation in 2D and 3D Environments. Gels, 10(3), 182.
  Wein, Svenja; Schemmer, Carina; Al Enezy-Ulbrich, Miriam Aischa; Jung, Shannon Anna; Rütten, Stephan; Kühnel, Mark; Jonigk, Danny; Jahnen-Dechent, Wilhelm; Pich, Andrij & Neuss, Sabine
  
• Impact of Fibrin Gel Architecture on Hepatocyte Growth Factor Release and Its Role in Modulating Cell Behavior for Tissue Regeneration. Gels, 10(6), 402.
  Wein, Svenja; Jung, Shannon Anna; Al Enezy-Ulbrich, Miriam Aischa; Reicher, Luca; Rütten, Stephan; Kühnel, Mark; Jonigk, Danny; Jahnen-Dechent, Wilhelm; Pich, Andrij & Neuss, Sabine