Alginate-based hydrogels have found extensive attention in the biomaterials community due to their capacity for facile chemical modification, their nontoxicity towards encapsulated cells, and their provocation of a minimal immune response upon implantation. Covalent crosslinking of this polysaccharide allows a higher degree of control over the initial and long-term mechanics compared to the traditional ionic mechanism - a clear advantage that comes at the cost of the material’s degradability. Though numerous single-phase constructs with homogeneous properties have already been investigated, hydrogels with patterned biophysical and biochemical properties have been more recently explored. These structures permit local control over cell activity, including attachment, differentiation and matrix deposition. The focus of this Ph.D. project was therefore two-fold: (i) to impart degradability to covalently-crosslinked alginate-based hydrogels and (ii) to introduce patterning to these structures for local control over cell behavior. In order to address the issue of lacking degradation behavior, we engineered an alginate-based material system that relies on two covalent crosslinking types and introduced two different degradation modes. First, we developed materials with spontaneous Diels-Alder crosslinking of norbornene and tetrazine functional groups with the potential to impart passive, hydrolytic degradation by oxidizing the polymer backbone. Second, we fabricated materials with ultraviolet light-initiated thiol-ene crosslinking with the potential to impart active, enzymatic degradation. These structures incorporate peptide crosslinkers susceptible to cleavage by matrix metalloproteinases. In order to form patterned materials, these two crosslinking schemes were combined, and by spatially controlling the location of the thiol-ene reaction using photomasks, patterns in stiffness, biomolecule presentation, and susceptibility to degradation were formed. These materials, or subsets thereof, were characterized for their rheological and mechanical properties by unconfined compression or microindentation, before tracking in vitro degradation behavior of degradable bulk hydrogels or patterns. Mouse pre-osteoblasts or embryonic fibroblasts were cultured on or within these hydrogels to assess cell attachment, morphology, proliferation, and viability. Human mesenchymal stem cells were applied to evaluate differentiation potential. Specifically for patterned gels, the effect of local substrate stiffness, biomolecule presentation or susceptibility to degradation on cell activity was examined. Hydrogels were then implanted subcutaneously into the backs of mice to determine the in vivo host cell and tissue infiltration based on histological staining of recovered hydrogels. Taken together, these alginate-based hydrogels featuring two different crosslinking and degradation modes, with the possibility to impart patterning in biophysical and biochemical cues, could prove extremely powerful not only for fundamental studies but also for tissue engineering applications.
Alginate-based hydrogels with patterned biophysical and biochemical cues
Alginat-Hydrogele mit strukturierten biophysikalischen und biochemischen Eigenschaften
2020
Sonstige
Elektronische Ressource
Englisch
DDC: | 629 |
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