In joint research at the Leibniz Institute for Polymer Research Dresden e.V. (IPF) and the German Center for Neurodegenerative Diseases (DZNE), novel 3D hydrogel cell culture assays based on human neural stem cells have been established by the founders. This system can simulate the endogenous development of the human neurons and mimic neurodegeneration processes in vitro.
Our technology was made possible thanks to the innovative bio-inspired materials. In a modularly adaptable platform of hydrogel materials, which is based on sulfated glycosaminoglycans (GAGs) such as heparin that is found in living tissues, and star-shaped branched polyethylene glycol (Star-PEG), which is adaptable in many application-relevant properties in a defined manner. The modular hydrogel system allows the independent control of physical (stiffness, swelling) and biochemical properties (presentation of adhesion ligands and glycosaminoglycan-binding signal molecules) as well as the localized conversion controlled by cells via enzymatically cleavable peptide units. The binding of peptide-based ligands of cellular adhesion receptors, such as fibronectin-derived RGD, enables the targeted adjustment of the anchoring of cells in the hydrogel matrix.
We can generate extensive human neuronal networks by incorporating human neural stem cells into our proprietary matrix (WO2010060485A1 WO2017198258A1). After a short culture period with defined culture conditions, mature human neuronal networks with physiological reminiscence to neurons in the human brain can be obtained. The function and morphology of the neurons correspond to human cortical neurons, as was demonstrated by matching molecular markers and electrophysiological function. These neuronal networks could also be used in an Alzheimer's model to simulate pathological changes, such as the amyloid toxicity known for Alzheimer's disease. In accordance with clinical symptoms, our model leads to neuronal cell death, loss of active synaptic connections and the formation of TAU pathology, which are rare to observe in 2D in vitro or in majority of the in vivo models.
Compared to the existing neuronal 3D cultures, which can only be modulated to a limited extent and are considerably limited by batch-to-batch variations, our highly reproducible system leads to a faster and more realistic network formation. By determining the genes that are active in neurons in 2D and 3D, we found that in our 3D hydrogel system, human neurons acquire a state that is physiologically reminiscent of the neurons in human brains. With our 3D model, we are overcoming several existing hurdles in the field and provide new solutions for drug development efforts!
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