Work performed and main results
Various collagen hydrogels have been successfully designed, optimized and fabricated which resulted in final products that proved to be non-toxic and highly stable both in vitro and in vivo. Secondly, these hydrogels have further successfully been used as a delivery system by encapsulating cells and drugs to target neuroprotection and neuro-inflammation. These so-called functionalised hydrogels did indeed decrease the inflammatory processes in the brain showing not only their biocompatibility and bio-protective qualities but also their substantial abilities to reduce the underlying inflammation that characterises PD.
Additionally, new in vitro next generation PD model systems have being developed within the project. A robust protocol for re-programming adult human fibroblasts (abundantly present in the body) from patients with PD into dopaminergic neurons has been designed. This is a crucial step for future treatments as these cells derived from the patients themselves and would obviate the use of stem cells. These cells resemble the physiological profile of healthy dopaminergic neurons and they withstand encapsulation within BMT scaffolds, which is a fantastic proof of applicability for future treatments.
Another model of Parkinson’s disease is the lab-on-a-chip model. A novel technique for the fabrication of microfluidic chips, termed 3D-printed soft lithography, was developed within BrainMatTrain that enables 3D printing of cells in liquid collagen as well as in hydrogels. Moreover, to refine this technique, we additionally developed 2D neurite guidance chips. Both chips will help researchers to create more in vitro models of neurological disorders as 3D-printed soft lithography allows the fabrication of microfluidic chips for the creation of interconnected neural networks in 2D.
To characterize the in vivo responses of the implanted biomaterials, a robust animal model of pure neuro-inflammation was successfully developed to be analysed by the non-invasive in vivo neuro imaging system positron emission tomography (PET). This animal model is a valuable tool which will enable the evaluation of the inflammatory aspect only of Parkinson’s disease. Additionally, the long-term survival and the functionality of the implanted dopaminergic neurons, within the hydrogel scaffolds was successfully tested in a relevant animal model of PD. Therefore, the degree of the pathophysiological effects can now be measured before and after implantation of different hydrogel variations by analysing certain inflammatory markers, the changes of the protein patterns (proteomics) and the in vivo characterization via PET.
Furthermore, our industry partners developed protocols and strategies for the scale-up of the biomaterial for later commercialization.
For designing the device that delivers the biomaterials including cells and drugs into the brain, several physical stress conditions of the material have been tested. This enhanced the material stability when injected through the device on a larger scale.
Additionally, to ensure that sufficient quantities of mesenchymal stromal cells (MSCs) will be available for use in the clinic, transformative technologies that deliver highly purified MSCs, called ORBCEL-CTM, have been successfully developed. These cells were modified and optimized to be used in a closed automated cell expansion system to scale-up the manufacture process.
