Influence of neuroimplant materials, drugs and drug-material combinations on healthy cells of the brain
Despite intensive research, many drugs or application forms are still not efficient enough for the adequate treatment of various brain disorders. The increasing knowledge of the respective diseases however can help to identify more suitable drugs or combinations to address the specific cellular disorder. The local drug-administration by drug delivery devices, such as implants, can improve treatment efficiency by increasing the bioavailability of a drug or overcoming systemic toxicity due to lower drug concentrations. Since implant materials or the infiltrated drugs themselves can elicit brain foreign body reactions of the healthy brain, implant materials or alternative drugs need to be investigated in suitable in vitro models. Therefore, selected alternative therapeutics, combination strategies as well as drug-loaded implant materials for the, as a model disease chosen highly malignant brain tumor glioblastoma multiforme, were investigated for their efficacy as well as biocompatibility in this thesis. A special focus was set on the investigation of brain foreign body reactions of the healthy brain towards possible brain implant materials and ways to elicit them. Different treatment strategies have been tested by combining alternative therapeutic compounds with the standard chemotherapeutic temozolomide (TMZ) either simultaneously or sequentially in monocultures of human GBM cells as well as human astrocytes over several days. Especially the sequential treatment of the three days combination of TMZ and AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, followed by the three days single AT101 stimulation, improved the therapy success in GBM cell lines significantly, whilst keeping healthy human astrocytes less affected than the standard treatment with TMZ. Interestingly, this approach was less successful in co-cultures of human primary GBM cells with human astrocytes and microglia mimicking the (in) complete resection of the tumor. Astrocytes and microglia seemed to have protective effects on the drug-induced cytotoxic and anti-proliferative effects on GBM cells. Likewise, GBM cells increased cytotoxic effects in astrocytes, in function of the GBM cell number present. To further improve the treatment efficiency by local drug administration, AT101 was infiltrated in biocompatible polydimethylsiloxane (PDMS) scaffolds with a hollow tetrapodal microtube network. We observed typical diffusion-based drug-release profiles with a therapeutic concentration range, which could be adjusted by scaffold size, porosity, open microchannels and infiltrated drug concentration. In vitro studies showed a sufficient treatment efficiency in GBM cells whilst not affecting astrocytes stronger than the free drug. Similar to this material scientific approach, graphene based three-dimensional scaffolds were produced for local drug-administration or electrical stimulation/recording applications in the brain. In suitable in vitro and ex vivo models of the healthy brain to study biocompatibility as well as brain foreign body reaction, we demonstrated that graphene oxide (GO) and reduced graphene oxide (rGO) scaffolds did hardly affect survival of human microglia, astrocytes and murine organotypic brain slices. Moreover, only moderate effects on material-specific inflammatory and glial scarring reactions occurred, however stronger for rGO scaffolds. These effects could be diminished in most cases to control levels by pre- and co-stimulations with the anti-inflammatory and fibrotic compound curcumin. Encapsulating curcumin into liposomes could significantly improve the long-term storage, bioavailability as well as in vitro efficacy to reduce inflammation and glial scarring reactions in in vitro models of reactive gliosis. In conclusion, novel drug combinations can improve treatment efficacies in glioblastoma multiforme whilst also reducing adverse drug effects in the healthy brain. More realistic in vitro and ex vivo models help to analyze the efficacy of novel drugs and drug delivery systems as well as adverse drug effects and implant-mediated brain foreign body reactions in the healthy brain. Three-dimensional scaffolds from PDMS, GO and rGO seem to be promising materials for brain applications, as they offer unique and tailorable physico-chemical properties, drug loading capacity or conductivity with minimal effects on reactive gliosis in vitro and ex vivo. Anti-inflammatory drugs such as curcumin can be used as surface coatings to elicit brain foreign body reactions towards the materials. Hence, to improve a drugs bioavailability and stability, nanoformulations such as liposomes are easily accessible tools which can greatly improve a drugs in vitro efficacy.
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