Implantable bioartificial hybrids for targeted therapy in the central nervous system

Sammanfattning: The rapid increase in the understanding of the CNS at the molecular level has brought us new knowledge and tools to attempt to locally manipulate the CNS microenvironment and thereby introduce reparative and ablative molecular therapeutic approaches in focal areas of the CNS. This targeted therapy will require neurosurgical intervention for the injection and implantation of cells, viral vectors, or drug release systems. In this thesis, the development of two hybrid systems are presented. One is based on implantable polymeric controlled-release devices that release neurotransmitters, neural growth factors, or synthetic drugs. The other is based on implantable macrocapsules housing neurosecretory cells that are protected from immune rejection. In paper I, the polymeric release of DA for the treatment of Parkinson's disease is studied in a 6-OHDA rat model. The results indicate that direct intrastriatal DA release and diffusion can alleviate Parkinsonian behavior. In paper II, the release of NGF in a rat Alzheimer's disease model is discussed, and the regeneration of cholinergic neurons shown. Paper III describes the development of a co-extrusion method to encapsulate living cells during phase-inversion of a polymeric solution. The use of these capsules for long- term release is discussed. In paper IV, the controlled-release of Amsacrine for glioma therapy is presented. Both histological tumor regression and increased survival are demonstrated in a malignant glioma rat model. In paper V, this system is applied in a human pilot patient and more recent patient data are discussed in conjunction. Paper VI concerns the development of methods to measure bioactivity of released protein factors with results showing that PC12 cells react to GDNF in specific manners. In paper VII the use of the polymeric system to deliver EGF and bFGF for the recruitment of neural stem-cells is investigated. Results show that both EGF and bFGF stimulate striatal progenitor cells but in different manners. The thesis concludes with a general discussion regarding drug transport issues in the brain and a discussion regarding the future of bioartificial hybrids for targeted CNS therapy.