Polymers, Encapsulation, and Artifical Organs (Report on Session 26.0)

Artificial Organs" at the Fourth International Symposium on Neurotransplantation consisted of five presentations examining the possibility that polymer capsules with or without cells could have therapeutic application for various neurological diseases. Dr. Robert Langer of the Massachusetts Institute of Technology provided an introduction to the use of polymers as systems for controlled release, long-term drug delivery/4/. Some of these systems are currently in use for the treatment of ophthalmic diseases, tobacco addiction, and birth control, and can continuously release drugs for over one year. Of interest is the use of these slow releasing polymers for delivering drugs and chemicals directly into the brain, bypassing the blood-brain barrier. Polyanhydride-containing bio-erodible polymers were discussed as a way to introduce both large and small molecules into the brain. Dr. Langer suggested that polymers which release drugs by surface erosion, thereby leading to nearly constant release rates, may be the most appropriate delivery system for CNS applications. The polymers are now used clinically in over 56 medical centers in an FDA-approved study examining delivery of BCNU in post-operative patients with primary cerebral malignancy. These polyanhydride polymer wafers are placed in the resection cavity and provide a sustained release of the chemotherapeutic agent. Dr. Langer reported preliminary data demonstrating increased efficacy of the localized BCNU polymer implants over intravenous systemic administration/4/. In another possible application it was shown that polymers impregnated with dopamine could release the compound steadily for over a year. Studies examining dopamine releasing polymers in Parkinson's disease models are currently underway in several laboratories. presented an overview of data showing the use of polymer membranes to encapsulate cells for transplantation into the nervous system/1/. While the previous presentation described polymers impregnated with dopamine for transplantation into parkinsonian brains, Dr. Aebischer described data demonstrating that dopamine secreting cells can be encapsulated by thermoplastic polymer membranes and virtually made into a living dopamine mini-pump. These polymer membranes with maximum molecular porosity at about 50,000 MW impair host rejection via either antibody or cellular responses. This allows the use of xenogeneic or allogeneic transplants without the need for pharmacological immunosuppression. The subsequent presentation by Dr. Meg Palmatier from CytoTherapeutics, Inc. gave further details of the basic science and potential clinical application of these encapsulated dopamine implants for Parkinson's disease/2/. The commercial utilization of these implants involves the use of PC12 cells in PAN/PVC membranes which will be implanted directly into the striata of Parkinson's disease …

Symposium on Neurotransplantation consisted of five presentations examining the possibility that polymer capsules with or without cells could have therapeutic application for various neurological diseases. Dr. Robert Langer of the Massachusetts Institute of Technology provided an introduction to the use of polymers as systems for controlled release, long-term drug delivery/4/. Some of these systems are currently in use for the treatment of ophthalmic diseases, tobacco addiction, and birth control, and can continuously release drugs for over one year.
Of interest is the use of these slow releasing polymers for delivering drugs and chemicals directly into the brain, bypassing the blood-brain barrier. Polyanhydride-containing bio-erodible polymers were discussed as a way to introduce both large and small molecules into the brain. Dr.
Langer suggested that polymers which release drugs by surface erosion, thereby leading to nearly constant release rates, may be the most appropriate delivery system for CNS applications. The polymers are now used clinically in over 56 medical centers in an FDA-approved study examining delivery of BCNU in post-operative patients with primary cerebral malignancy. These polyanhydride polymer wafers are placed in the resection cavity and provide a sustained release of the chemotherapeutic agent. Dr. Langer reported preliminary data demonstrating increased efficacy of the localized BCNU polymer implants over intravenous systemic administration/4/.
In another possible application it was shown that polymers impregnated with dopamine could release the compound steadily for over a year.
Studies examining dopamine releasing polymers in Parkinson's disease models are currently underway in several laboratories.
Dr. Patrick Aebischer from Brown University presented an overview of data showing the use of polymer membranes to encapsulate cells for transplantation into the nervous system/1/. While the previous presentation described polymers impregnated with dopamine for transplantation into parkinsonian brains, Dr. Aebischer described data demonstrating that dopamine secreting cells can be encapsulated by thermoplastic polymer membranes and virtually made into a living dopamine minipump. These polymer membranes with maximum molecular porosity at about 50,000 MW impair host rejection via either antibody or cellular responses. This allows the use of xenogeneic or allogeneic transplants without the need for pharmacological immunosuppression. The subsequent presentation by Dr. Meg Palmatier from CytoTherapeutics, Inc. gave further details of the basic science and potential clinical application of these encapsulated dopamine implants for Parkinson's disease/2/. The commercial utilization of these implants involves the use of PC12 cells in PAN/PVC membranes which will be implanted directly into the striata of Parkinson's disease animal models and humans. These implants were shown to release dopamine continuously and to improve behavioral recovery in rodent and primate models. This product was noted to be undergoing safety and toxicology studies in preparation for commercial marketing. Of interest were additional data which demonstrated that implanting these dopamine sources into aged rodents seemed to improve some of the abnormal motor behavior seen in aged animals. through these cables from the septum to the hippocampus. Their observations support the hypothesis that Schwann cells produce a more favorable environment than do endogenous CNS glia for axonal regeneration, probably by producing growth factors and cell adhesion molecules necessary for such regeneration to occur. The application of these polymer channel technologies goes beyond the experiments on cholinergic system regeneration presented by the groups of Aebischer and Kromer. Clearly there is future use for these channels in spinal cord injury and other sensory/motor system regeneration. The presentation by Dr. Woerly of the Czecholslovakian Academy of Sciences discussed the use of another type of polymer matrix for neural transplantation/5/. Hydrogels were shown to form porous matrices, which, when coated with collagen, could serve as artificial bridge substrates and regeneration templates for CNS lesions. Cells attached to the polymers could be maintained in vitro, where they were shown to differentiate and extend axons throughout the hydrogel's surface. Such hydrogels may have application in transplantation of neural tissue in which axons are required to extend into the host brain. Immunoprotective thermoplastic membranes, as discussed above, do not allow for anatomical connections between the transplanted and host cells because of their small pore size. Hydrogels may serve as a potentially important matrix for implantation of cells within the brain that need to make functional connections. If these hydrogels are impregnated with surface active molecules, such as basement membrane proteins, glucosamine or various peptides, they can provide substrates that influence cell adhesion, differentiation and axonal growth of the transplanted cells, thereby facilitating restoration of function compared to transplantation of the cells alone. This strategy may also facilitate the survival of the transplanted cells prior to transplantation since various growth promoting substances can be used with the hydrogel matrix.
Interestingly, the scientists from CytoTherapeutics, Inc. /2/ and Dr. Aebischer's lab /1/ discussed data combining hydrogel and other types of matrices within the immunoprotective outer thermoplastic polymer membranes used in these encapsulated cell implants. The matrices were shown to provide a substrate for enhanced growth and survival of cells within the thermoplastic membranes in both in vitro and in vivo animal studies.
In summary, the session on "polymers, encapsulation and artificial organs" provided important data demonstrating the unique nature of intracerebral application of polymers of different types with and without cells and their potential clinical application. In the periphery, some prosthetic implants have been noted to produce tissue scarring and poor biocompatibility over time. Interestingly, polymer implants into the brain seemed significantly biocompatible, with little inflammatory scarring, edema or immune response. Nevertheless, before polymer implants are used in humans, additional long-term data will be needed on their biocompatibility and sustained function.