TRANSPLANTATION OF ENCAPSULATED BOVINE CHROMAFFIN CELLS IN THE SHEEP SUBARACHNOID SPACE - A PRECLINICAL STUDY FOR THE TREATMENT OF CANCER PAIN

Chromaffin cells have been shown to release a combination of pain-redu cing neuroactive compounds including catecholamines and opioid peptide s. The allogeneic transplantation of chromaffin cells in the subarachn oid space has been shown to alleviate pain in various rodent models an d possibly in terminal cancer patients. Because of the shortage of hum an cadaver donor tissue, we are investigating the possibility of trans planting xenogeneic cells in polymer capsules. In this technique, cell s are surrounded by a permselective synthetic membrane whose pores are suitably sized to allow diffusion of nutrients, neurotransmitters and growth factors, but restrict the diffusion of the large molecules of the immune system and prevent contact with immunocompetent cells. The encapsulation technique therefore allows transplantation of xenogeneic tissue between species as well as retrieval of transplanted cells. Pr eviously we have reported that encapsulated bovine chromaffin cells su rvive and alleviate pain in various rodent models. The purpose of the present study was to assess the feasibility of implanting a human size d device in a large animal model. Adrenals from 5 calves were surgical ly removed; chromaffin cells were isolated from these glands using a c ollagenase-based digestion-filtration technique. Cells were loaded int o acrylic-based tubular (5 cm long, 920 mu m wide) permselective capsu les attached to silicone tethers. The capsules were maintained in vitr o for at least 7 days following the encapsulation procedure. Nicotine evoked release was analyzed in a defined subgroup from each batch. One capsule was then implanted using a guiding cannula system in the lumb ar subarachnoid space of each sheep for 4 (n = 5) and 8 (n = 1) wk. Al l capsules were retrieved intact by gentle pulling on the silicone tet her. Except for one capsule, the evoked catecholamine release of the r etrieved capsules was in the same range as that of other capsules from the same cohort that had been maintained in vitro. All retrieved caps ules were devoid of host fell reaction. Clusters of viable cells dispe rsed in an alginate immobilizing matrix were observed throughout all t he implanted capsules. This study demonstrates the feasibility of tran splanting functional encapsulated xenogeneic chromaffin cells into the cerebrospinal fluid of a large animal model using a capsule of approp riate dimensions for human implants. We believe that these results sug gest the appropriateness of human clinical trials in patients sufferin g from refractory terminal cancer pain.