title: Intraventricular encapsulated calf adrenal chromaffin cells: viable for at least 500 days in vivo without detectable adverse effects on behavioral/cognitive function or host immune sensitization in rats.
abstract: Numerous studies have reported that adrenal chromaffin cell transplants, including encapsulated xenogeneic adrenal chromaffin cells, have analgesic effects. However, in addition to efficacy, the clinical utility of encapsulated xenogeneic adrenal chromaffin cells for treatment of chronic pain is dependent on the duration of cell viability in vivo, and their relative safety. The objectives of the present study in rats were to: (1) examine encapsulated calf adrenal chromaffin (CAC) cells for evidence of viable cells and continued release of analgesic agents after an extended period in vivo; (2) determine if intraventricular encapsulated CAC cells produce detectable adverse effects on behavioral/cognitive function; and (3) test for evidence of host immune sensitization after an extended period of exposure to encapsulated xenogeneic adrenal chromaffin cells. Results of the present study suggest that some encapsulated CAC cells remain viable for nearly 1.5 years in vivo and continue to produce catecholamines and met-enkephalin. Post-explant device norepinephrine output was equivalent to amounts previously shown to produce analgesic effects with intrathecal implants. Encapsulated adrenal chromaffin cells also appeared relatively safe, even when implanted in the cerebral ventricals, with a lower side-effect profile than systemic morphine (4 mg/kg). There was no evidence that encapsulated CAC-cells implanted in the ventricles affected body weight, spontaneous activity levels, or performance in the delayed matching to position operant task which is sensitive to deficits in learning, memory, attention, motivation, and motor function. Finally, encapsulated CAC cells produced no detectable evidence of host immune sensitization after 16.7 months in vivo, although unencapsulated CAC cells produced a robust immune response even in aged rats. The results of the present study suggest that adrenal chromaffin cells remain viable in vivo for long periods of time, and that long-term exposure to encapsulated xenogeneic adrenal chromaffin cell implants appears relatively safe.
authors.affiliation: CytoTherapeutics, Inc., 4 Richmond Square, Providence, RI 02906, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Lindner
authors.forename: M A
authors.initials: MA
authors.lastname: Plone
authors.forename: B
authors.initials: B
authors.lastname: Frydel
authors.forename: F A
authors.initials: FA
authors.lastname: Kaplan
authors.forename: P M
authors.initials: PM
authors.lastname: Krueger
authors.forename: W J
authors.initials: WJ
authors.lastname: Bell
authors.forename: T J
authors.initials: TJ
authors.lastname: Blaney
authors.forename: S R
authors.initials: SR
authors.lastname: Winn
authors.forename: S S
authors.initials: SS
authors.lastname: Sherman
authors.forename: E J
authors.initials: EJ
authors.lastname: Doherty
authors.forename: D F
authors.initials: DF
authors.lastname: Emerich