DIRECT CONVECTIVE DELIVERY OF MACROMOLECULES TO THE SPINAL-CORD

Object. Because of the limited penetration of macromolecules across th e blood-spinal cord barrier, numerous therapeutic compounds with poten tial for treating spinal cord disorders cannot be used effectively. Th e authors have developed a technique to deliver and distribute macromo lecules regionally in the spinal cord by using convection in the inter stitial space. Methods. The authors designed a delivery system connect ed to a ''floating'' silica cannula (inner diameter 100 mu m, outer di ameter 170 mu m) that provides for constant volumetric inflow to the s pinal cord. A solution containing albumin that was either unlabeled or labeled with carbon-14 or gadolinium was infused at various volumes ( 3, 6, 10, 20, 40, or 50 mu l) at a rate of 0.1 mu l/minute into the sp inal cord dorsal columns of nine swine and into the lateral columns of three primates (Macaca mulatta). Volume of distribution (Vd), concent ration homogeneity, and percentage of recovery were determined using s cintillation analysis, kurtosis calculation (K), and quantitative auto radiography (six swine), magnetic resonance imaging (one swine and thr ee primates), and histological analysis (all animals). Neurological fu nction was observed for up to 3 days in four of the swine and up to 16 weeks in the three primates. The Vd of C-14-albumin was linearly prop ortional (R-2 = 0.97) to the volume of infusion (Vi) (Vd/Vi = 4.4 +/- 0.5; [mean +/- standard deviation]). The increases in Vd resulting fro m increases in Vi were primarily in the longitudinal dimension (R-2 = 0.83 in swine; R-2 = 0.98 in primates), allowing large segments of spi nal cord (up to 4.3 cm; Vi 50 mu l) to be perfused with the macromolec ule. The concentration across the area of distribution was homogeneous (K = -1.1). The mean recovery of infused albumin from the spinal cord was 85.5 +/- 5.6%. Magnetic resonance imaging and histological analys is combined with quantitative autoradiography revealed the albumin inf usate to be preferentially distributed along the white matter tracts. No animal exhibited a neurological deficit as a result of the infusion . Conclusions. Regional convective delivery provides reproducible, saf e, region-specific, and homogeneous distribution of macromolecules ove r large longitudinal segments of the spinal cord. This delivery method overcomes many of the obstacles associated with current delivery tech niques and provides for research into new treatments of various condit ions of the spinal cord.