Direct convective delivery of macromolecules to the spinal cord.
OBJECTIVE
Because of the limited penetration of macromolecules across the blood-spinal cord barrier, numerous therapeutic compounds with potential for treating spinal cord disorders cannot be used effectively. The authors have developed a technique to deliver and distribute macromolecules regionally in the spinal cord by using convection in the interstitial space.


METHODS
The authors designed a delivery system connected to a "floating" silica cannula (inner diameter 100 microm, outer diameter 170 microm) that provides for constant volumetric inflow to the spinal 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 microl) at a rate of 0.1 microl/minute into the spinal cord dorsal columns of nine swine and into the lateral columns of three primates (Macaca mulatta). Volume of distribution (Vd), concentration homogeneity, and percentage of recovery were determined using scintillation analysis, kurtosis calculation (K), and quantitative autoradiography (six swine), magnetic resonance imaging (one swine and three primates), and histological analysis (all animals). Neurological function was observed for up to 3 days in four of the swine and up to 16 weeks in the three primates. The Vd of 14C-albumin was linearly proportional (R2=0.97) to the volume of infusion (Vi) (Vd/Vi=4.4+/-0.5; [mean+/-standard deviation). The increases in Vd resulting from increases in Vi were primarily in the longitudinal dimension (R2=0.83 in swine; R2=0.98 in primates), allowing large segments of spinal cord (up to 4.3 cm; Vi 50 microl) to be perfused with the macromolecule. 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 analysis combined with quantitative autoradiography revealed the albumin infusate 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, safe, region-specific, and homogeneous distribution of macromolecules over large longitudinal segments of the spinal cord. This delivery method overcomes many of the obstacles associated with current delivery techniques and provides for research into new treatments of various conditions of the spinal cord.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
R R
RR
Lonser
N
N
Gogate
P F
PF
Morrison
J D
JD
Wood
E H
EH
Oldfield
D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes; D002404:Catheterization / Q000295:instrumentation; D003287:Contrast Media; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004867:Equipment Design; D005260:Female; D005682:Gadolinium; D008253:Macaca mulatta; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D009460:Neurologic Examination; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D012449:Safety; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012822:Silicon Dioxide; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013118:Spinal Cord Diseases / Q000188:drug therapy; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D003287:Contrast Media; D046911:Macromolecular Substances; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D012822:Silicon Dioxide; D005682:Gadolinium