Direct convective delivery of macromolecules to peripheral nerves.
OBJECTIVE
Although many macromolecules have treatment potential for peripheral nerve disease, clinical use of these agents has been restricted because of limitations of delivery including systemic toxicity, heterogeneous dispersion, and inadequate distribution. In an effort to overcome these obstacles, the authors examined the use of convection to deliver and distribute macromolecules into peripheral nerves.


METHODS
For convective delivery, the authors used a gas-tight, noncompliant system that provided continuous flow through a small silica cannula (inner diameter 100 microm, outer diameter 170 microm) inserted into a peripheral nerve. Increases in the volume of infusion (Vi) (10, 20, 30, 40, and 80 microl) of 14C-labeled (nine nerves) or gadolinium-labeled (two nerves) albumin were infused unilaterally or bilaterally into the tibial nerves of six primates (Macaca mulatta) at 0.5 microl/minute. The volume of distribution (Vd), percentage recovery, and delivery homogeneity were determined using quantitative autoradiography, an imaging program developed by the National Institutes of Health, magnetic resonance (MR) imaging, scintillation counting, and kurtosis (K) analysis. One animal that was infused bilaterally with gadolinium-bound albumin (40 microl to each nerve) underwent MR imaging and was observed for 16 weeks after infusion. The Vd increased with the Vi in a logarithmic fashion. The mean Vd/Vi ratio over all Vi was 3.7+/-0.8 (mean+/-standard deviation). The concentration across the perfused region was homogeneous (K=-1.07). The infusate, which was limited circumferentially by the epineurium, followed the parallel arrangement of axonal fibers and filled long segments of nerve (up to 6.8 cm). Recovery of radioactivity was 75.8+/-9%. No neurological deficits arose from infusion.


CONCLUSIONS
Convective delivery of macromolecules to peripheral nerves is safe and reliable. It overcomes obstacles associated with current delivery methods and allows selective regional delivery of putative therapeutic agents to long sections of nerve. This technique should permit the development of new treatments for numerous types of peripheral nerve lesions.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
R R
RR
Lonser
R J
RJ
Weil
P F
PF
Morrison
L S
LS
Governale
E H
EH
Oldfield
D000818:Animals; D001345:Autoradiography; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D002404:Catheterization / Q000295:instrumentation; D003287:Contrast Media; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004867:Equipment Design; D005500:Follow-Up Studies; D005682:Gadolinium; D007260:Infusion Pumps; D008253:Macaca mulatta; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D012449:Safety; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012822:Silicon Dioxide; D013979:Tibial Nerve / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D003287:Contrast Media; D046911:Macromolecular Substances; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D012822:Silicon Dioxide; D005682:Gadolinium