DIRECT CONVECTIVE DELIVERY OF MACROMOLECULES TO PERIPHERAL-NERVES

Object. Although many macromolecules have treatment potential for peri pheral nerve disease, clinical use of these agents has been restricted because of limitations of delivery including systemic toxicity, heter ogeneous dispersion, and inadequate distribution. In an effort to over come these obstacles, the authors examined the use of convection to de liver and distribute macromolecules into peripheral nerves. Methods. F or convective delivery, the authors used a gas-tight, noncompliant sys tem that provided continuous flow through a small silica cannula (inne r diameter 100 mu m, outer diameter 170 mu m) inserted into a peripher al nerve. Increases in the volume of infusion (Vi) (10, 20, 30, 40, an d 80 mu L)) of C-14-labeled (nine nerves) or gadolinium-labeled (two n erves) albumin were infused unilaterally or bilaterally into the tibia l nerves of six primates (Macaca mulatta at 0.5 mu l/minute. The volum e 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 (M R) imaging, scintillation counting, and kurtosis (K) analysis. One ani mal that was infused bilaterally with gadolinium-bound albumin (40 mu l to each nerve) underwent MR imaging and was observed for 16 weeks af ter infusion. The Vd increased with the Vi in a logarithmic fashion. T he mean Vd/Vi ratio over all Vi was 3.7 +/- 0.8 (mean +/- standard dev iation). 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 fil led long segments of nerve (up to 6.8 cm). Recovery of radioactivity w as 75.8 +/- 9%. No neurological deficits arose from infusion. Conclusi ons. Convective delivery of macromolecules to peripheral nerves is saf e and reliable. It overcomes obstacles associated with current deliver y methods and allows selective regional delivery of putative therapeut ic agents to long sections of nerve. This technique should permit the development of new treatments for numerous types of peripheral nerve l esions.