Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation.

Abstract

BACKGROUND Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium "stent" wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition. METHODS AND RESULTS A series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm). CONCLUSIONS We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.

New Frontiers in Interventional Cardiology

“…Coupling the radiation delivery to the stent itself makes radiation delivery more efficient, obviating the need for a separate radiation delivery step. Several radioactive stent systems have been developed including ion-implantation of phosphorous-32 ( 32 P) 11 and activation of a stainless steel stent in a cyclotron producing a spectrum of radioisotopes. 12 Most clinical investigation has been undertaken with the 32 P ␤-emitting stent.…”

Frontiers in Interventional Cardiology

“…It is also believed that radioactive stents can act by culling the smooth muscle cell population as these cells pass through the "electron fence" at the plane of the stent wires. 115 Hehrlein and colleagues 116,117 were the first to describe the use of radioactive stents, which they implanted in nondiseased rabbit iliac arteries. The stainless steel stents were made radioactive by ion bombardment in a cyclotron and emitted both ␥-and ␤-radiation from the radionuclides 55,56,57 Co, 52 Mg, and 55 Fe.…”

<b>Irradiation and Postangioplasty Restenosis</b>

“…However, stent thrombosis is not always seen in animal models of catheter based brachytherapy. Fischell and co-workers 67) postulated delayed endothelialization predisposing the thrombus formation. Hehrlein and co-workers have shown that the reendothelialization after low-dose radioactive stent implantation was delayed, with the rate of stent endothelialization being dose-dependent.…”

“…88) A similar technique was independently developed and tested by Fis-chell and co-workers. 67) 31 P was ion-implanted beneath the outer surface of the titanium wire of stents, which were exposed for several hours to a flux of slow neutrons to produce a pure beta-emitter. It offers the advantages of no associated gamma radiation, a short half-life (14.3 days), and limited range of the beta particles in tissue (3 to 4 mm).…”