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(Circulation. 1996;93:641-645.)
© 1996 American Heart Association, Inc.

Articles

Pure ß-ParticleEmitting Stents Inhibit Neointima Formation in Rabbits

Christoph Hehrlein, MD; Marc Stintz, BS; Ralf Kinscherf, PhD; Klaus Schlösser, PhD; Ehrhard Huttel, PhD; Ludwig Friedrich, PhD; Peter Fehsenfeld, PhD; Wolfgang Kübler, MD

From the Department of Cardiology (C.H., M.S., W.K.) and the Department of Anatomy (R.K.), University of Heidelberg (Germany), and the Forschungszentrum Karlsruhe/Cyclotron Department (K.S., E.H., L.F., P.F.), Karlsruhe, Germany.

Correspondence to Christoph Hehrlein, MD, Department of Cardiology, University of Heidelberg, Bergheimerstr 58, 69115 Heidelberg, Germany.

	Abstract

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Background Considerable experimental evidence exists that neointimal hyperplasia after angioplasty is inhibited by -irradiation of the treated arteries. A ß-particle radiation is absorbed in tissue within a shorter distance away from the source than -radiation and may be more suitable for localized vessel irradiation. This study outlines a method to implant a ß-particle–emitting radioisotope (³²P; half-life, 14.3 days) into metallic stents. The effects of these stents on the inhibition of neointimal hyperplasia was compared with conventional stents in a rabbit model.

Methods and Results ³²P was produced by irradiation of red amorphous phophorus (³¹P) with neutrons and was implanted into Palmaz-Schatz stents (7.5 mm in length) after being kept apart from ³¹P in a mass separator. The radioisotope was tightly fixed to the stents, and the ion implantation process did not alter the surface texture. Stent activity levels of 4 and 13 µCi were chosen for the study. Four and 12 weeks after placement of conventional stents and ³²P-implanted stents in rabbit iliac arteries, vascular injury and neointima formation were studied by histomorphometry. Immunostaining for smooth muscle cell (SMC) -actin was performed to determine SMC cellularity in the neointima. SMCs were quantified by computer-assisted counting of -actin immunoreactive cells. Endothelialization of the stents was evaluated by immunostaining for endothelial cell von Willebrand factor. No difference in vessel wall injury was found after placement of conventional and ³²P-implanted stents. Neointima formation was potently inhibited by ³²P-implanted stents only at an activity level of 13 µCi after 4 and 12 weeks. Neointimal SMC cellularity was reduced in ³²P-implanted stents compared with conventional stents. Radioactive stents were endothelialized after 4 weeks, but endothelialization was less dense than in conventional stents.

Conclusions Neointima formation in rabbits is markedly suppressed by a ß-particle–emitting stent incorporating the radioisotope ³²P. In this model, a dose-response relation with this type of radioactive stent was observed, indicating that a threshold radiation dose must be delivered to inhibit neointima formation after stent placement over the long term.

Key Words: stents • radioisotopes

	Introduction

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In several recent studies, radiation therapy after balloon angioplasty or stent implantation has been shown to reduce restenosis rates by inhibiting stenotic neointima formation in animal models and in humans.^{1 2 3 4} Initially, the endovascular application of -radiation using catheters loaded with ¹⁹²Iridium seeds was used to reduce neointima formation after balloon angioplasty.^{1 2} A potential disadvantage of endovascular ¹⁹²Iridium sources is the irradiation of non–target tissue around the arterial wall. The -radiation requires extensive radiation protection of the operating personel. In this study, we investigated the effect of a pure ß-particle emitter (³²P; half-life, 14.3 days) on the inhibition of neointima formation. A ß-particle emission from ³²P is absorbed in living tissue by more than 99% within a distance of 5 mm away from the source. Very low-dose ß-particle irradiation of smooth muscle cells (SMCs) in vitro showed a marked reduction in cell proliferation rates.⁵ Animal studies have indicated that a catheter-based, short-term endovascular ß-irradiation is effective in inhibiting neointima formation.^{6 7} In a previous study, we reported that radioactive stents with very low activity levels prevent neointimal hyperplasia over the long term in rabbits.⁸ Radioactive stents continuously deliver very low doses of radiation and require less radiation protection during the actual angioplasty than catheter-based radiation sources. The previously studied stents produced predominantly ß⁺-particle radiation and much lower doses of - and x-radiation from ⁵⁵Co and isotopes with partially long half-lives (⁵¹Cr, ⁵²Mn, ⁵⁷Ni, ⁵⁶Co, and ⁵⁵Fe). It is unknown whether stents emitting exclusively ß-particles are equally effective in inhibiting neointima formation. This study outlines a method to implant radioisotopes into endovascular stents after investigation of the effects of a pure ß-particle–emitting stent on neointimal hyperplasia in a rabbit model. The extent of vascular injury and neointima formation was evaluated based on the histology of rabbit iliac arteries 4 and 12 weeks after stent placement.

	Methods

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Ion Implantation of ³²P Into Metallic Stents
Methods of radioisotope implantation into metals have been described previously by Dearnaley et al.⁹ In brief, ³²P activity was produced by neutron irradiation of red amorphous phosphorus (³¹P) in the research reactor, Petten, Netherlands. The samples (20 mg) were irradiated for about 10 days, achieving a concentration of approximately 20x10^{-6 32}P/³¹P (100 mCi). The irradiated phosphorus was placed into the Nielson ion source of the Karlsruhe mass separator,¹⁰ ionized, and accelerated to an energy of 60 keV (Fig 1). ³²P and ³¹P were separated by the magnet, and the ³²P ions were bombarded into Palmaz-Schatz stents (7.5 mm in length). At an energy level of 60 keV, the ³²P ions penetrate to a depth of 35 nm into the metallic surface of the stent. The homogeneity in distribution of activity per surface area of each stent was assessed by autoradiographic means (exposure to x-ray films). The activity level of each stent was examined by a special device inducing Bremsstrahlung in copper and tungsten and was measured by a germanium radiation detector (error less than ±3%). This setup was calibrated by absolute ß-activity measurements with a 4- liquid scintillation detector. The surface texture of the stents was evaluated by light and scanning electron microscopy.

View larger version (18K): [in this window] [in a new window]   Figure 1. 32P implantation into metallic stents. At the Karlsruhe mass separator (radius, 1.025 m; deflection angle, 191°), phosphorus was ionized with an ion source and accelerated to an energy level of 60 keV. The isotopes 32P and 31P were separated by the magnet, and only the 32P component was implanted into the stents.

Animal Study
Twenty-six New Zealand White rabbits weighing between 2.4 and 2.8 kg were anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg) IM. The femoral artery was exposed, and a 4F pediatric sheath was introduced via an arteriotomy. Heparin 500 IU and aspirin 60 mg were given intravenously before stent implantation. Conventional stents as well as radioisotope stents were mounted on a 20-mm balloon angioplasty catheter and expanded to a diameter of 3 mm in one common iliac artery at 8 atm for 2 minutes. The balloon-expanded stent to artery ratio was 1.2:1. After the femoral artery was ligated and the wound was closed, the animals received 60 mg IM aspirin every 3rd day for 4 weeks. Seventeen rabbits were followed for 4 weeks. The rabbits that received conventional stents were assigned to group 1 (n=6), rabbits with radioisotope stents and an initial activity of 4.2±0.2 µCi to group 2 (n=6), and rabbits with radioisotope stents and an activity of 13±0.2 µCi to group 3 (n=5). For a 12-week follow-up study, 3 rabbits received conventional stents, 3 rabbits received radioisotope stents with a 4±0.2 µCi activity, and 3 rabbits received radioisotope stents with 13±0.2 µCi activity.

Histomorphometry
After the animals were given a lethal dose of sodium pentobarbital, the iliac arteries were harvested, and two thirds of the stented region was cut off of each one. The segments were immersed in 4% paraformaldehyde. After stepwise dehydration with graded alcohols, specimens were embedded in epoxy-araldit resin. The stented arteries were serially sectioned into 7 to 12 slices (70 µm) with a rotating diamond-coated saw (Leica) and were stained with toluidine blue. The vessel perimeters and the neointimal areas were measured by morphometry as described previously.⁸ The extent of the vessel injury caused by the stent struts was quantified using the method of Schwartz et al.¹¹

Immunocytochemistry
After the wires had been removed from the remaining third of the stented region, specimens were immersed in Carnoy's solution for 18 hours and embedded in paraffin. Segments were cut into 4-µm sections and dried on albumin-glycerol–coated slides overnight at 56°C. After deparaffinization, they were incubated with the primary antibody at 37°C for 1.5 hours. Species-appropriate biotinylated secondary antibodies were applied followed by a streptavidin-horseradish-peroxidase complex (Amersham). Antibody binding was visualized with 3,3 diaminobenzidine (Pierce). Counterstaining was done with Gill's hematoxylin. To identify SMCs, a monoclonal mouse anti-rabbit SMC -actin antibody (Boehringer) was applied at a 1:800 dilution. Endothelial cells were detected by von Willebrand factor (vWf) staining using a polyclonal anti-human vWf antibody (Atlantic) at 1:500 dilution.

Cell Counting
The density of -actin immunoreactive SMCs in five randomly chosen 0.1-mm² neointimal areas close to the stent struts was measured (computer-assisted) at x400 light magnification.

Statistical Analysis
All data are presented as mean±SD. The unpaired Student's t test was used to compare group means. Simultaneous comparisons of more than two means were performed with ANOVA followed by Scheffé's test. A probability value <.05 was considered significant.

	Results

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Ex Vivo Analysis of ³²P-Implanted Stents
The overall inhomogeneity of the activity of radioisotope stents was less than 10% over circumference and length of the stents. A homogeneous distribution of the activity was found in all stents except for 3 radioisotope stents (4±0.2 µCi) used for the 12-week study. These stents had a 10% to 20% decrease in activity at one end. A loss of 0.5% ³²P from radioisotope stents was found after 15 minutes of ultrasonic washing in saline solution. An additional loss of 0.5% was found after stent expansion to a diameter of 4 mm and 5 weeks of ultrasonic washing. A modification of the surface texture after ³²P ion implantation was not observed.

Vascular Injury
No differences in vessel perimeter were found in iliac arteries 4 and 12 weeks after the implantation of conventional stents and radioisotope stents (8.3±0.7 and 8.4±0.6 mm versus 8.1±0.5 and 8.3±0.6 mm, respectively, P=NS). The overall injury imposed by the struts of conventional stents was not different from that imposed by the struts of radioisotope stents (score, 0.8±0.2 versus 0.7±0.2, P=NS). However, the injury score differed significantly over the stent length (in center of conventional stents, 0.6±0.1 versus 1.2±0.05 at the end, P<.01). Radioisotope stents with activity levels of 4 and 13 µCi imposed similar overall injury over the length of the stents (center and end) in rabbits followed for 4 weeks (score, 0.5±0.3 versus 0.4±0.3, respectively, P=NS). In rabbits followed for 12 weeks, no difference in overall injury was found in arteries treated with 4-µCi radioisotope stents compared with 13-µCi radioisotope stents (score, 0.9±0.1 versus 0.8±0.1, P=NS).

Neointima Formation
The mean cross-sectional neointimal area (MECNA) over the length of the stents (groups 1 through 3) 4 and 12 weeks after implantation in rabbit arteries is shown in the Table. After 4 weeks, we found a marked inhibition of neointima formation in arteries with 4- and 13-µCi radioisotope stents compared with arteries treated with conventional stents. After 12 weeks, however, neointima formation was potently inhibited only with 13-µCi radioisotope stents (Figs 2 and 3). In the center of 4-µCi radioisotope stents, neointima formation was increased by more than 100% compared with the center of 13-µCi radioisotope stents after 12 weeks. MECNA of arteries stented with 4-µCi radioisotope stents was only slightly reduced compared with arteries treated with conventional stents after 12 weeks (Table).

View this table: [in this window] [in a new window]   Table 1. Mean Cross-sectional Neointimal Area in mm2/Stent

View larger version (117K): [in this window] [in a new window]   Figure 2. Smooth muscle cells and neointima formation. A, Smooth muscle cell -actin immunoreaction in the neointima 12 weeks after the implantation of a conventional stent. B, Severely depressed -actin immunoreaction and minimal neointima covers a 32P-implanted stent (13 µCi) after 12 weeks. *Strut region. Magnification x400.

View larger version (45K): [in this window] [in a new window]   Figure 3. Arterial cross sections with stents. A, Conventional stent. 32P-implanted stent with an activity of 4 µCi (B) and 13 µCi (C) after 12 weeks. Toluidine blue stain; magnification x40.

The maximum cross-sectional neointimal area (MXCNA) was found predominantly at the ends of all stents, including conventional stents. Conventional stents induced a MXCNA of 1.9±0.2 mm² 12 weeks after stenting. MCXNA was markedly smaller in arteries treated with 13-µCi radioisotope stents than in arteries treated with conventional stents after 12 weeks (0.9±0.4 versus 1.9±0.2 mm² neointima, respectively; P<.02).

SMC Cellularity
The SMC density in the neointima decreased in a dose-dependent fashion after implantation of the radioisotope stent compared with the conventional stent. Four weeks after conventional stent implantation, 782±41 SMCs/0.1 mm² were counted in the neointima, 113±18 SMCs/0.1 mm² neointima after 4-µCi radioisotope stent implantation, and 77±9 SMCs/0.1 mm² neointima after 13-µCi radioisotope stent implantation into the rabbit arteries (P<.001 versus conventional stent and 4-µCi radioisotope stent). After 12 weeks, the neointimal SMC cellularity was still markedly reduced in arteries treated with the 13-µCi radioisotope stent compared with the conventional stent (103±31 versus 670±56 SMCs/0.1 mm² neointima, P<.001). The cellularity of the neointima in the group of animals with 13-µCi radioisotope stent followed for 12 weeks did not substantially differ from the animals followed for 4 weeks (77±9 versus 103±31, P=NS).

Stent Endothelialization
Immunostaining for endothelial cell vWf revealed that conventional stents as well as each of the ³²P-implanted stents (4 and 13 µCi) were endothelialized after 4 weeks. However, the endothelialization of the radioisotope stent was less dense compared with the conventional stent. The decrease in endothelial cell density was found to be higher in the 13-µCi radioisotope stent than in the 4-µCi radioisotope stent. Stent endothelialization progressed from the 4-week to the 12-week observation period.

	Discussion

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This study introduces a technique to implant selected radioisotopes into the metallic surface of stainless steel stents. The surface texture of the stent is not affected by the implantation procedure and the risk of environmental contamination is neglectable. We have shown previously that stent surface irregularities may be an important cause of neointima formation.¹² The results of this study indicate that pure ß-particle–emitting stents are very effective in inhibiting neointima formation after angioplasty in rabbits.

Relation With Previous Studies
Radiation therapy after angioplasty and stent implantation has yielded promising results with respect to the reduction of neointimal hyperplasia according to several animal studies and preliminary clinical trials.^{1 2 4} Catheter-based endovascular -irradiation has been shown to markedly reduce neointimal thickening after angioplasty in porcine models.^{1 2 3} We previously demonstrated that radioactive stents emitting ß-, -, and x-radiation potently inhibit neointimal hyperplasia in rabbits.⁸ The present study suggests that ³²P-implanted stents emitting pure ß-particles cause a persistent inhibition of neointima formation. However, this effect appears to be dose dependent. ³²P-implanted stents with an activity level of 4 µCi and lower may not markedly reduce neointima formation over the long term, particularly when deep vessel injury is induced during angioplasty. It has been indicated by Verin et al⁶ that the inhibition of neointima formation after angioplasty via a catheter-based ß-particle source depends on the radiation dose. Applying fairly low radiation doses (6 and 12 Gy), these investigators observed an inhibition of SMC proliferation at 8 days but did not find an inhibition of neointimal thickening after 6 weeks. A persistent inhibition of neointima formation was noted only after using higher radiation doses (18 Gy).^{6 7} The dose measurements of the ³²P-implanted stents used in this study are currently in progress at the Forschungszentrum Karlsruhe. Fischell et al⁵ introduced the concept of ß-particle–emitting stents showing the inhibition of SMC proliferation in vitro at extremely low activity levels (0.006 µCi/cm) of a ³²P-impregnated wire. Concerns regarding the potential leaching of radioactive material from a ³²P-impregnated stent prompted us to implant ³²P into metallic stents. Preliminary in vivo studies by Laird et al¹³ indicated that ³²P-coated stents with an activity level of 0.14 µCi inhibit neointimal hyperplasia after 28 days in swine. However, using such stent activity levels may require a longer follow-up to derive conclusions concerning a persistent inhibition of neointima formation. Studies on the prevention of keloids by radiation suggest that the rate of keloid recurrence depends on the radiation dose and that a long-term follow-up is necessary to evaluate the efficacy of the treatment.^{14 15 16}

Vascular Injury
Neointimal hyperplasia correlates with the severity of the arterial injury after angioplasty.¹⁷ We found that the arterial injury caused by Palmaz-Schatz stents in this study was greater at the ends of the stents than at the center, and the ends of the stents induced enhanced neointima formation. Severe vessel injury appears to require more radiation for preventing neointimal hyperplasia than moderate injury. In addition, the radiation dose of a homogeneously activated ³²P-implanted stent decreases at the ends by one half of that of the center of the stent.¹⁸ In combination with more than moderate arterial injury, a decrease in radiation dose at the ends of a ß-particle–emitting stent may account for a greater loss of efficacy. However, this predicted loss could be counteracted by increasing the stent activity level toward the ends of the stent. In our study, the overall vessel injury imposed by the stent struts was slightly less severe in the 4-week follow-up group of rabbits being treated with ³²P-implanted stents than in the 12-week group. We conclude that the more severe vascular injury during stenting in the 12-week group had contributed the failure of the 4-µCi stents to significantly inhibit neointima formation.

Neointimal Cellularity and Stent Endothelialization
We found a dose-dependent reduction in neointimal SMCs and endothelial cells in ³²P-implanted stents compared with conventional stents. However, judged by light microscopy, vascular thrombosis was not increased in ³²P-implanted stents.

Study Limitations
A single animal model does not sufficiently reflect the pathomechanisms that occur in human restenosis after angioplasty. Dose measurements of ³²P-implanted stents will be required. Trials studying the effects of radioactive stents in atherosclerotic vessels as well as larger series of animal studies are desirable.

	Acknowledgments

 
This study was supported by a grant from the Deutsche Forschungsgemeinschaft (He-1603/2-1). The authors would like to thank the Joint Research Center, HFR, Petten, Netherlands, for performing the phosphorus irradiations for the production of ³²P at the high flux reactor.

Received September 20, 1995; revision received December 11, 1995; accepted December 19, 1995.

	References

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