Surgery – Radioactive substance applied to body for therapy – Radioactive substance placed within body
Reexamination Certificate
1999-02-09
2001-02-06
Hindenburg, Max (Department: 3736)
Surgery
Radioactive substance applied to body for therapy
Radioactive substance placed within body
Reexamination Certificate
active
06183409
ABSTRACT:
BACKGROUND
After balloon angioplasty, a metal tubular scaffold structure called a stent may be permanently implanted to physically hold open the repaired coronary artery. Unfortunately, up to 30% of such procedures result in narrowing or reclosure (restenosis) of the artery within six months to one year. One solution to the problem is to provide acute local, postoperative radiation treatment of the site using a catheter tipped with iridium-192 radioisotope. In this method, called intra-vascular brachytherapy, the iridium-192-tipped catheter is placed at the arterial site for thirty to forty minutes after stent deployment and then retracted. This type of acute high dose treatment using gamma radiation has been found to substantially reduce the rate of subsequent restenosis, as noted in Wiedermann, J. G. et al., “Intracoronary Irradiation Markedly Reduces Restenosis After Balloon Angioplasty in a Porcine Model,” 23 J. Am. Coll. Cardiol., 1491-1498 (May 1994) and Teirstein, P. S. et al., “Catheter-Based Radiotherapy to Inhibit Restenosis After Coronary Stenting,” 336 New England Journal of Medicine, 1697-1703 (Jun. 12, 1997).
This method of irradiating the patient suffers from the hazards associated with the required high radiation intensity. In addition to the surgeon, an oncologist and a radiation physicist are typically required for the procedure. A heavily shielded lead vault is needed to separate the patient from the operating room personnel, and the task of safely inserting the catheter containing the intense source, which is on the order of about 0.2 Curies, is particularly difficult. If irregularities occur in the procedure, the surgeon has relatively little time to respond, and therefore emergency procedures must be well-rehearsed. It is felt that this method, while possible in a research environment, may not be practical for normal usage.
An alternate method of addressing the restenosis problem is to use a permanently implanted radioactive stent, the method preferred by most physicians for its greater safety. Sources of radiation which are either pure beta particle or x-ray emitters are preferred because of the short range of the radiation, thus automatically protecting both the patient and the operating room personnel, particularly after the arterial insertion of the stent on the catheter.
As a result of studies in rabbits and swine, it is believed that a total dose of between 15 and 25 Grays is required to successfully inhibit restenosis in coronary arteries. Existing radioactive stent designs utilizing ion implantation of radioisotopes such as
32
P,
186
Re,
90
Y or
103
Pd require a highly specialized facility to perform the activations at considerable cost. U.S. Pat. Nos. 5,050,166 and 5,376,617 to Fischell et al. describe radioactive stents wherein radioactive material is either placed within the stent body or is electroplated onto the surface. Other methods involving cyclotron irradiation or coatings with radioactive liquids have contamination and safety problems respectively. Handling radioactive materials in these methods is difficult, expensive, and risky.
To avoid such difficult procedures, it is possible to ion-implant or coat a stent with a stable isotope, such as
31
P,
185
Re,
89
Y, or
102
Pd, which can be activated by neutron bombardment in order to generate a radioisotope, such as
32
P,
186
Re,
90
Y, or
103
Pd, respectively. In this manner, the stent would be fabricated in the absence of any radioactive species and then activated prior to implantation into the patient. The material used for the body of the stent to be activated must be carefully selected not to include elements that are easily activated by neutron bombardment to produce isotopes that give off undesirable radiation. For example, stainless steel, an otherwise ideal material, cannot be used in the above method because the neutron bombardment will activate the stent body to produce long-lived, high-energy gamma ray-emitting isotopes such as
51
Cr and
59
Fe, which are unacceptable in a permanently implanted stent.
Even small impurities in otherwise acceptable metals may give rise to harmful radiation. For example, Laird (“Inhibition of Neointinol Proliferation with Low-Dose Irradiation from a &bgr;-Particle-Emitting Stent”, Laird J. R. et al.,
Circulation,
93, No. 3, February 1996) ion-implanted a titanium stent with stable
31
P and generated the radioisotope
32
P by inserting the ion-implanted stent in a nuclear reactor. This technique produced only a very small amount of
32
P, and the trace impurities in the titanium body produced high energy gamma rays which were comparable in strength to the desired
32
P radiation. This technique suffered from the fact that
31
P has a very small neutron activation cross-section (0.18 barns), and thereby requires a long activation time. Even though titanium itself does not activate with thermal neutrons to form long-lived radioisotopes, titanium does activate with fast neutrons to
46
Ti, having a long half-life of 83 days, and the high cross-section impurities in the titanium body produced too much harmful contaminating gamma radiation. These experiments on titanium stents suggest that ion implantation of stable isotopes into stainless steel stents would present even greater obstacles.
SUMMARY OF THE INVENTION
The present invention comprises radioactive, x-ray-emitting medical devices for temporary or permanent implantation and methods of preparing such devices. The methods of the present invention reduce the generation of undesirable radioisotopes by ion implanting a stable isotope having a very high neutron activation cross-section, e.g., at least about 180 barns, or at least about 3000 barns, and then activating the stable isotope by thermal neutron activation to form a radioactive isotope. In a currently preferred embodiment, an implantable therapeutic medical device is prepared by ion-implanting the stable isotope
168
Yb, which has a thermal neutron cross-section of 3470 barns, into the body of the device and activating the
168
Yb atoms in a nuclear reactor for a time sufficient to produce
169
Yb, a soft x-ray emitter with a half-life of approximately 32 days. In an alternate embodiment, a temporarily implanted device is prepared by ion-implanting
124
Xe, which has a thermal neutron activation cross-section of 193 barns, into the outside surface of a wire. Thermal neutron activation of
124
Xe generates
125
I, a soft X-ray emitter with a half-life of 60 days.
A medical device according to a preferred embodiment of the invention comprises a substrate or body comprising
168
Yb,
169
Yb,
124
Xe, or
125
I associated with the body, such as disposed on, incorporated within, or carried with the body. Preferably, the device comprises between about 1×10
15
and about 5×10
17 168
Yb atoms. In certain embodiments, the device comprises a concentration of
168
Yb at least about 1×10
16
atoms/cm
2
. In a currently preferred embodiment, the medical device comprises a stent. In an alternate embodiment, wherein the body comprises a source wire, between about 1×10
17
and about 5×10
18
atoms of
124
Xe per centimeter of length are associated with the wire.
The stable isotope can be any isotope having a sufficiently large neutron activation cross-section so that upon thermal neutron activation, it forms a radioactive isotope having a desirable emission profile in a sufficiently short time that concurrent activation of undesirable isotopes from metals in the body is minimized or avoided. Exemplary isotopes having this property are
124
Xe and
168
Yb, which are currently preferred.
The body refers to that portion of the device which comprises the underlying structure of said device. The body may be formed from any material suitable for use in medical devices, particularly in implantable medical devices. In a preferred embodiment, the body is formed from one or more materials selected from the group consisting of metals and metal alloys, organic polymers, and ceramic oxides. Suitable metals and metal alloys com
Foley, Hoag&Eliot, LLP
Halstead David P.
Hindenburg Max
Implant Sciences Corporation
Szmal Brian
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