Cardiovascular implants of enhanced biocompatibility

Medical leads fabricated from low-modulus Ti-Nb-Zr alloys to provide enhanced biocompatibility and hemocompatibility. The medical leads may be surface hardened by oxygen or nitrogen diffusion or by coating with a tightly adherent, hard, wear-resistant, hemocompatible ceramic coating. It is contemplated that the Ti-Nb-Zr alloy can be substituted as a fabrication material for any portion of a medical lead that either comes into contact with blood thereby demanding high levels of hemocompatibility, or that is subject to microfretting, corrosion, or other wear and so that a low modulus metal with a corrosion-resistant, hardened surface would be desirable.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a range of cardiovascular and other implants 
fabricated of metallic alloys of enhanced hemocompatibility that can 
optionally be surface hardened to provide resistance to wear, or 
cold-worked or cold-drawn to reduce elastic modulus, if necessary. More 
specifically, the invention is of pacemaker leads and other electrical 
leads and sensors fabricated of Ti-Nb-Zr alloys. 
2. Description of the Related Art 
Cardiovascular implants have unique blood biocompatibility requirements to 
ensure that the device is not rejected (as in the case of natural tissue 
materials for heart valves and grafts for heart transplants) or that 
adverse thrombogenic (clotting) or hemodynamic (blood flow) responses are 
avoided. 
Cardiovascular implants, such as heart valves, can be fabricated from 
natural tissue. These bioprostheses can be affected by gradual 
calcification leading to the eventual stiffening and tearing of the 
implant. 
Non-bioprosthetic implants are fabricated from materials such as pyrolytic 
carbon-coated graphite, pyrolytic carbon-coated titanium, stainless steel, 
cobalt-chrome alloys, cobalt-nickel alloys, alumina coated with 
polypropylene and poly-4-fluoroethylene. 
For synthetic mechanical cardiovascular devices, properties such as the 
surface finish, flow characteristics, surface structure, charge, wear, and 
mechanical integrity all play a role in the ultimate success of the 
device. Pacers, defibrillators, leads, and other similar cardiovascular 
implants are made of Ni-Co-Cr alloy, Co-Cr-Mo alloy, titanium, and 
Ti-6Al-4V alloy, stainless steel, and various biocompatible polymers. 
One of the most significant problems encountered in heart valves, 
artificial hearts, assist devices, pacers, leads, stents, and other 
cardiovascular implants is the formation of blood clots (thrombogenesis). 
Protein coatings are sometimes employed to reduce the risk of blood clot 
formation. Heparin is also used as an anti-thrombogenic coating. 
It has been found that stagnant flow regions in the devices or non-optimal 
materials contribute to the formation of blood clots. These stagnant 
regions can be minimized by optimizing surface smoothness and minimizing 
abrupt changes in the size of the cross section through which the blood 
flows or minimizing either flow interference aspects. While materials 
selection for synthetic heart valves, and cardiovascular implants 
generally, is therefore dictated by a requirement for blood compatibility 
to avoid the formation of blood clots (thrombus), cardiovascular implants 
must also be designed to optimize blood flow and wear resistance. 
Even beyond the limitations on materials imposed by the requirements of 
blood biocompatibility and limitations to designs imposed by the need to 
optimize blood flow, there is a need for durable designs since it is 
highly desirable to avoid the risk of a second surgical procedure to 
implant cardiovascular devices. Further, a catastrophic failure of an 
implanted device will almost certainly result in the death of the patient. 
SUMMARY OF THE INVENTION 
The invention provides cardiovascular and other medical implants of a low 
modulus, biocompatible, hemocompatible, metallic alloy of titanium with 
niobium and optionally zirconium. The invention implants include pacers, 
electrical leads and sensors. The invention also provides surface hardened 
versions of these devices produced by oxygen or nitrogen diffusion 
hardening to improve resistance to cavitation, microfretting wear, and 
impact-induced wear. 
The inherently low modulus of Ti-Nb-Zr alloys, between about 6 to about 12 
million psi depending on metallurgical treatment and composition, provide 
a more flexible and forgiving construct for cardiovascular applications 
while improving contact stress levels. 
The preferred low modulus titanium alloys of the invention have the 
compositions: (i) titanium; about 10 wt. % to about 20 wt. % niobium; and 
optionally from about 0 wt. % to about 20 wt. % zirconium; and (ii) 
titanium; about 35 wt. % to about 50 wt. % niobium; and optionally from 
about 0 wt. % to about 20 wt. % zirconium. Tantalum can also be present as 
a substitute for Nb. These alloys are referred to herein as "Ti-Nb-Zr 
alloys," even though tantalum may also be present and the zirconium 
percentage may be zero. 
The exclusion of elements besides titanium, zirconium, and niobium, or 
tantalum results in an alloy which does not contain known toxins or 
carcinogens, or elements that are known or suspected of inducing diseases 
or adverse tissue response in the long term. 
Without the presence of zirconium in the composition, the ability of the 
Ti-Nb-Zr alloy to surface harden during oxygen or nitrogen diffusion 
hardening treatments is more limited. Therefore, presence of zirconium is 
especially preferred when the alloy implant must be diffusion hardened. 
Other non-toxic filler materials such as tantalum, which stabilize the 
.beta.-phase of titanium alloy, but do not affect the low modulus, i.e., 
maintain it at less than about 85 GPa, could also be added.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The implants of the invention are fabricated from an alloy containing 
titanium as a component. The preferred low modulus titanium alloys have 
the compositions: (i) titanium, about 10 wt. % to about 20 wt. % niobium, 
and optionally from about 0 wt. % to about 20 wt. % zirconium; and (ii) 
titanium, about 35 wt. % to about 50 wt. % niobium, and optionally from 
about 0 wt. % to about 20 wt. % zirconium. 
In a preferred embodiment wherein the implants are surface hardened by 
oxygen or nitrogen diffusion, zirconium is beneficially present in amounts 
ranging from about 0.5 to about 20 wt. %. 
Even though it is apparent that the titanium proportion of alloy used to 
make the invention implants could be less than 50 wt. % and the zirconium 
proportion zero percent, nevertheless, for the purposes of this 
specification, it is referred to as a "Ti-Nb-Zr alloy" or a "titanium 
alloy." The alloy most preferably comprises about 13 wt. % of zirconium, 
13 wt. % of niobium and remainder being titanium. While tantalum may be 
substituted for niobium to stabilize .beta.-phase titanium, niobium is the 
preferred component due to its effect of lowering the elastic modulus of 
the alloy when present in certain specific proportions. Other elements are 
not deliberately added to the alloy but may be present in such quantities 
that occur as impurities in the commercially pure titanium, zirconium, 
niobium, or tantalum used to prepare the alloy and such contaminants as 
may arise from the alloying process. 
In the specification and claims, the term "high strength" refers to an 
alloy having a tensile strength above at least about 620 MPa. 
The term "low modulus," as used in the specification and claims, refers to 
a Young's modulus below about 90 GPa. 
Although the hot rolled, reheated, and quenched Ti-Nb-Zr alloy is a 
suitable implant material, its properties can be improved by forging or 
other metallurgical processes or an aging heat treatment or a combination 
of these. Aging treatment can increase the strength and hardness of the 
material, and reduce its elongation while maintaining a relatively low 
modulus of elasticity. The treatment can be varied to obtain the desired 
properties. U.S. Pat. No. 5,169,597 to Davidson, et al. and U.S. Pat. No. 
5,477,864 to Davidson, both hereby fully incorporated by reference, deal 
in more detail with the useful Ti-Nb-Zr alloys. Further, U.S. Ser. No. 
08/036,414, issued as U.S. Pat. No. 5,509,933, hereby fully incorporated 
by reference, teaches how to hot work Ti-Nb-Zr alloys to produce high 
strength, low modulus medical implants. 
It may be desirable for other reasons, such as reducing microfretting wear 
between mating mechanical components, to surface harden the alloy implants 
using oxygen or nitrogen diffusion hardening methods, or coating with a 
hard wear resistant coating. In the latter event, the surface of the 
prosthesis may be coated with an amorphous diamond-like carbon coating or 
ceramic-like coating such as zirconium or titanium oxide, zirconium or 
titanium nitride, or zirconium or titanium carbide using chemical or 
plasma vapor deposition techniques to provide a hard, impervious, smooth 
surface coating. These coatings are especially useful if the prosthesis is 
subjected to conditions of wear or as an electrically insulative coating 
on electrical leads (i.e., pacemaker, defibrillator, neurological, 
sensors) of Ti-Nb-Zr alloy. 
Methods for providing hard, low-friction, impervious, biocompatible 
amorphous diamond-like carbon coatings are known in the art and are 
disclosed in, for example, EPO patent application 302 717 A1 to Ion Tech 
and Chemical Abstract 43655P, Vol. 101, describing Japan Kokai 59/851 to 
Sumitomo Electric, all of which are incorporated by reference herein as 
though full set forth. 
A preferred process for oxygen diffusion hardening is described in the U.S. 
Pat. No. 5,372,560, which is hereby fully incorporated by reference. 
Oxygen diffusion hardening according to this process requires the supply 
of oxygen, or an oxygen containing atmosphere, or compounds partially 
composed of oxygen, such as water (steam), carbon dioxide, nitrogen 
dioxide, sulfur dioxide, and the like. These substances are supplied to 
the implant to be hardened which is maintained at a temperature preferably 
between 200.degree. C. and 1200.degree. C. The amount of time required at 
a given temperature to effectively produce the surface and near-surface 
hardened implants is related exponentially, by an Arhennius-type 
relationship to the temperature. That is, shorter periods of time are 
required at higher temperatures for effective diffusion hardening. The 
resultant oxygen diffusion hardened implants are characterized in that the 
oxide film contains primarily a mixture of titanium and zirconium oxides 
in the implant surface. Niobium oxides may also be present. Immediately 
underlying this mixed-oxide film is sometimes a region of oxygen-rich 
metal alloy. Underlying the sometimes-obtained oxygen-rich alloy layer is 
the core Ti-Nb-Zr alloy. The interface between the sometimes-obtained 
oxygen-rich alloy layer and the oxide regions is typically zirconium-rich 
in comparison to the underlying Ti-Nb-Zr alloy. In a most preferred 
embodiment, the Ti-Nb-Zr alloy is subjected to temperature and an 
environment of argon gas that has been moisturized by bubbling through a 
water bath. The water vapor disassociates at the implant surface to 
produce oxygen which diffuses into the implant to produce the desired 
hardened surface. 
Nitrogen diffusion processes can also be utilized in which nitrogen sources 
are provided instead of oxygen. These nitrogen diffusion surface hardening 
processes will tend to harden the metal alloy substrate in a similar 
manner to that of oxygen diffusion hardening or conventional oxygen 
hardening (which is also useful), and produce a yellow-orange insulative, 
wear-resistant surface oxide instead of the blue-black surface oxide which 
typically forms from the in situ oxygen diffusion hardening process. 
Further, the implants of the invention may optionally be surface coated 
with medicaments such as anti-inflammatory agents, anti-thrombus agents, 
antibiotics, proteins that reduce platelet adhesion, and the like to 
improve their acceptability in a living body. 
Pacemakers and Electrical Signal Carrying Leads/Sensors 
Pacemaker and other electronic leads are manufactured by several 
corporations, including Medtronic, which produces a range of pacemaker 
lead designs. 
One of these designs is shown in schematic form in FIGS. 3A and B. The 
pacemaker lead body 150 has a centrally disposed metallic conductor 152 
typically made of cobalt-nickel alloy, such as MP35N.RTM.. This conductor 
152 is usually made up of several strands of wire, each having a diameter 
of about 0.15-0.20 mm. The conductor 152 is covered by an insulative, 
protective polymer sheath 153 so that the elongate body 150 of the 
pacemaker lead has an overall diameter ranging from about 2.2 to about 3 
mm. The pacemaker has a first end 154 with an electrode 158 for connecting 
to a pulse generator and a second end 156 with an electrode 157 for 
contacting heart muscle. An alternative embodiment is shown in FIG. 3C. As 
supplied, these two ends are covered with protective polyurethane caps 
which can be removed for installation of the pacemaker. In order to 
prevent electrical interference with the conductor 152, a polymeric 
insulative sleeve 153 is disposed over the entire pacemaker lead body 150, 
with the exception of the exposed electrodes 157 for contacting heart 
muscle and the contact electrode 158 for engaging with the pulse generator 
that houses the electronics and power pack for the pacemaker. As explained 
before, the organic polymeric sheath compositions, typically polyurethane, 
can slowly degenerate in the body causing problems, not only due to 
potential deterioration of electrical insulation and interference with 
electrical signals but also because of potentially toxic products of 
degradation. 
The invention provides, as shown in FIG. 3C, a pacemaker wherein the 
conductor 152 is fabricated from a Ti-Nb-Zr alloy that is coated with a 
tightly adherent, low friction, bio- and hemocompatible coating, with the 
exception of the electrode for contacting heart muscle 157, and the 
electrode 158 at the other end of the lead for engaging the pulse 
generator. The coatings can be formed by in situ oxidation or nitriding of 
the Ti-Nb-Zr to produce an electrically insulative surface layer of from 
about 0.1 to about 3 microns in thickness, preferably less than about 0.5 
microns in thickness. This process can be carried out at the same time the 
material is age-hardened. Alternatively, an insulative inert ceramic 
coating can be applied by conventional CVD or PVD methods either on the 
original Ti-Nb-Zr alloy surface or onto the diffusion hardened Ti-Nb-Zr 
surface. For these overlay coatings, the thickness can be as great as 20 
microns. The overlay coatings include ceramic metal oxides, metal 
nitrides, metal carbides, amorphous diamond-like carbon, as detailed 
above. The electrical signal conductor 152 can comprise either a single 
wire or multiple wires. Exposed Ti-Nb-Zr metallic ends of the wire or 
wires are preferably connected directly to a pulse generator thereby 
avoiding the necessity for a weld or crimp to attach an electrode to the 
conductor which may result in local galvanic corrosion or physically 
weakened regions. Further, since the coatings provide a natural protective 
insulative surface, the use of a coiled construct could be avoided by 
using only a preferred single-strand, non-coiled low modulus Ti-Nb-Zr 
metallic wire construct for the conductor 152. This will also eliminate 
the need for stiff guide wire. Finally, the overall diameter of the 
pacemaker lead body 150 could be reduced considerably from the range of 
about 2.2-3 mm for current commercially available leads to about 0.2-1 mm. 
Optionally, the leads of the invention may be covered with a polymeric 
sheath. 
Defibrillators 
FIGS. 1 and 2 show a defibrillator including a flexible silicone polymeric 
patch 300 with a coil of conductive wire 320 (typically titanium, 
stainless steel, or cobalt-nickel-chromium) on the side of the silicone 
patch 300 that will contact muscle tissue. When in place in the body, the 
lead wire 320 that carries power to the coil 340 extends out of the body 
(through the skin) and is electrically connected to a power source 
contained in a protective container 360. According to the invention, the 
lead wire 320 is fabricated with an electrically conductive core 350 of 
Ti-Nb-Zr alloy and is coated with an adherent electrically insulative 
coating 380, such as metal oxides, carbides, or nitrides, or with 
amorphous diamond-like carbon as shown in exaggerated detail FIG. 2. This 
coating electrically insulates the lead wire from electrical contact with 
surrounding body tissue while also protecting the metallic core from 
corrosion and attack by body fluids, as described previously for the 
pacemaker lead. Elimination of the polymer coating results in the 
elimination of potentially toxic products of gradual degradation of the 
polymer and also the consequent shorting the system when the insulative 
coating is breached. 
The Hardened Surfaces 
The oxygen or nitrogen diffusion hardened surface of the alloy implants may 
be highly polished to a mirror finish to further improve blood flow 
characteristics. Further, the oxide- or nitride-coated surfaces maybe 
coated with substances that enhance biocompatibility and performance. For 
example, a coating of phosphatidyl choline, heparin, or other proteins to 
reduce platelet adhesion to the surfaces of the implant, or the use of 
antibiotic coatings to minimize the potential for infection. Boronated or 
silver-doped hardened surface layers on the implant reduces friction and 
wear between contacting parts of the invention cardiovascular implants. 
Additionally, amorphous diamond-like carbon, pyrolytic carbon, or other 
hard ceramic surface layers can also be coated onto the diffusion hardened 
surface to optimize other friction and wear aspects. The preferred 
diffusion hardened surface layer described in this application provides a 
hard, well-attached layer to which these additional hard coatings can be 
applied with a closer match between substrate and coating with respect to 
hardness. Other, conventional methods of oxygen surface hardening are also 
useful. Nitriding of the substrate leads to a hardened nitride surface 
layer. Methods of nitridation known in the art may be used to achieve a 
hard nitride layer. 
Regardless of how a Ti-Nb-Zr alloy implant's surface is hardened, the 
friction and wear (tribological) aspects of the surface can be further 
improved by employing the use of silver doping or boronation techniques. 
Ion-beam-assisted deposition of silver films onto ceramic surfaces can 
improve tribiological behavior. The deposition of up to about 3 microns 
thick silver films can be performed at room temperature in a vacuum 
chamber equipped with an electron-beam hard silver evaporation source. A 
mixture of argon and oxygen gas is fed through the ion source to create an 
ion flux. One set of acceptable silver deposition parameters consists of 
an acceleration voltage of 1 kev with an ion current density of 25 
microamps per cm.sup.2. The silver film can be completely deposited by 
this ion bombardment or formed partially via bombardment while the 
remaining thickness is achieved by vacuum evaporation. Ion bombardment 
improves the attachment of the silver film to the Ti-Nb-Zr alloy 
substrate. Similar deposition of silver films on existing metal 
cardiovascular implants may also be performed to improve tribological 
behavior, as well as antibacterial response. 
An alternate method to further improve the tribological behavior of 
Ti-Nb-Zr alloy surfaces of cardiovascular implants is to apply boronation 
treatments to these surfaces such as commercial available boride vapor 
deposition, boron ion implantation or sputter deposition using standard 
ion implantation and evaporation methods, or form a boron-type coating 
spontaneously in air. Boric Acid (H.sub.3 BO.sub.3) surface films provide 
a self-replenishing solid lubricant which can further reduce the friction 
and wear of the ceramic substrate. These films form from the reaction of 
the B.sub.2 O.sub.3 surface (deposited by various conventional methods) on 
the metal surface with water in the body to form lubricous boric acid. 
Conventional methods that can be used to deposit either a boron (B), 
H.sub.3 BO.sub.3, or B.sub.2 O.sub.3 surface layer on the cardiovascular 
implant surface include vacuum evaporation with or without ion 
bombardment) or simple oven curing of a thin layer over the implant 
surface. The self-lubricating mechanism of H.sub.3 BO.sub.3 is governed by 
its unique layered, triclinic crystal structure which allows sheets of 
atoms to easily slide over each other during articulation, thus minimizing 
substrate wear and friction. 
Additionally, surfaces (metal or coated) of all the cardiovascular and 
medical implants discussed may optionally be coated with agents to further 
improve biological response. These agents include anticoagulants, 
proteins, antimicrobial agents, antibiotics, and the like medicaments. 
Although the invention has been described with reference to its preferred 
embodiments, those of ordinary skill in the art may, upon reading this 
disclosure, appreciate changes and modifications which may be made and 
which do not depart from the scope and spirit of the invention as 
described above and claimed below.