Medical device having a biocompatible coating and oxidation method of coupling therefor

A medical device for implantation in the tissue of a human body having a biocompatible coating thereon including a foreign body formed of a material which is substantially biocompatible with the tissue of the human body. The foreign body has a surface adapted to come in contact with the tissue of the human body and is capable of being oxidized. An organic linker is carried on the surface and forms an oxidative coupling with the surface. A bioactive agent is bonded to the organic linker by a chemical reaction or photochemical function.

This invention relates to a medical device having a biocompatible coating 
and oxidation method of coupling therefor and particularly for medical 
devices made of metal and plastic. 
Heretofore it has been found difficult to bind a bioactive molecule such as 
a peptide or a protein directly to the metal forming the medical device. 
One approach is to use a coating or a primer which when activated 
facilitates attachment of the bioactive molecule. Such primers have 
typically been in the form of polyurethane coatings or poly lactic acid or 
polyimide coatings. Such approaches have not been particularly 
satisfactory for several reasons. Bonding between the metal and the primer 
is not very strong and therefore there is a tendency for the bioactive 
agent to flake off. The primer itself is formed of a material which may be 
less biocompatible than the metal device which has been implanted. There 
is therefore need for a medical device having a biocompatible coating 
which overcomes these problems and a method for accomplishing the same. 
In general, it is an object of the present invention to provide a medical 
device having a biocompatible coating thereon and an oxidation method of 
coupling therefor. 
Another object of the invention is to provide a medical device and method 
of the above character in which the linker or base for the biocompatible 
coating is biocompatible. 
Another object of the invention is to provide a device and method of the 
above character which utilizes the oxidation characteristics of the metal 
used in the medical device to covalently attach an organic linker to form 
an organic coupler. 
Another object of the invention is to provide a device and method of the 
above character in which the organic coupler is utilized for attaching the 
bioactive molecule in the form of a peptide or a protein. 
Another object of the invention is to provide a device and method of the 
above character in which the biocompatible coating can be rapidly and 
inexpensively applied. 
Another object of the invention is to provide a medical device and method 
of the above character including implants formed of metal and of plastic.

In general, the medical device is for implantation in tissue of the human 
body and has a biocompatible coating thereon comprised of a foreign body 
formed of a material which is substantially biocompatible with the tissue 
of the human body. The foreign body has a surface adapted to come into 
contact with the tissue of the human body. The surface of the foreign body 
is capable of being oxidized. An organic coupling agent is carried on the 
surface and forms an oxidative coupling with the surface. The coupling 
agent also carries a reactive group. A bioactive agent is bonded to the 
organic coupling agent by a chemical reaction. 
In general, the method is for coupling a bioactive agent to a medical 
device implantable as a foreign body in the tissue of the human body. The 
medical device is formed of a material which is substantially 
biocompatible with the tissue of the human body and has an oxidizable 
surface coming into contact with the tissue of the human body. The method 
comprises the steps of removing any oxide present on the surface of the 
foreign body. Air or oxygen is then prevented from coming into contact 
with the surface of the body. An organic coupling agent is placed in 
contact with the surface to form an oxidative coupling with the surface of 
the foreign body. A bioactive agent is attached to the surface of the 
foreign body by reaction with the organic coupling agent. 
More in particular, an example of a medical device incorporating the 
present invention as shown in FIGS. 1 and 2 and as shown therein is in the 
form of a dental post 11 which is provided with a cylindrical base 12 and 
a centrally disposed upstanding post 13. The dental post 11 is formed of a 
suitable biocompatible material such as titanium. The base 12 can have a 
suitable size as for example a diameter of 1 to 2 millimeters and a height 
of 2 to 3 millimeters whereas the post 13 can have a diameter ranging from 
0.5 to 1 millimeter and a height ranging from 5 to 10 millimeters. The 
dental post thus far described is conventional and is utilized for 
implantation in the human jaw. Typically, the tooth is drilled to receive 
the cylindrical base 12 with the dental post 11 being utilized for 
supporting a false tooth which has been removed from the patient's mouth. 
In accordance with the present invention, it is desirable to coat the 
cylindrical base 12 with a biocompatible coating so as to promote bone 
tissue growth onto the cylindrical base 12 to thereby firmly secure the 
cylindrical base within the jaw of the patient. The cylindrical base 12 is 
provided with a cylindrical surface 16 which has sintered titanium 
microspheres or globules adhered to the surface in a conventional 
commercial process. The microspheres can have a suitable diameter as for 
example 1/2 of a millimeter and less. Described in another way, they can 
have a size of approximately one half the size of a conventional pin head. 
These microspheres 17 have been coated with a biocompatible coating in 
accordance with the present invention as described in connection with the 
step or flow diagram as shown in FIG. 5. 
The medical device 11 can be considered as being a foreign body which is to 
be implanted into the tissue of the human body. This foreign body has a 
surface which is adapted to come in contact with the tissue of the human 
body. The material which forms the foreign body is one which has been 
selected in accordance with the present invention which is capable of 
being oxidized. They are made of suitable materials such as metal and 
plastic. Metals of particular interest are stainless steel, titanium and 
titanium alloys and particularly nickel titanium alloys. These materials 
have been selected because they are biocompatible with the tissue of the 
human body. The devices have surfaces which are adopted to come in contact 
with the tissue of the human body and with which it is desired to promote 
tissue growth. The surfaces of such materials are also characterized as 
being capable of being oxidized. 
In accordance with the present invention, the medical device 11 which is to 
be treated in accordance with the present invention has any existing oxide 
thereon removed as shown by step 21. This oxide removal can be 
accomplished in a conventional manner such as by removing the same in an 
etching solution. One etching solution found particularly suitable for 
etching of titanium and titanium alloys is a mixture of 4% hydrofluoric 
acid, 30% nitric acid and 15% sulfuric acid with the balance being water. 
The medical devices are placed in the etching solution for a period of 1 to 
5 minutes utilizing ultrasound agitation. After this oxide removal step 
has been completed, the medical devices or parts are removed from the 
etching solution and rinsed with deionized water three successive times 
without exposing the medical devices or parts to air or oxygen to thereby 
prevent the formation of a new oxide on the surfaces of the parts. 
Although the etching solution selected may be varied, the particular 
etching solution identified above has been found to be efficacious to 
remove the oxide without creating pits in the metal. 
After the parts have been washed with deionized water, the parts are 
introduced into a blanket of an inert atmosphere such as nitrogen gas in a 
hooded bench and are transferred into a saturated cystine solution. One 
solution found to be satisfactory is one comprising of 50% acetic acid and 
water with some undissolved cystine. The parts are left in the solution 
for a period of 8 to 12 hours at room temperature for shorter periods of 
time as for example 1/2 hour to 2 hours at elevated temperatures as for 
example at 60.degree. C. The cystine solution which is an organic coupling 
agent or linker is placed in contact with the surface of the parts or in 
the case of the dental post in contact with the microspheres 17 carried by 
the cylindrical surface 16 to form an oxidative coupling with the surface 
as for example the surface of the metal microspheres. The oxidative 
reaction forms a very thin layer as for example a monolayer having a 
thickness of approximately 20A. In FIG. 2, this layer is represented as an 
exaggerated layer 26 which covers the microspheres 17. The oxidative 
coupling which occurs using the organic linker cystine occurs because the 
cystine has a disulfide bond and the sulfur acts as an oxidizing agent. At 
the same time it oxidizes, it binds itself to the metal which in the case 
of titanium creates a titanium-sulfur covalent bond. 
It should be appreciated that other organic linkers can be utilized in 
connection with the present invention for oxidizing metals and also for 
oxidizing polymers as hereinafter described. These oxidizers include 
organic peroxides, organic sulfoxide, sulfones and sulfonic acids. By 
placing the oxide-free surface of the medical device or part in contact 
with the organic linker, there is formed an oxidative coupling as shown by 
step 28 in FIG. 5. 
After the oxidative coupling has been formed, the parts can be removed from 
the cystine solution and rinsed with deionized water. There is no longer 
need to keep the parts out of contact with air or oxygen because the 
oxidative reaction has already occurred during the formation of the 
oxidative coupling 28 represented by the layer 26 in FIG. 2. 
Next a bioactive agent or growth promoter is attached as shown by step 31 
in FIG. 5. This is accomplished by utilizing an organic coupling agent. 
For example, one commonly available is EDC which is 
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl. The purpose of this 
coupling agent is to cause the bioactive agent to become attached to the 
surface of the foreign body by a reaction with the organic linker. The 
reaction can be any one of a number of types as for example a condensation 
reaction, oxidative reaction, an exchange reaction and a substitution 
reaction. In other words, the bond is one which is formed by a reactive 
function. Thus a variety of organic reactions can be used, resulting for 
example in an ester, ether or a carbon-carbon bond. When an unsaturated 
double bond is present, a polymerization reaction may be used. 
In step 31 in which the bioactive agent is attached, it is desirable to 
place in this solution a small amount of a peptide which is a polymeric 
material but of a smaller chain length than proteins. For example, a 
15-amino acid along cell binding peptide can be utilized of the type 
disclosed in U.S. Pat. No. 5,354,736. In step 31 shown in FIG. 5, it is 
desirable that the reactive function and the peptide react together to 
form an amide bond. Thus, there can be provided an amino terminal bound 
bioactive agent or a carboxyl terminal bound bioactive agent. 
It should be appreciated that if desired, materials other than growth 
promoters can be adhered to surface in the manner hereinbefore described. 
For example Heparin, although not a growth promoter, can be adhered to the 
metal in a similar method. This attachment of a bioactive agent 
implemented by step 31 is represented by the layer 32 as shown in FIG. 2. 
Step 31 can be carried out at room temperature at a period of time ranging 
from 4 to 8 hours and preferably about 6 hours. In an elevated temperature 
as for example, 60.degree. C., the same reaction can be accomplished in 
approximately 2 to 3 hours. 
In FIGS. 3 and 4 there are shown photographs taken with an electron 
microscope of the medical device in the form of the dental post 11 which 
has been treated in accordance with the present invention. In FIG. 3 there 
has been a spot magnification of 14 times and in FIG. 4 a spot 
magnification of 49 times. The dental post after being subjected to the 
method hereinbefore described was placed in a tissue culture having 
therein grown human osteoblast cells. The growth promoter used had a 
peptide identified as P15 produced in accordance with the teaching of U.S. 
Pat. No. 5,354,736. In a period of three days it was found that with the 
biocompatible coating applied in accordance with the present invention, 
the cells from the tissue culture grew onto the surfaces of the 
microspheres 17 substantially as if they were in normal surroundings. Thus 
the cells did proliferate all over the coated surface indicating the 
efficacy of the biocompatible coating of the present invention. This was 
compared to a similar uncoated medical device placed in similar tissue 
culture in which very few cells from the human osteoblast cells adhered to 
the surface and none adhered where they were not in actual contact with 
the cells. 
Another medical device having a biocompatible coating thereon incorporating 
the present invention is shown in FIG. 6 in the form of an expandable 
deformable stent 36 in which the stent is formed by elongated elements 37 
formed of a suitable biocompatible material such as titanium, nickel 
titanium alloys and like as hereinbefore described which have diamond 
shaped openings 38 between the same through which tissue can grow. It has 
been found desirable to coat these elements 37 with a biocompatible 
coating in accordance with the present invention. As shown in FIG. 7, a 
cross-sectional view of one of the elements 37 has an outer surface 41, an 
inner surface 42 and end surfaces 43 and 44, all of which are coated with 
a biocompatible coating 45 of the present invention. Thus there has been 
provided an organic linker represented by a layer 46 which forms an 
oxidative coupling with the surfaces 41, 42, 43 and 44. A bioactive agent 
is bonded to the organic linker by a reaction function in the manner 
hereinbefore described and is represented by the layer 47. Thus it can be 
seen in connection with the present invention that all of the exposed 
surfaces of the stent 36 are covered with the biocompatible coating of the 
present invention to greatly promote the growth of endothelial cells on 
the same after the stent has been implanted in a vessel of the human body 
to maintain the patency of a vessel in the patient, as for example in an 
angioplasty procedure. 
Another embodiment of the invention is shown in FIG. 8 in which the medical 
device 51 is in the form of a breast implant. Typically such breast 
implants have a flexible plastic envelope 52 formed of a suitable material 
such as a polyurethane or a polyester. The interior of the envelope is 
filled with a suitable liquid 53 such as silicon or a variety of vegetable 
oils such as soy bean oil. The envelope 52 has an exterior surface 56 
which is adapted to be placed in engagement with the tissue of the human 
body. This exterior surface 56 is treated in the same manner as the 
exterior surfaces of the metal medical devices hereinbefore described. 
The breast implant is dipped in a suitable oxidizing agent such as an 
organic peroxide for a suitable period of time ranging from a few minutes 
to an hour depending upon the nature of the plastic and the reagent 
utilized. Thereafter, the breast implant can be removed from the oxidizing 
agent and washed with deionized water after which it is placed in a 
solution of the desired growth promoter along with other reagents to 
enhance the rate of reaction. Thus, the coupling agent and the growth 
promoter are placed in the same solution so that they can coact in the 
solution over a suitable period of time as for example 5 to 6 hours at 
room temperature. At elevated temperatures the reaction takes place within 
a few minutes to within an hour. Thereafter, the breast implant can be 
removed from the solution, washed in deionized water, dried and packaged 
for shipment for later use. 
In connection with the present invention, it can be seen that there has 
been provided a biocompatible coating on medical devices including plastic 
and metal devices which although foreign objects in the human body are 
disguised from the human autoimmune system and leading the autoimmune 
system of the human body to believe that the device is not a foreign body 
and thus will encourage cell growth on the same by providing a foundation 
for such cell growth. The medical devices on which the present invention 
would be useful include the following: cardiovascular devices, including 
implantable defibrillators, implantable defibrillator leads, pacemakers 
and pacemaker leads, artificial heart valves, LVAD's, stents, stent 
grafts, soft tissue implant devices including implantable pumps, 
implantable leads, cochlear implants, implants for reconstructive surgery, 
urinary incontinence devices, penile and breast implants, and surgical 
aids including sutures, vascular occlusion devices and surgical supplies.