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|United States Patent Application
BJURSTEN; LARS M.
;   et al.
September 15, 2011
MATERIALS FOR IMPLANTATION
The present invention includes a method for sensing glucose in a mammal,
which includes implanting an a sensor having a permeable membrane and a
plurality of spaced apart patches of titanium dioxide disposed on the
permeable membrane and sensing glucose in the mammal.
BJURSTEN; LARS M.; (Limhamn, SE)
; Frangos; John A.; (La Jolla, CA)
May 20, 2011|
|Current U.S. Class:
|Class at Publication:
||A61B 5/00 20060101 A61B005/00|
Foreign Application Data
|Jan 31, 2002||SE||0200269-9|
1. A method for sensing glucose comprising the steps of: providing an
implant comprising: a sensor having a permeable membrane; and a plurality
of spaced apart patches of titanium dioxide disposed on the permeable
membrane, each patch having a distance of separation from its nearest
adjacent patch, the distance of separation being from about 10 nm to
about 10 .mu.m, wherein the permeable membrane allows the exchange of a
molecule to be monitored by the sensor; implanting the implant in a
mammal; and sensing glucose in the mammal.
2. The method of claim 1, wherein the spaced apart patches have a
thickness of less than about 1 .mu.m.
3. The method of claim 1, wherein the spaced apart patches have a
thickness of from about 1 nm to about 100 .mu.m.
4. The method of claim 1, wherein the spaced apart patches are
distributed on the permeable membrane.
 This is a divisional of U.S. application Ser. No. 12/475,224, filed
May 29, 2009, which is a continuation of U.S. application Ser. No.
10/503,405, filed Jul. 30, 2004, now issued as U.S. Pat. No. 7,547,471,
which is a national stage application of international application no.
PCT/SE03/00163, filed Jan. 31, 2003, which in turn claims priority to
Swedish Application No. 0200269-9, filed Jan. 31, 2002. All of the above
applications are expressly incorporated herein by reference in their
FIELD OF THE INVENTION
 The present invention relates to a material for implantation, a
method of manufacturing a material for implantation and use of a material
BACKGROUND OF THE INVENTION
 Tissue reaction after implantation of a foreign material or device
in the body follows a general pattern, independent of the material used.
The initial inflammatory response to an implant consists of acute
vasculature changes induced by surgical trauma. Neutrophils migrate to
the wound site after this trauma. Migration of monocytes follows. These
monocytes then differentiate into macrophages. The macrophage can be
viewed as a control cell in the inflammatory response, playing a central
role in the interaction of inflammatory mediators.
 Titanium is a biomaterial that exhibits good biocompatibility and
minimal inflammatory response following implantation. Early studies
observed that titanium bone implants in animals were well accepted when
compared to other metals. Other studies have shown that titanium evokes
less tissue reaction in rabbit muscle as compared to other metals.
Clinical trials performed in 1965 indicated a 90% success rate for
titanium dental implants (Albrektsson, Branemark et al. 1983). Titanium
is used extensively in restorative surgery, particularly as a
bone-anchoring and joint-replacement material. Further, there is
experimental evidence that titanium as an implant material is less
susceptible to infections than stainless steel (Johansson et al., 1999).
 Given the normal initial tissue response to titanium, it would be
expected that titanium implants would produce a typical inflammatory
response. Macrophages near titanium implants, however, do not appear
activated and leukocytes associated with titanium implants are less
responsive. Although titanium is widely used as an implant material, the
mechanisms of its superior biocompatibility are currently unknown.
 One explanation is that the surface of titanium implants down
regulate the inflammatory response (whose initiation is inevitable) by
preventing its prolongation, thereby reducing the overall tissue response
and allowing healing to proceed. Titanium readily forms a stable surface
layer of oxide upon exposure to air, predominantly consisting of titanium
dioxide, TiO.sub.2. This oxide layer of titanium is the surface
encountered by inflammatory cells after insertion of the implant. It has
been proposed that the oxide layer plays a fundamental role in tissue
response (Albrektsson, Branemark et al. 1983) and the oxide layer has
been regarded as important because of its corrosion resistance
 Polymer and glass surfaces have been coated with titanium. The
reasons for these procedures are to achieve methodological advantages
when evaluating the responses of biomolecules, cells and tissues to
titanium. By coating a glass surface with metallic titanium an extremely
flat surface suitable for spectroscopy may be obtained. By coating a
polymeric material like epoxy resin or polycarbonate you allow for
sectioning of the coated implant material in situ together with the
adjacent tissue as the solid metal is only sectional through expensive
and time consuming grinding techniques that also restrict the subsequent
 Devices have also been coated with metallic titanium to benefit
from the perceived but not defined good biocompatibility of titanium. An
example of many such applications is described in PCT/SE93/00924.
 Current manufacturing technology can provide a wide range of
materials with various physical properties but most cannot be utilized as
biomaterials because of issues of biocompatibility. The response of cells
of foreign materials placed within the body can lead to inflammation and
rejection unless the implanted device is made of a relatively small
number of materials which include titanium and Ti-6Al-4V alloy. This
small selection of biocompatible materials limits the design and
development of devices which can be implanted in the body.
 Since titanium is a metal it does not have the wide variation of
physical characteristics which polymers can achieve. Yield strength,
elastic modulus and elongation are some of the factors which can be
varied more easily in polymeric materials compared to metallic materials.
 Also, titanium is not suitable in biosensors. They have to be
constructed with other materials than titanium to achieve their function.
Many such sensors must have semi permeable membranes to allow the
exchange of molecules to be monitored.
SUMMARY OF THE INVENTION
 The object of the present invention is to give materials for
implantation the superior catalytic properties of titanium, without
having to rely on the inherent limitations of titanium.
 In one aspect of the invention this object is full filled by a
material for implantation, characterized in that the surface of the
material partially comprises at least one area of an inorganic, catalytic
substance for improved biocompatibility of the material.
 Thus, the present invention will allow a wider range of choices
when selecting biomaterials and permit medical engineers to choose the
precise material best suited for the needs of a particular implant. The
use of the present invention will also improve the biocompatibility of
medical devices already in use. One important object is to obtain the
right pattern with respect to the distribution of catalytic areas over
the surface, i e the spacing between adjacent catalytic areas.
 In one embodiment of the material for implantation according to the
invention, the distance between the areas of inorganic, catalytic
substance is from 10 nm to 10 .mu.m.
 In another embodiment of the material for implantation according to
the invention, the surface of the material is partially covered by a
layer of the inorganic, catalytic substance patterned into an array of
areas and in yet another embodiment the layer has a thickness of from 1
nm to 100 .mu.m, preferably from 10 to 100 nm.
 The entire surface cannot in many instances be coated with the
catalytic thin film, for example, permeable membranes in implantable
glucose sensors. The membrane needs to remain permeable to perform its
sensing function and coating the entire surface is not an option. Coating
the surface with a catalytic thin film patterned into an array of areas
will resolve this problem.
 In another embodiment of the material for implantation according to
the invention, the inorganic, catalytic substance is comprised throughout
the material as particles, forming the at least one area of inorganic,
catalytic substance on the surface and in yet another embodiment the
particles have a size in the range from 1 to 500 nm, preferably from 10
to 100 nm.
 The invention relates the use of nano particle that are embedded
into the implant in order to form the areas of inorganic, catalytic
substance for improved biocompatibility of the material. The nano
particles are made of catalytic material. The amount of particles added
to the bulk material should be such that the average spacing between
exposed particle falls into the ranges describe above for micro patterned
surface coatings. The particles are mixed with the bulk material to be
exposed on the surface of the implant. As the implant surface wear down
the newly formed surface will present randomly arranged nano particle in
the bulk material, throughout the life time of the implant.
 In one embodiment of the material for implantation according to the
invention, the inorganic, catalytic substance is chosen from the group
comprising titanium dioxide, zirconium dioxide, palladium, gold, and
 In another embodiment of the material for implantation according to
the invention, the inorganic, catalytic substance is the crystalline
phase of titanium dioxide or zirconium dioxide.
 In yet another embodiment of the material for implantation
according to the invention, the at least one area of inorganic, catalytic
substance comprised in the surface of the material for implantation is
obtainable by a layer of titanium or zirconium patterned into an array of
 In still another embodiment of the material for implantation
according to the invention, said material comprises a base material,
which is chosen from the group comprising polymers, metals and ceramics
and in yet another embodiment the base material is chosen from the group
comprising polyurethane, polyethylene and silicone elastomer.
 In one embodiment of the invention the material for implantation
according to the invention, said material is a medical sensor, a drug
delivery system, an orthopedic and reconstructive implant or an
 In a second aspect of the present invention the object is fulfilled
by a method of manufacturing a material for implantation according to the
invention, characterized in that the inorganic, catalytic substance is
added by chemical or physical deposition techniques.
 In one embodiment of the method according to the invention the
deposition techniques are sol-gel, metallorganic chemical vapour
deposition, d c magnetron sputtering or radio frequency sputtering.
 In a third aspect of the present invention the object of the
invention is fulfilled by use of a material for implantation as a medical
sensor, a drug delivery system, an orthopedic and reconstructive implant
or an articulating surface.
DESCRIPTION OF THE DRAWINGS
 FIG. 1. Chemiluminescent signal from the reaction of MCLA with
superoxide produced by J774.1A murine macrophages after stimulation by
phorbol myristate acetate. A) Macrophages cultured on quartz petri dishes
with different crystalline forms of titanium dioxide. B) Macrophages
cultured on thermoset silicone polymer substrates with and without
amorphous titanium oxide coatings. Error bars given as SEM.
 FIG. 2. Correlation between protein nitrosylation and synovial
capsule thickness with implanted discs of 316L stainless steel in the
suprapatellar pouch of arthritic Lewis rats. Implants were maintained for
 FIG. 3. Comparison of the tissue response as indicated by
anti-nitrotyrosine staining and ED-1 positive cells to silicone elastomer
versus titanium dioxide coated elastomer. Densities for nitrotyrosine
positive cells as well as ED1 positive macrophages.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
 It has been known for decades that TiO.sub.2 can act as a catalyst
in reactions involving reactive oxygen species. Crystalline TiO.sub.2
powder has been examined as a photocatalyst for the purification of
water. Hydroxyl radicals that initiate oxidation of hydrocarbons to
carbon dioxide, water and water-soluble organics are involved in these
reactions. These findings indicate that titanium oxide can act as a
catalyst in reactions involving free radical species.
 Macrophages produce both superoxide and nitric oxide when
stimulated. Polymorphonuclear leukocytes produce superoxide after
stimulation. Superoxide undergoes a rapid reaction with superoxide
dismutase to form hydrogen peroxide. Superoxide dismutase has a critical
role in regulating reactive oxygen species concentrations. This
regulatory process appears to be compromised, however, in tissues
surrounding polyester implants (Glowinski, Farbiszewski et al. 1997).
This is likely due to inactivation of the enzyme by the oxidative
environment generated by the inflammatory response, thus compounding the
deleterious accumulation of oxidant species in the vicinity of the
 In addition to superoxide, another reactive species, peroxynitrite,
is a mediator in the inflammatory response. Peroxynitrite is formed by
the reaction of superoxide with nitric oxide at near-diffusion limited
rates which are several times faster than the reaction of superoxide with
superoxide dismutase. Macrophages and cells from inflammatory exudates
are suspected to produce peroxynitrite in vivo.
 Peroxynitrite is a very reactive oxidant thought to play a role in
inflammation. Peroxynitrite directly induces colonic inflammation in rats
and has been demonstrated to be present in the inflamed guinea pig ileum.
Peroxynitrite was found to be produced by acute inflammation from edema
induced in hind paws of rats. This edema was inhibited by selective
superoxide and nitric oxide inhibitors. Peroxynitrite has also been
implicated in experimental autoimmune encephalomyelitis in mice. Proteins
with tyrosine residues nitrosylated by peroxynitrite dramatically induced
granulomas when injected into rabbits (personal communication, Dr. Harry
 Clinical studies also provide evidence that peroxynitrite is
produced during inflammation. The blood serum and synovial fluid from
patients with the inflammatory joint disease rheumatoid arthritis were
found to contain 3-nitrotyrosine markers indicating peroxynitrite
formation, while body fluids from normal patients contained no detectable
3-nitrotyrosine. Similarly, no 3-nitrotyrosine markers were detected in
body fluids from patients with osteoarthritis, a largely non-inflammatory
joint disease. Importantly, it has been reported that 3-nitrotyrosine
markers for peroxynitrite were also observed at the interface membrane of
hip implants suffering from aseptic loosening, which is characterized by
local inflammation (Hukkanen, Corbett et al. 1997; Hukkanen, Corbett et
 Furthermore, synthetic decomposition catalysts specific for
peroxynitrite are being explored as a method of inhibiting damage induced
by this potent reactive species (Misko, Highkin et al., 1998).
Metalloporphyrin catalysts capable of breaking down peroxynitrite have
been shown to have protective effects in animal models involving
inflammatory states ranging from splanchinic artery occlusion and
reperfusion, experimental autoimmune encephalomyelitis, endotoxin induced
intestinal damage, and carrageenan-induced paw-edema. (Salvemini, Riley
et al. 1999; Cuzzocrea, Misko et al. 2000). These results clearly
indicate the potential therapeutic benefits of reducing cellular damage
at site of the inflammatory response after implantation through catalytic
breakdown of peroxynitrite.
 Polyethylene implants coated with superoxide dismutase mimics have
showed a notable decrease in the adverse foreign body response when
measuring its thickness compared to uncoated controls (Udipi, Ornberg et
al. 2000). This is consistent with the reported direct link between
superoxide to the production of proinflammatory mediators, including
cytokines, through two transcriptional activators, NF-.kappa.B and AP-1.
These results indicate that species such as superoxide, a precursor of
peroxynitrite, also plays a role in the inflammatory response to
 Results of studies show that titanium is capable of enhancing the
breakdown and inhibiting the reactivity of peroxynitrite (Suzuki and
Frangos 2000). Titanium oxide was also shown to inhibit the nitration
reactions of peroxynitrite at physiological pH levels compared to
polyethylene. Titanium surfaces retained the ability to inhibit
peroxynitrite while in the presence of 10% fetal bovine serum, fibrinogen
 It has also been shown that zirconium also possesses the ability to
inhibit peroxynitrite as well (Suzuki and Frangos 2000). Zirconium falls
directly below titanium in the periodic table, thus both elements share
similar chemical properties since both have the same outer electron
configuration and form a stable 4.sup.+ ion. It was also found that
palladium can inhibit the reactivity of peroxynitrite at physiological pH
levels. Palladium, like titanium dioxide, has been used as an industrial
catalyst for decades indicating that the catalytic properties of these
materials may be responsible for their ability to inhibit peroxynitrite.
Gold and platinum are also well known catalysts for many applications and
have been shown to facilitate the decay of reactive oxygen species like
peroxynitrite and superoxide.
 The present invention is based on the hypothesis that the oxide
surface layer of titanium implants plays a critical role as an inorganic
catalyst which neutralizes reactive inflammatory mediators thus
inhibiting the ability of these mediators to induce an inflammatory
response. A biomaterial which could be given an inorganic catalytic
surface layer similar to titanium could thus be imparted with the
superior biocompatible properties of titanium. The patent is primarily
based on the fact that the surface does not need to be completely covered
with the catalytic compound to achieve the beneficial effects of the
 Surface treatments of biomaterials to enhance biocompatibility have
been mostly directed toward modification of the chemical functional
groups on the surface of addition of biomolecules to the surface. These
functional groups of biomolecules are added in an attempt to modify blood
compatibility, cell adhesion and protein adsorption. There are numerous
methods used to modify materials in this manner. Among them are chemical
surface reactions, surface layers grafted on by radiation of
photografting, plasma deposition of chemical functional groups,
self-assembling films, and surface-modifying components added during
fabrication. These result in surfaces covered with alkyl, hydroxyl,
phenol, fluoroalkyl or chemical functional groups. The underlying reasons
for the biocompatibility of certain material have remained unanswered
largely due to the emphasis on functional group modification as a way of
 Surface treatments that do not involve modification or addition of
surface functional groups are limited. Ion beam implantation is used to
modify a metal's hardness or corrosion resistance. Passivation is another
method used to increase corrosion resistance by increasing the thickness
of the metal oxide layer. Application of an inorganic catalytic layer to
metallic or non-metallic materials has not yet been attempted.
 The invention provides material for implantation, which comprises
metallic and non-metallic base materials, which partially comprises an
inorganic catalytic substance in the surface, which substance will serve
as an inorganic catalyst to breakdown reactive inflammatory species.
Titanium oxide films can be deposited onto various substrates, such as
silicone elastomers. The titanium oxide films can also be applied to
other polymers, metals and ceramics and can thus be used to coat
non-biocompatible material with catalytic surface areas. Inorganic
catalytic coatings of other materials can also be applied. Published
experiments regarding zirconium and palladium (Suzuki and Frangos 2000),
also lead to the suggestion that their oxides may also serve as potential
inorganic catalysts for reactive inflammatory species.
 Several methods to fabricate these coatings can be applied. Thin
film oxide coatings are from 1 nm to 100 .mu.m, typically <1 .mu.m, in
thickness and can be produced by chemical or physical vapor deposition
techniques. The deposited films are directly after deposition mostly
amorphous and can be crystallized under post-deposition thermal
annealing. Physical vapor deposition techniques, such as radio frequency
(r. f.) and d. c. magnetron sputtering are limited to the use of flat
substrates. In r. f. sputtering, the material to be deposited is
originally from a disk of the selected material (the target). The target
is bombarded by Ar plasma to transfer material from the target to the
substrate. This method results in uniform, flat stoichiometric films with
controllable thickness. R. F. sputtering can be carried out at
temperatures low enough to allow the films to be applied to polymers.
 By varying the oxygen partial pressure during deposition, different
oxidation states of TiO.sub.2-x will be deposited ranging from x=0-1.5.
The oxides deposited will be amorphous for low substrate temperatures and
crystalline for higher (>250.degree. C.) substrate temperatures.
Depending on the choice of the substrate, different crystallographic
orientations can be induced in the films. For examples, glass substrates
produce polycrystalline films while single crystal sapphire (oriented in
the (001) direction, a=0.4759 nm) substrates produce oriented rutile
films. By varying the thicknesses (2-200 nm) the final grain size can be
controlled. Longer deposition result in larger grain sizes due to the
prolonged exposure to high temperatures. By using such crystalline
coatings we have found that the catalytic properties of the titanium
oxide can be drastically improved compared to the amorphous phase. Such
crystalline phases should be considered whenever possible.
 Alternatively, chemical techniques involve a reaction between
precursor compounds, such as in sol gel techniques or metallorganic
chemical vapor deposition (MOCVD). Sol gel typically refers to the
hydrolysis reaction of a metal alkoxide. The reaction sequence is
complicated, but can be generally expressed by the below reaction, for a
metal (z+ valence) isopropoxide and water:
 A substrate or shaped piece can be dipped into the alkoxide
solution and then allowed to hydrolyze in a moist atmosphere. The coating
thickness can be controlled by the number of times the piece is dipped
into the solution, as well as the temperature and concentration. In
MOCVD, the precursors are long chain organic molecules with a metal ion
attached. An example are the metal
tris(2,2,6,6,-tetramethyl-3,5-heptanedionates). The precursors are heated
and the sublimated vapor is carried by argon gas to the reactor where the
metallorganic vapor species deposits on a heated substrate and decomposes
with oxygen introduced into the chamber to form an oxide film. The
substrate need not be flat, but can be a shaped piece that is suspended
in the reactor. The temperature of the precursors, the flow rate of the
carrier gases and the deposition time control the film thickness.
 The deposition techniques mentioned, but not limiting, have been
selected to not only complement each other, but to examine the best
deposition method for coating oxides on various industrially relevant
polymers. The techniques are widely used by industry for metal,
semiconductor and ceramic coatings. For some applications, curved
surfaces may need to be coated. However, it is to be ascertained which
technique, MOCVD or sol gel, would produce the most adherent coating on a
curved surface. This is an example of how the techniques complement each
 Silicone is a family of synthetic polymers derived from the
reaction of elemental silicon with methyl chloride to form dimethyl
cholorsilane. Hydrolysis with water generates a silicon backbone polymer
chain. Polydimethylsiloxane is the most widely used form of silicone
polymer and has been used both in silicone gels and as silicone elastomer
 Due to the physical properties and ease of manufacturing of
silicone elastomers, this polymer has served as a biomaterial for
numerous medical devices including coverings for cardiac pacemaker leads,
renal dialysis tubing, uterine rings, contact lenses, artificial heart
valves, finger joint prostheses, and testicular and breast implants.
 Silicone is therefore a good candidate as a base material to
receive an inorganic catalytic surface coating to improve its
biocompatibility and minimize the inflammatory response resulting from
this material's implantation.
 These coating methods can be applied to nearly any material to
allow previously non-biocompatible materials to be accepted by the body.
This opens and enormous range of base materials which can be used for
implanted devices and greatly enhances the choices available in terms of
physical properties. This coating method can be applied to any kind of
material for implantation placed in the body including medical sensors,
drug delivery systems, orthopedic and reconstructive implants.
 We have surprisingly found that a surface modification does not
need full coverage of the surface of an implanted biomaterial to serve
the intended purpose. Instead significant biological effects may be
obtained with only partial but well dispersed patches of such coatings.
The distance between these patches should be in the same order of
magnitude as a cell or smaller. This means that the distance between two
adjacent patches should be less than 10 .mu.m. The lower limit is set by
fabrication considerations and how much non-covered area is needed to
achieve the function of the base material or surface.
 An example of such an application is an implantable sensor. The
patches of the catalytic material, as described in this application,
serve to reduce the adverse biological effects of the implanted device
while the uncovered areas will provide the sensing surface of the sensor.
The lower limits of the distance between two adjacent patches are set by
the function of the sensor in this example while manufacturing
considerations may be the limiting factor in other applications. In
general the distance between two adjacent patches should preferably be
larger than 10 nm.
 For surfaces that are susceptible to wear another approach to
create the catalytic properties of the surface of the material for
implantation may be employed. A surface coating will under these
circumstances only have a limited life span as the coating will wear off.
An example of such an application is the articulating surface of a joint
prosthesis. Polyethylene is a commonly used material in such surfaces. It
is known that wear particles generated from such joint prostheses will
cause inflammation and in some instances loosening of the prosthesis.
This invention teaches that the adverse effects of such wear particles
may be reduced by adding the catalytic substance throughout the base
material, which is described in this patent, as minute suspended
particles. These catalytic particles should be as small as possible for
two reasons: Firstly the particles per se, if they become free and
separated from the material, should not elicit inflammatory cells that
ingest the particles. To avoid this, the particles should be less than
0.5 .mu.m, but preferably as small as the size of the constituting
molecules allows. The lowest achievable limit is therefore set to 1 nm.
The particles should preferably have a size of 10-100 nm.
Experiments with Inorganic, Catalytically Coatings
 Titanium dioxide coatings which have been sputter-coated onto glass
and polymer substrates have been found to inhibit superoxide production
in stimulated macrophages (FIG. 1). Interestingly, the anatase
crystalline isoform of TiO.sub.2 was more effective than the rutile
isoform. With the use of quantitative photon counting microscopy, we are
able to measure the chemiluminescent signal from MCLA
induced by production of superoxide from J774A.1 mouse macrophages
stimulated with PMA (phorbol 12-myristate 13-acetate).
 FIG. 2 demonstrates that peroxynitrite production correlates well
with classical indicators of the foreign body response such as fibrotic
capsule thickness. This result strongly supports our hypothesis that
peroxynitrite levels (and the inability to degrade reactive oxygen
species) reflect the degree of inflammation induced by a foreign body,
and thus is an indicator of biocompatibility.
 Preliminary experiments comparing the tissue response to silicone
elastomer coated with titanium dioxide indicate that the coated material
induces less inflammatory, ED1-positive cells as well as fewer cells
positive for anti-nitrotyrosine staining when implanted in the rat
abdominal wall for 28 days (FIG. 3).
Method of Manufacturing of Oxide Coated Silicone Elastomer Samples
 Silicone elastomer was obtained of a thickness of 1 mm. Silicone
was cut in circles about 5 cm in diameter. These circles were cleaned
using acetone and ethanol in an ultrasonic bath and dried with clean
flowing air. Animal experiments used circular samples, which were 5 mm in
diameter and punched from the larger 5 cm silicone circles. These samples
were then placed back in the holes of the original 5 cm silicone circle
to facilitate deposition of the coating. The silicone was cleaned again
using ethanol to rinse away any contaminants from the punching process.
Copper rings were used to hold the silicone elastomer in place in the
plasma sputtering chamber. A cleaned sputtering chamber with the
appropriate target was used to deposit the coatings. Plasma power and
argon pressure settings appropriate for the coating material was used to
R.F. magnetron plasma sputter films of thickness ranging from 10 nm to
100 .mu.m. Both sides of the samples were coated in this manner. After
deposition the samples were stored in covered petri dishes until they
were ready for use. They were sterilized using standard means.
 In some instances, glass or quartz materials were used instead of
silicone elastomer as the substrate material. In these cases, the glass
was cleaned ultrasonically using acetone and ethanol and clean flowing
air. Deposition occurred in a similar manner, except that adhesive tape
was used to mount the samples instead of copper rings.
 These experiments indicate that titanium oxide coatings can act as
an inorganic catalyst to inhibit reactive oxygen species and
down-regulate the inflammatory response which results from the
implantation of a biomaterial in the body. Reduction of the inflammatory
response would serve to improve wound recovery around the site of
implantation and increase the overall biocompatibility of an implant.
 Evidence has been published, which indicate that zirconium and
palladium also share these catalytic properties with titanium. Any
material which possesses these catalytic properties and which can be
coated onto surfaces through the processes described here could serve in
a similar manner as titanium oxide coatings.
 Such coatings can be applied to a variety of substrates thus
imparting improved biocompatibility to materials lacking this critical
property. The process of applying inorganic catalytic coatings can open a
wide range of materials with different physical properties for use as
implants, medical devices and any application which requires biomaterials
with good biocompatibility.
 Albrektsson, T., P. I. Branemark, et al. (1983). "The interface
zone of inorganic implants in vivo: Titanium implants in bone." Annals of
Biomedical Engineering 11: 1-27.
 Cuzzocrea, S., T. P. Misko, et al. (2000). "Beneficial effects of
peroxynitrite decomposition catalyst in a rat model of splanchinic artery
occlusion and reperfusion." FASEB Journal 14(N9): 1061-1072.
 Glowinski, J., R. Farbiszewski, et al. (1997). "Activity and
distribution of superoxide dismutase in the layers of polyester grafts."
European Surgical Research 29: 368-374.
 Hukkanen, M., S. Corbett, et al. (1997). "Aseptic loosening of
total hip replacement. Macrophage expression of inducible nitric oxide
synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as
a possible mechanism for early prosthesis failure." Journal of Bone and
Joint Surgery, British Volume 79(3): 467-474.
 Hukkanen, M., S. A. Corbett, et al. (1998). "Nitric oxide in the
local host reaction to total hip replacement." Clinical Orthopaedics and
Related Research 352: 53-62.
 Johansson, A; Lindgren, J U; Nord, C E; Svensson, O. (1999)
Material and design in haematogenous implant-associated infections in a
rabbit model. Injury 30(10):651-7.
 Misko, T. P., M. K. Highkin, et al. (1998). "Characterization
cytoprotective action of peroxynitrite decomposition catalysts." Journal
of Biological Chemistry 273(25): 15646-15653.
 Salvemini, D., D. Riley, et al. (1999). "Protective effects of a
superoxide dismutase mimetic and peroxynitrite decomposition catalysts in
endotoxin-induced intestinal damage." British Journal of Pharmacology
 Suzuki, R. and J. A. Frangos (2000). "Inhibition of inflammatory
species by titanium surfaces." Clinical Orthopaedics and Related Research
 Udipi, K., R. L. Ornberg, et al. (2000). "Modification of
inflammatory response to implanted biomedical materials in vivo by
surface bound superoxide dismutase mimics." Journal of Biomedical
Materials Research 51(549-560).
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