U.S. patent application number 15/680757 was filed with the patent office on 2018-01-18 for bioactive material.
The applicant listed for this patent is SMITH & NEPHEW PLC. Invention is credited to Paul Gunning, Graeme Howling.
Application Number | 20180014936 15/680757 |
Document ID | / |
Family ID | 40280858 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180014936 |
Kind Code |
A1 |
Howling; Graeme ; et
al. |
January 18, 2018 |
BIOACTIVE MATERIAL
Abstract
The present invention relates to a bioactive material and to a
method of producing a bioactive material which is suitable for use
as an implant or for use as a bone substitute for repairing
bone.
Inventors: |
Howling; Graeme; (Leeds,
GB) ; Gunning; Paul; (York, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SMITH & NEPHEW PLC |
LONDON |
|
GB |
|
|
Family ID: |
40280858 |
Appl. No.: |
15/680757 |
Filed: |
August 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14595837 |
Jan 13, 2015 |
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15680757 |
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12674236 |
Nov 12, 2010 |
8980425 |
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PCT/GB2008/002814 |
Aug 19, 2008 |
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14595837 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/306 20130101;
A61L 27/04 20130101; A61F 2/28 20130101; Y10T 428/265 20150115;
Y10T 428/24942 20150115; A61L 24/04 20130101; Y10T 428/31678
20150401; C23C 22/64 20130101; Y10T 428/256 20150115; Y10S 977/755
20130101 |
International
Class: |
A61F 2/28 20060101
A61F002/28; A61L 27/30 20060101 A61L027/30; A61L 27/04 20060101
A61L027/04; C23C 22/64 20060101 C23C022/64; A61L 24/04 20060101
A61L024/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 20, 2007 |
GB |
0716220.9 |
Sep 6, 2007 |
GB |
0717317.2 |
Feb 1, 2008 |
GB |
0801840.0 |
Jun 19, 2008 |
GB |
0811268.2 |
Claims
1. A material suitable as an implant comprising a titanium or
titanium alloy substrate comprising a first surface and a primary
layer on the first surface, the primary layer comprising a
plurality of micron scale structures, wherein the plurality of
micron scale structures collectively comprise a second surface, and
a surface layer on the second surface, the surface layer comprising
alkali titanates, wherein the thickness of the surface layer is
between 100 and 500 nm, wherein the surface layer comprises a
plurality of nanoscale structures, and wherein the plurality of
nanoscale structures collectively comprise a third surface.
2. The material of claim 1, wherein the alkali titanates comprise
sodium titanate.
3. The material of claim 1, wherein the alkali titanates comprise
discrete elements or fibrils comprising a width in the range of 2
to 20 nm and a length in the range of 200 nm to 300 nm.
4. The material of claim 1, wherein the thickness of the surface
layer is between 100 and 500 nm.
5. The material of claim 1, wherein the primary layer further
comprises hydroxyapatite.
6. The material of claim 1, wherein the primary layer further
comprises titanium oxide.
7. The material of claim 1, wherein the first surface has a first
surface area, the second surface has a second surface area, and the
third surface has a third surface area, wherein the third surface
area is greater than the second surface area, and wherein the
second surface area is greater than the first surface area.
8. The material of claim 7, wherein the third surface area is
between 1000 and 50000 times greater than the first surface
area.
9. The material of claim 1, wherein the third surface comprises a
reflectance to visible light in the range of 1% to 20%.
10. The material of claim 9, wherein the third surface comprises a
reflectance to visible light in the range of 6% to 10%.
11. The material of claim 1, wherein the primary layer further
comprises alumina in a concentration greater a concentration of
alumina in the substrate.
12. The material of claim 11, wherein the surface layer of the
primary layer comprises alumina in a concentration lesser than a
concentration of alumina in a subsurface of the primary layer.
13. The material of claim 1, wherein the primary layer is formed by
a process comprising soaking at least a portion of the substrate in
an alkaline solution comprising a concentration of 2 to 6 molar at
a temperature of 50.degree. C. to 70.degree. C., for 1 to 24
hours.
14. A material suitable as an implant comprising a titanium or
titanium alloy substrate comprising a first surface and a primary
layer on the first surface, the primary layer comprising a
plurality of micron scale structures, wherein the plurality of
micron scale structures collectively comprise a second surface; a
surface layer on the second surface, wherein the surface layer
comprises alkali titanates, wherein the alkali titanates comprise a
plurality of nanoscale structures, and wherein the plurality of
nanoscale structures collectively comprise a third surface; and
alumina in a concentration greater than a concentration of alumina
in the titanium or titanium alloy substrate.
15. The material of claim 14, wherein the surface layer of the
primary layer comprises alumina in a concentration lesser than a
concentration of alumina in a subsurface of the primary layer.
16. The material of claim 14, wherein the alkali titanates comprise
discrete elements or fibrils comprising a width in the range of 2
to 20 nm and a length in the range of 200 nm to 300 nm.
17. The material of claim 14, wherein the primary layer further
comprises hydroxyapatite.
18. The material of claim 14, wherein the primary layer further
comprises titanium oxide.
19. The material of claim 14, wherein the first surface has a first
surface area, the second surface has a second surface area, and the
third surface has a third surface area, wherein the third surface
area is between 1000 and 50000 times greater than the first surface
area.
20. The material of claim 14, wherein the third surface comprises a
reflectance to visible light in the range of 1% to 20%.
Description
[0001] The present invention relates to a material and to a method
of producing a material which is suitable for use as an implant or
for use as a bone substitute for repairing bone.
[0002] Restoration of skeletal defects or wounds such as femoral
neck fracture, spine fusion and lost teeth is a common procedure.
For example, over 500,000 hip prosthesis implantations, 250,000
spine fusion surgeries, and 500,000 dental implant surgeries are
performed annually in the United States alone.
[0003] Titanium and its alloys, due to their high toughness and
excellent biocompatibility, are widely used in medical implants
such as joint prostheses, fracture fixation devices, and dental
implants. Other materials commonly used in medical and dental
implants, include cobalt chrome, polished zirconium, oxinium
(zirconium oxide) and stainless steel. However, titanium and these
other materials demonstrate poor ability to bond to bone
chemically, and thus osteolysis and subsequent loosening of
implants comprising these materials are common.
[0004] The performance of an orthopaedic implant can be influenced
by the quality of the interface formed between the implant and bone
or bone cement. The development of the implant-to-bone (or cement)
interface relies on a number of factors including surface area,
charge, topography, chemistry and contamination of the implant. The
implant-to-bone interface is the surface of the implant which
interfaces or lies adjacent the bone when implanted.
[0005] Various techniques are known to modify the implant-to-bone
interface topography to enhance implant-to-bone integration. These
techniques include plasma spraying and electrochemical anodising of
the implant-to-bone interface surface. Problems associated with
plasma spraying and electrochemical anodising include, the
formation of an implant-to-bone interface which has low fatigue
strength, demonstrates poor adherence to the implant, and suffers
from degradation, delamination or cracking during long term
implantation.
[0006] A commonly used technique for improving tissue ingrowth into
orthopaedic implants is abrasive particle blasting of the implant
surface, alternatively known as grit-blasting or sand blasting.
This, cost efficient process, imparts a micron scale surface
structure by blasting abrasive particles on the implant surface.
Such roughened surfaces have been shown to promote cell attachment
and thus improved physical implant-to-bone bonding. Furthermore,
the increased area of a roughened surface means that more cells can
attach to the implant-to-bone interface which also improves
implant-to-bone physical bonding. The implant having such a
modified implant-to-bone interface demonstrates good
osseointegrative properties even in poor quality bone.
[0007] However the technique of abrasive particle blasting can
cause significant changes to surface topography by damaging the
metal elements on the surface of the implant. The technique of
abrasive particle blasting can also cause heterogeneity of the
surface chemistry due to the presence of abrasive particles
embedded in the surface of the implant. The presence of the
abrasive particles contaminate the surface of the implant and
adversely affect the quality of the implant-to-bone interface.
Furthermore, the abrasive particles can detach from the surface of
the implant, leading to increased wear on the bone, implant and
implant site.
[0008] Additionally, a percentage of the embedded abrasive
particles protrude from the surface of the implant causing
localised micromotion, movement of the implant relative to the
implant site, and disruption of tissue ingrowth in the surface of
the implant. Up to 40% of the surface area of the grit blasted
implant can become contaminated with abrasive particles which can
lead to implant-to-bone interface problems, reduced
bio-compatibility of the implant and inflammation of the area local
to the implant.
[0009] It is the object of the present invention to provide an
implant which has an enlarged implant-to-bone interface layer with
reduced or no contamination caused by surface embedded abrasive
particles. The implant-to-bone interface is the surface of the
implant which interfaces or lies adjacent the bone when implanted.
It is also an object of the present invention to provide an implant
which has a bioactive, porous and nano-structured surface layer
with improved osteoconductive and osteoinductive properties.
[0010] Therefore, according to a first aspect of the invention,
there is provided a material suitable as an implant comprising a
metal or metal alloy substrate and a primary layer formed on a
surface of the substrate, said primary layer having a surface area
greater than the surface area of the substrate. Surprisingly it has
been found that the primary layer according to the present
invention, having a surface area greater than the surface area of
the substrate, encourages (to a greater extent) bone to be formed
on the surface. Thus increasing bone formation and giving a secure
hold on the implant, giving a greater implant success rate both in
terms of speed to recover from the implant operation and overall
success of the implant being secured in place.
[0011] In use, the surface of the primary layer of the implant
interfaces the bone or bone cement. Thus, the primary layer, or
more specifically, the surface of the primary layer provides the
implant-to-bone interface. The increased surface area of the
primary layer means that a larger surface area is presented to
surrounding cells/cement for increased cell/cement attachment and
hence improved integration with the material and thus with the
implant.
[0012] According to a second aspect of the invention, there is
provided a method of forming the material of the first aspect,
comprising the steps of providing a metal or metal alloy substrate
and forming a primary layer on a surface of the substrate such that
the surface area of the primary layer is greater than the surface
area of the substrate covered by the primary layer.
[0013] Preferably, the substrate comprises a transition metal, a
transition metal alloy or a transition metal oxide, for example,
titanium, TiAlNb, or titanium oxide. Titanium and its alloys, due
to their high toughness and excellent biocompatibility are ideally
suited as orthopaedic implants. Optionally, the substrate may
comprise cobalt chrome, polished zirconium, oxinium (zirconium
oxide), stainless steel, tantalum or any combination of these. The
substrate according to the present invention may comprise any
metal, or metal alloy, or metal oxide or combination of these but
suitably it would comprise titanium.
[0014] Preferably, the step of forming the primary layer on the
metal substrate comprises physically altering the surface of the
substrate. Physically altering the surface of the substrate
roughens the surface of the substrate thereby increasing its
surface area. The primary or rough layer promotes cell attachment
and thus physical bonding of the implant to bone or to the implant
site. The roughened surface presented by the primary layer provides
a surface area significantly larger than the surface area of the
substrate covered by the primary layer.
[0015] The step of physically altering the surface of the substrate
to form the primary layer may comprise, for example, machining,
sand blasting or grit blasting, or any combination of these.
Preferably, the physical altering step comprises grit blasting the
surface of the substrate with abrasive particles such as alumina.
The primary layer thus formed presents a roughened, uneven surface
texture of peaks, troughs, pits and trenches which increases the
surface area available for cell attachment.
[0016] Alternatively, the step of physically altering the substrate
may comprise, for example, a macro or micro physical
surface-treatment in which a coating of metallic beads is adhered
to the surface of the substrate. The beads form a 3D porous
geometry on the surface of the substrate thereby providing a
primary layer having a greater surface area than the surface of the
substrate covered by the coating. Preferably, the primary layer
comprises a double or triple layer of beads sintered onto the
surface of the substrate. Preferably, the beads are titanium beads
and have a mean diameter of 328 .mu.m.
[0017] Alternatively, or in addition, the coating may contain a
sponge or foam like network of metallic fibres and/or wires.
Alternatively, the substrate itself can be porous or sponge like,
negating the requirement to physically treat the surface of the
substrate. Preferably, the foam or sponge-like structure is
composed of sintered beads having diameters of between 15 and 50
.mu.m and pore diameters of several hundred microns to
approximately 1 mm.
[0018] In addition, and subsequent to the physically formed primary
layer, the method of forming or completing the primary layer
ideally includes chemically treating the physically formed primary
layer. The step of chemically treating the physically formed
primary layer comprises soaking the substrate in an alkaline
solution at approximately 30-90.degree. C. The titanium or titanium
alloy reacts with the alkaline solution to form alkali titanates.
The surface of the completed primary layer thus comprises alkali
titanates. Typically, the surface of the completed primary layer
also includes titanium oxide or titanium oxides.
[0019] Preferably, the temperature of the alkaline solution is
between 50-70.degree. C. and more preferably between 55-65.degree.
C.
[0020] It has been found that to heat the substrate or alkaline
solution to a higher temperature can compromise the integrity of
the primary layer so formed. For example, where the substrate or
alkaline solution is heated to or above 150.degree. C., a primary
layer having a deposit of alkali titanates of a thickness in the
micron scale will form. The thicker the alkali titanate deposit or
layer, the greater will be the risk of delamination or cracking of
the alkali titanate layer. Thus the alkali titanate layer, which
will in effect form the implant-to-bone interface, bonding the
implant to the bone, may be weak and ultimately fail causing
separation of the implant from the bone.
[0021] Preferably, the substrate is soaked in an alkaline solution
for between 1 and 24 hours. Typically, the soaking time is between
1 and 5 hours but is preferably between 1 and 3 hours. It has been
found that soaking times above 5 hours but in particular above 24
hours also produce a primary layer having a thickness in the micron
scale.
[0022] The alkali titanate layer creates a surface to the primary
layer which comprises a nanostructure of alkali titanates. A
nanostructure or nano-textured surface generally means a surface
which includes particles or elements of a size falling within the
nanometer range. The nanostructure of alkali titanates resembles a
strut-like morphology containing discrete elements, structurally
resembling fibres or fibrils, of alkali titanate having a width of
between 1 and 20 nanometers (nm). The fibrils are generally
cylindrical in shape.
[0023] Typically, the length of the fibrils range from 200-300 nm
and the distance between fibrils ranges from 5 nm to 80 nm. The
fibrils are generally overlaid or stacked one atop another forming
the alkali titanate layer or surface. Preferably, the thickness of
the alkali titanate layer is in the range of 100-500 nanometers,
more preferably 100-300 nanometers.
[0024] The physical treatment step creates the primary layer having
an increased surface area in preparation for the formation of the
alkali titanate nanostructure. The nanostructure of the alkai
titanate layer completes the primary layer and significantly
increases the surface area of the primary layer and hence
implant-to-bone interface surface area available for cell
attachment and integration. The alkali titanate layer also masks
the adverse affects caused by the presence of any abrasive
particles present in the implant-to-bone interface of the
implant.
[0025] Preferably, the primary layer has a surface area of between
1000 and 50000 times greater than the surface area of the substrate
covered by the primary layer. More preferably, the primary layer
has a surface area of between 20000 and 50000 times and ideally
between 40000 and 50000 times greater than the surface area of the
substrate covered by the primary layer.
[0026] Typically, the alkaline solution comprises a hydroxide.
Preferably, the hydroxide is sodium hydroxide. Other hydroxides can
be used with the present invention, e.g. lithium hydroxide or
potassium hydroxide or any other suitable metal hydroxide. In this
case, the alkali titanate nanostructure of the primary layer will
be sodium titanate. Sodium titanate is an ionic compound that can
be readily modified by ion-exchange chemistry into other compounds
such as lithium titanate or strontium titanate to confer different
physico-chemical or biocompatibility characteristics suitable for
different applications. The concentration of the hydroxide solution
is preferably between 2 and 8 molar, more preferably between 3 and
6 molar, and ideally 4 molar. Higher concentrations of hydroxide
can lead to re-dissolution of the nanostructure.
[0027] The primary layer formed is typically hydrophilic in nature.
This is generally due to the chemical treatment step in completing
the primary layer. The hydrophilic nature of a material is
generally measured by the contact angle water forms on its surface.
The smaller the contact angle the greater the hydrophilic nature of
the material. Preferably, the contact angle of the primary layer is
less than 5.degree., more preferably is less than 3.degree..
[0028] Preferably, the primary layer has a low reflectance to
visible light. Typically, the primary layer has a reflectance to
visible light in the range of 1% to 20%. More preferably, the
primary layer has a reflectance to visible light in the range of 5%
to 15% and ideally in the range of 6% to 10%. The reflectance range
gives the primary layer a black colour.
[0029] Preferably, the primary layer includes hydroxyapatite, for
example calcium hydroxyapatite. Typically, the hydroxyapatite is
incorporated in the primary layer by soaking the material in mixed
buffer salts.
[0030] The material may be used in both medical and dental implants
for improved implant-to-bone integration. More specifically, the
material may be used in bone replacement implants including, for
example, knee joint, hip joint and shoulder joint prosthesis,
femoral neck replacement, spine replacement and repair, neck bone
replacement and repair, jaw bone repair, fixation and augmentation,
transplanted bone fixation, and other limb prosthesis.
[0031] Embodiments of the invention will now be described by way of
example only and with reference to the accompanying drawings, in
which:--
[0032] FIG. 1 is a scanning electron micrograph (SEM) of a titanium
alloy surface;
[0033] FIG. 2 is an SEM of the titanium alloy surface of FIG. 1
after grit blasting with alumina particles;
[0034] FIG. 3 is an SEM of a titanium alloy porous beaded
surface;
[0035] FIG. 4 is an SEM of a titanium alloy sintered bead foam
surface;
[0036] FIG. 5a is an SEM of titanium alloy surface after grit
blasting with alumina particles;
[0037] FIGS. 5b-5g are SEMs of samples of the titanium alloy
surface of FIG. 5a after soaking in a 2M (2 molar), 3M, 4M, 6M, 8M
and 10M solution respectively of sodium hydroxide solution at
60.degree. C. for 2 hours;
[0038] FIG. 6a-6c are SEMs of an alumina grit blast titanium alloy
surface, a titanium porous beaded surface, and a titanium sintered
bead foam surface respectively, soaked in a 4M sodium hydroxide
solution at 60.degree. C. for 2 hours;
[0039] FIGS. 7 and 8 are magnified views of the titanium alloy
surfaces FIG. 6b and FIG. 6c respectively;
[0040] FIG. 9 is an SEM of a Porous Beaded Titanium surface prior
to forming the primary layer;
[0041] FIG. 10 is an SEM of the porous beaded titanium surface of
FIG. 9, the primary layer having been formed by soaking in a 4M
sodium hydroxide solution at 60.degree. C. for 2 hours in a
sonicating water bath;
[0042] FIG. 11a is an SEM of the Porous Beaded Titanium surface of
FIG. 9 soaked in a 2M solution of sodium hydroxide at 60.degree. C.
for 10 minutes;
[0043] FIG. 11b is a magnified SEM of the Porous Beaded Titanium
surface of FIG. 11a, more clearly showing the early formation of
the nanostructured primary layer comprising nano-sized fibrils
having a size in the region of 1-20 nanometers;
[0044] FIG. 11e is an SEM of the Porous Beaded Titanium surface of
FIG. 11a soaked in a 2 Molar solution of sodium hydroxide at
60.degree. C. for a further 15 minutes clearly showing the
development of the nanostructured primary layer;
[0045] FIG. 11d is an SEM of a different portion of the Porous
Beaded Titanium surface of FIG. 11a clearly showing the irregular
nature of the formation of the primary layer;
[0046] FIG. 12 is an SEM of a commercially pure titanium surface
after grit blasting with alumina particles with subsequent soaking
in a 4M solution of sodium hydroxide solution at 60.degree. C. for
2 hours;
[0047] FIGS. 13a-13c are SEMs of increasing magnification of areas
of the surface of TiAlNb alloy after grit blasting with alumina
particles but prior to soaking in sodium hydroxide, the SEM
employing a 2 kv beam to analyse the upper structure of the primary
layer created;
[0048] FIGS. 14a-14c are SEMs of the same areas of the surface of
the TiAlNb alloy of FIGS. 13a-13c after soaking in 4M sodium
hydroxide solution at 60.degree. C. for 2 hours, the SEM employing
a 2 kv beam to analyse the upper structure of the completed primary
layer;
[0049] FIGS. 15a and 15b are SEMs of the same areas of the surface
of the TiAlNb alloy of FIGS. 14b and 14c respectively, the SEM
employing a 15 kv beam to analyse the substructure of the completed
primary layer;
[0050] FIG. 16 is a graph showing the percentage reflectance from
the surface of the primary layer for different substrates; and
[0051] FIGS. 17a and 17b are pictorial views of samples of the
material according to the present invention showing the primary
layer prior to treatment with sodium hydroxide and post treatment
with sodium hydroxide respectively.
[0052] FIG. 18 shows grit blasted titanium coupons p-NPP data
normalised to DNA (Pico Green) with error bars of standard
deviation. This data is from Table 2.
[0053] FIG. 19 shows porous beaded titanium coupons p-NPP data
normalised to DNA (Pico Green) with error bars of standard
deviation. This data is from Table 3.
[0054] FIG. 20 shows polished titanium coupons p-NPP data
normalised to DNA (Pico Green) with error bars of standard
deviation. This data is from Table 4.
[0055] Sample titanium alloy plates of various dimensions having
surface areas ranging from approximately 40 mm.sup.2 to 100
mm.sup.2 were washed cleaned and dried to form sample substrates.
The prepared or sample substrate surfaces are approximately smooth.
This can be seen most clearly from FIG. 1 which is a view of the
substrate surface taken by a ultra-high resolution scanning
electron microscope.
[0056] A FEI Nova 200 NanoSEM ultra-high resolution Scanning
Electron Microscope with a stated resolution of 1.8 nm at 3 kV and
1 nm at 15 kV using immersion optics was used to characterise
primary layers formed on the titanium alloy substrate. The views or
micrographs of the primary layer show detail on the nanoscale.
However, it will be appreciated that other suitable methods and
equipment may also be used to explore the surface detail of the
primary layer.
[0057] A surface of a prepared substrate sample was blasted with
abrasive alumina particles otherwise known as alumina grit-blast.
The process of alumina grit-blasting roughens the surface of the
substrate creating or partially forming a primary layer which has a
greater surface area than the surface area of the prepared
substrate prior to grit-blasting. This can be seen most clearly in
FIGS. 2 and 5a. The primary layer was completed by soaking the
substrate with the partially formed primary layer in a 4 molar
solution of sodium hydroxide at 60.degree. C. for two hours. FIG.
5b is a view of the completed primary layer which clearly shows the
development of strut-like formations, fibres or fibrils of sodium
titanate having dimensions on the nanoscale. The diameter or width
of these fibrils fall within the range of between 1 and 20
nanometers. Approximately 80% of the fibrils have been measured as
having a diameter in the range of 5 to 12 nanometers. The length of
the fibrils are between 200 and 300 nanometers.
[0058] Five further samples of the prepared substrate were alumina
grit blasted and soaked in sodium hydroxide solutions of
concentration 3 molar, 4 molar, 6 molar, 8 molar and 10 molar
respectively at 60.degree. C. for two hours and FIGS. 5c to 5g are
views of the completed primary layer formed in each case. As can be
seen from FIGS. 5c to 5g, the best etching, texturing or
nanostructure formed or greatest density of fibril formation was
observed where the substrate was soaked in 4 molar solution of
sodium hydroxide. The greater the density of fibril formation, the
greater the surface area of the primary layer. Treatment with
higher concentrations of sodium hydroxide was less effective and
lead to re-dissolution of the nanostructure of the primary layer
resulting in a smoother surface and thus a reduced surface
area.
[0059] FIGS. 6a to 6c are views of a primary layer formed according
to the present invention wherein the starting substrate and thus
the initial topography is different in each case. FIG. 6a is a view
of a primary layer which has been formed on a surface of a solid
titanium alloy substrate which has been blasted with abrasive
alumina particles and subsequently chemically treated by soaking in
a 4 molar concentrated solution of sodium hydroxide at 60.degree.
C. for 2 hours. FIG. 6b and FIG. 6c are views of the primary layer
which have been formed on a surface of a porous beaded titanium
substrate and a titanium foam substrate respectively, which have
been chemically treated in the same way as the solid titanium alloy
substrate.
[0060] The porous beaded titanium substrate and titanium foam
substrate were not subjected to any physical treatment such as in
the case of the solid titanium alloy substrate. It was found that
the greater the surface area of the starting substrate, the greater
the surface area of the primary layer formed. As can be quite
clearly seen from FIGS. 6a to 6c the fibrils formed in the case of
the titanium foam substrate, which had the greatest starting
substrate surface area, were the most fine, and thus fibril
formation density was greatest presenting the highest primary layer
surface area. FIG. 9 is an SEM of a portion of a surface of a
porous beaded titanium alloy prior to completing the primary layer.
FIGS. 11a to 11d illustrate the development of the primary layer
over time when soaked in a 2 molar solution of sodium hydroxide at
60.degree. C.
[0061] FIGS. 13a-13c are SEMs of increasing magnification (200, 500
and 1200 times magnified respectively) of areas of the surface of
TiAlNb alloy after grit blasting with alumina particles but prior
to soaking in sodium hydroxide; the SEM employing a 2 kv beam to
analyse the upper structure of the completed primary layer. FIGS.
14a-14c are SEMs of the same areas and at the same magnifications
of the surface of the TiAlNb alloy of FIGS. 13a-13c respectively
after soaking in 4 molar sodium hydroxide solution at 60.degree. C.
for 2 hours; the SEM employing a 2 kv beam to analyse the upper
structure of the primary layer thus formed. FIGS. 15a and 15b are
SEMs of same areas and at the same magnifications of the surface of
the TiAlNb alloy of FIGS. 13b and 13c respectively; the SEM
employing a 15 kv beam to analyse the substructure of the primary
layer formed.
[0062] The surfaces of the primary layers were analysed by scanning
electron microscopy (SEM) before and after soaking the substrate in
sodium hydroxide solution to analyse surface topography and alumina
content throughout the primary layer. This technique can be carried
out at different voltages which enables the surface and subsurface
of the primary layer to be analysed; the greater the voltage the
deeper the penetration of the beam. Titanium alloy has a higher
average atomic number than alumina. The higher the average atomic
number of the material being analysed using SEM, the greater will
be the electron backscatter and thus the brighter will be the SEM
image.
[0063] Alumina has an average atomic number less than titanium
alloy and thus an SEM image of titanium alloy with alumina present
is darker than titanium alloy without alumina. It is quite clear
when comparing FIG. 1, which shows a titanium alloy substrate prior
to alumina grit blasting, with FIGS. 13a to 13c, for example, which
show the titanium alloy substrate post alumina grit blasting, that
quite a substantial amount of alumina becomes embedded in the
surface of the substrate forming the primary layer. FIGS. 14a to
14c represent the primary layer of FIGS. 13a to 13c which have been
completed by chemical treatment with sodium hydroxide as described
above. As can be seen, the SEM images of the primary layer
illustrated in FIGS. 14a to 14c are brighter than the SEM images of
the primary layer illustrated in FIGS. 13a to 13c because the
sodium titanate layer formed masks the alumina particles present in
the upper surface of the primary layer. Sodium titanate has an
average atomic number higher than that of alumina and thus the SEM
image of the completed primary layer will appear brighter than the
primary layer created by alumina grit blasting and prior to
treatment with sodium hydroxide.
[0064] The higher voltage SEM images illustrate the composition of
the subsurface of the primary layer which is clearly darker and
thus higher in alumina content than the upper surface regions.
However, it is only critical to mask the alumina particles in the
upper surface of the primary layer which forms the implant-to-bone
interface and thus is in direct contact with the bone, as
contamination of the subsurface of the primary layer with abrasive
particles has little affect on the bond formed between the bone and
implant.
[0065] Analysis of the reflectance of various substrates prior to
and after treatment with 4 molar sodium hydroxide was also
undertaken. As can be seen quite clearly from table I below, the
greater the surface area of the primary layer, the less visible
light is reflected. The titanium foam substrate which produced the
primary layer having the greatest surface area reflected only
between 5 and 10% of the visible light. All the primary layers
completed were black in colour when viewed by the naked eye.
TABLE-US-00001 TABLE 1 4M NaOH 4M NaOH Control Control treated
treated 4M NaOH Wavelength Grit-Blast Porous Control Grit-Blast
Porous treated (nm) Ti6Al4V Beaded Ti Foam Ti Ti6Al4V Beaded Ti
Foam Ti 400 22.83 17.99 17.61 12.71 4.78 5.56 410 23.23 18.32 17.86
12.61 4.94 5.71 420 23.6 18.58 18.05 12.53 5.06 5.82 430 23.95
18.75 18.19 12.47 5.12 5.88 440 24.26 18.92 18.3 12.47 5.18 5.96
450 24.55 19.17 18.44 12.54 5.31 6.1 460 24.82 19.42 18.6 12.67
5.45 6.25 470 25.11 19.6 18.8 12.88 5.59 6.39 480 25.39 19.79 19.03
13.14 5.72 6.53 490 25.64 19.99 19.31 13.41 5.84 6.63 500 25.92
20.28 19.61 13.74 5.98 6.76 510 26.3 20.75 19.92 14.18 6.2 7 520
26.67 21.19 20.21 14.63 6.4 7.23 530 26.89 21.4 20.42 14.99 6.51
7.37 540 27.07 21.54 20.61 15.33 6.6 7.49 550 27.76 21.72 20.8 15.7
6.7 7.61 560 27.44 21.89 20.97 16.06 6.8 7.74 570 27.6 22.02 21.09
16.41 6.91 7.88 580 27.74 22.15 21.19 16.72 7 8.01 590 27.87 22.32
21.27 16.95 7.02 8.1 600 27.99 22.51 21.35 17.15 7.04 8.19 610
28.12 22.68 21.48 17.36 7.15 8.31 620 28.28 22.85 21.67 17.6 7.3
8.46 630 28.52 23.06 21.95 17.95 7.54 8.63 640 28.78 23.27 22.23
18.29 7.74 8.8 650 28.9 23.4 22.34 18.42 7.73 8.92 660 28.96 23.51
22.38 18.45 7.62 9 670 29.04 23.65 22.41 18.46 7.55 9.06 680 29.14
23.79 22.46 18.47 7.52 9.11 690 29.31 23.88 22.59 18.48 7.55 9.18
700 29.52 23.94 22.78 18.49 7.63 9.27
[0066] Sample titanium materials, titanium alloy coupons, having
different pre-treatments (grit blasted, polished, porous beaded)
were compared for osteogenic activity on the surface after being
chemically treated with an alkaline solution, compared to each
other type and of pre-treatment and to not being chemically
treated.
[0067] The alkaline solution was a 4 molar solution of sodium
hydroxide for 2 hours at 60.degree. (as described here before).
[0068] The pre-treatments of the titanium alloy coupons were
polishing the surface, grit blasting and porous beading as known in
the art.
[0069] After the chemical treatment the titanium alloy coupons were
inserted into individual silicone tubes so that any fluid placed on
to the coupon remained on the test surface. Coupons were then
sterilised.
[0070] Human mesenchymal stem cells were resurrected and passaged
in suitable medium and incubated overnight. After incubation the
medium was replaced with an osteogenic medium containing
R-Glycerophosphate and this was changed twice a week.
[0071] Live/dead staining on the cells was performed on all surface
types at all time points.
[0072] The samples were subject to cell lysis and P-nitrophenol
alkaline phosphatase p-NPP assay analysis to indicated osteogenic
activity of the cells and thus, bone formation.
[0073] The results are as shown in Table 2 for grit blasted
pre-treated coupons alkaline solution treated compared to not being
subject to alkaline solution.
TABLE-US-00002 TABLE 2 GB GB GB GB Non- GB Non- GB Non- GB Non- GB
treated Alkali treated Alkali treated Alkali treated Alkali Grit
(Day (Day (Day (Day (Day (Day (Day (Day blasted 3) 3) 7) 7) 14) 14)
21) 21) p-NPP Rep 1 25.493 38.760 79.569 155.813 165.721 211.735
149.917 226.772 Rep 2 21.630 37.081 63.447 142.378 184.362 263.529
228.443 380.482 Rep 3 19.783 36.745 95.859 129.446 235.583 306.969
243.480 327.018 Pico Rep 1 6.702 5.965 5.227 7.439 11.863 7.439
10.388 9.651 Green Rep 2 6.702 6.702 6.702 5.227 10.388 5.965 8.176
8.176 Rep 3 6.702 7.439 6.702 5.965 9.651 7.439 10.388 8.176
Normal- Rep 1 3.804 6.498 15.222 20.945 13.970 28.463 14.432 23.498
isation Rep 2 3.228 5.533 9.467 27.237 17.748 44.183 27.940 46.535
Rep 3 2.952 4.939 14.304 21.703 24.411 41.265 23.439 39.996 Mean
3.328 5.657 12.998 23.295 18.709 37.970 21.937 36.676 Standard
0.435 0.787 3.092 3.435 5.286 8.362 6.878 11.872 deviation
[0074] Table 3 shows pre-treated porous beaded coupons with and
without alkaline solution treatment.
TABLE-US-00003 TABLE 3 Porous Porous Porous Porous Non- Porous
Alkali + Non- Porous Alkali + treated Alkali heat treated Alkali
Heat Porous (Day (Day (Day (Day (Day (Day beaded 3) 3) 3) 7) 7) 7)
p-NPP Rep 1 74.363 125.584 150.271 76.404 295.273 198.369 Rep 2
75.874 161.187 187.553 153.259 322.005 250.163 Rep 3 94.851 151.278
174.622 139.893 231.784 265.200 Pico Rep 1 14.074 5.965 8.914
10.388 8.914 6.702 Green Rep 2 8.914 8.176 8.914 11.125 9.651 6.702
Rep 3 8.176 8.176 8.176 9.651 7.439 6.702 Normal- Rep 1 5.284
21.055 16.859 7.355 33.126 29.600 isation Rep 2 8.512 19.714 21.041
13.776 33.366 37.328 Rep 3 11.601 18.502 21.357 14.495 31.158
39.572 Mean 8.466 19.757 19.752 11.875 32.550 35.500 Standard 3.159
1.277 2.511 3.931 1.212 5.231 deviation Porous Porous Porous Porous
Non- Porous Alkali + Non- Porous Alkali + treated Alkali Heat
treated Alkali Heat Porous (Day (Day (Day (Day (Day (Day beaded 14)
14) 14) 21) 21) 21) p-NPP Rep 1 612.718 1137.336 734.683 636.108
744.708 945.199 Rep 2 617.730 1132.324 709.622 843.282 968.589
1035.420 Rep 3 729.671 1052.127 846.624 764.757 1100.579 1017.041
Pico Rep 1 11.125 8.176 8.176 10.388 6.702 8.914 Green Rep 2 10.388
8.914 8.176 11.125 8.914 9.651 Rep 3 11.125 8.176 9.651 10.388
8.176 9.651 Normal- Rep 1 55.074 139.102 89.855 61.235 111.121
106.041 isation Rep 2 59.466 127.034 86.790 75.799 108.665 107.289
Rep 3 65.587 128.681 87.726 73.619 134.606 105.384 Mean 60.042
131.606 88.124 70.218 118.131 106.238 Standard 5.280 6.544 1.571
7.855 14.321 0.967 deviation
[0075] Table 4 shows polished coupons with and without alkaline
solution treatment.
TABLE-US-00004 TABLE 4 Polished Polished Polished Polished Non-
Polished Alkali + Non- Polished Alkali + treated Alkali heat
treated Alkali heat (Day (Day (Day (Day (Day (Day Polished 3) 3) 3)
7) 7) 7) p-NPP Rep 1 20.287 37.920 38.088 136.668 186.209 87.630
Rep 2 24.149 34.729 31.203 94.683 152.958 118.866 Rep 3 20.119
36.913 31.203 67.477 148.927 132.133 Pico Rep 1 8.914 5.227 6.702
5.965 5.965 5.227 Green Rep 2 6.702 5.227 9.651 7.439 5.227 5.227
Rep 3 12.600 4.490 5.965 22.921 5.227 5.227 Normal- Rep 1 2.276
7.254 5.683 22.913 31.220 16.764 isation Rep 2 3.603 6.644 3.233
12.728 29.261 22.740 Rep 3 1.597 8.221 5.231 2.944 28.490 25.278
Mean 2.492 7.373 4.716 17.821 29.657 21.594 Standard 1.021 0.795
1.304 7.202 1.407 4.371 deviation Polished Polished Polished
Polished Non- Polished Alkali + Non- Polished Alkali + treated
Alkali Heat treated Alkali Heat (Day (Day (Day (Day (Day (Day
Polished 14) 14) 14) 21) 21) 21) p-NPP Rep 1 206.723 527.509
158.271 288.590 -15.488 -20.500 Rep 2 265.200 470.703 357.091
352.079 908.442 484.069 Rep 3 196.699 554.241 731.342 7.903 527.509
388.836 Pico Rep 1 5.965 8.176 5.965 8.914 -0.671 0.067 Green Rep 2
6.702 5.227 5.227 8.176 8.176 9.651 Rep 3 7.439 5.965 7.439 0.067
7.439 6.702 Normal- Rep 1 34.659 64.517 26.535 32.377 23.091
-308.186 isation Rep 2 39.572 90.048 68.313 43.061 111.107 50.159
Rep 3 26.441 92.923 98.311 118.804 70.911 58.020 Mean 33.557 82.496
64.387 37.719 91.009 54.089 Standard 6.634 15.636 36.049 7.555
28.423 5.559 deviation
[0076] The results show that there is more Osteogenic activity
where the coupons have been chemically treated e.g. with an
alkaline solution compared to not being chemically treated.
[0077] It will be appreciated that the primary layer may include
various bio-active materials including antimicrobials. It will also
be appreciated that the primary layer may be further treated to
impart anti-biofouling, cytogenic, catalytic, osteogenic or
electrochemical properties to the implant.
[0078] It will be further appreciated that the substrate may
comprise other metals or alloys instead of titanium, for example,
nitinol or zirconium.
[0079] It is envisaged that the material formed maybe subjected to
further physical treatment steps to improve or enhance the surface
characteristics of the primary surface layer. For example, on
completion of the primary layer, the material can be rinsed in
water or phosphate buffered-saline solution to remove the alkali.
After drying the material, it can be heated to a target temperature
of between 300-600.degree. C. The target temperature can be reached
by raising the temperature of the material by 5.degree. C. per
minute. The target temperature, once reached can be maintained for
at least one hour.
[0080] It will be appreciated that the invention is not limited to
the embodiments hereinbefore described but may be varied in
construction and detail within the scope of the appended
claims.
* * * * *