U.S. patent application number 12/537353 was filed with the patent office on 2010-02-11 for medical device for bone implant and method for producing such device.
This patent application is currently assigned to Exogenesis Corporation. Invention is credited to Richard C. Svrluga, Laurence B. Tarrant.
Application Number | 20100036502 12/537353 |
Document ID | / |
Family ID | 41653669 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100036502 |
Kind Code |
A1 |
Svrluga; Richard C. ; et
al. |
February 11, 2010 |
MEDICAL DEVICE FOR BONE IMPLANT AND METHOD FOR PRODUCING SUCH
DEVICE
Abstract
A bone implantable medical device made from a biocompatible
material, preferably comprising titania or zirconia, has at least a
portion of its surface modified to facilitate improved integration
with bone. The implantable device may incorporate a surface infused
with osteoinductive agent and/or may incorporate holes loaded with
a therapeutic agent. The infused surface and/or the holes may be
patterned to determine the distribution of and amount of
osteoinductive agent and/or therapeutic agent incorporated. The
rate of release or elution profile of the therapeutic agent may be
controlled. Methods for producing such a bone implantable medical
device are also disclosed and employ the use of ion beam
irradiation, preferably gas cluster ion beam irradiation for
improving bone integration.
Inventors: |
Svrluga; Richard C.;
(Newton, MA) ; Tarrant; Laurence B.; (Cambridge,
MA) |
Correspondence
Address: |
BURNS & LEVINSON, LLP
125 SUMMER STREET
BOSTON
MA
02110
US
|
Assignee: |
Exogenesis Corporation
Billerica
MA
|
Family ID: |
41653669 |
Appl. No.: |
12/537353 |
Filed: |
August 7, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61086986 |
Aug 7, 2008 |
|
|
|
Current U.S.
Class: |
623/23.6 ;
427/2.27 |
Current CPC
Class: |
A61C 8/0012 20130101;
A61F 2002/3068 20130101; A61F 2/30771 20130101; A61L 2300/606
20130101; A61L 27/54 20130101; A61L 2400/18 20130101; A61F
2002/30795 20130101; A61L 27/50 20130101; A61F 2002/30677 20130101;
A61L 2300/414 20130101; A61C 8/0018 20130101; A61F 2250/0068
20130101; B05D 3/068 20130101; A61L 27/10 20130101; A61L 2300/602
20130101; A61L 2300/406 20130101; C23C 14/221 20130101; A61L
2300/426 20130101; C23C 14/48 20130101; A61F 2310/00796 20130101;
A61L 2300/45 20130101; A61F 2/28 20130101 |
Class at
Publication: |
623/23.6 ;
427/2.27 |
International
Class: |
A61F 2/28 20060101
A61F002/28; A61L 27/32 20060101 A61L027/32; B05D 3/04 20060101
B05D003/04 |
Claims
1. A method of modifying a surface of bone-implantable medical
device comprising the steps of: coating at least a first portion of
the surface of the medical device with an osteoinductive agent to
form a coated surface region; and first irradiating at least a
portion of the coated surface region with a first ion beam.
2. The method of claim 1, wherein the first irradiating step forms
a shallow surface and subsurface layer comprising embedded
molecules and/or dissociation products of the osteoinductive
agent.
3. The method of claim 2, wherein the first ion beam is a first gas
cluster ion beam and further wherein the shallow surface and
subsurface layer is an infused surface layer.
4. The method of claim 1, wherein the osteoinductive agent
comprises, separately or in combination, any of the materials from
the group consisting of: a nutrient material, tricalcium phosphate,
hydroxyapatite, Bioglass 45S5, Bioglass 58S, a bone
growth-stimulating agent, a growth factor, a cytokine, a TGF-.beta.
protein, a BMP, a GPI-anchored signaling protein, an RGM, and a
growth regulatory protein.
5. The method of claim 1, wherein the surface of the
bone-implantable medical device comprises, separately or in
combination, any of a metal, an oxide, or a ceramic.
6. The method of claim 5, wherein the surface comprises titanium,
titania, or zirconia.
7. The method of claim 1, further comprising the steps, prior to
the coating step: forming a second ion beam that is a gas cluster
ion beam; and second irradiating at least a second portion of the
surface of the medical device to clean the at least a second
portion of the surface.
8. The method of claim 1, wherein the first irradiating step
further comprises employing a mask to control the at least a
portion of the coated surface region that is irradiated.
9. The method of claim 1, wherein the first irradiating step
further comprises directing the first ion beam to control the at
least a portion of the coated surface region that is
irradiated.
10. The method of claim 1, further comprising the steps of: forming
one or more holes in the surface of the medical device; loading at
least one of the one or more holes with a therapeutic agent; and
third irradiating an exposed surface of the therapeutic agent in at
least one loaded hole with a third ion beam to form a barrier layer
at the exposed surface.
11. The method of claim 10, wherein the third ion beam is a gas
cluster ion beam.
12. The method of claim 10, wherein the barrier layer controls an
elution rate of therapeutic agent.
13. The method of claim 10, wherein the barrier layer controls a
rate of inward diffusion of a fluid into the hole.
14. A method of modifying a surface of bone-implantable medical
device comprising the steps of: forming one or more holes in the
surface of the medical device; first loading at least one of the
one or more holes with a first therapeutic agent; and first
irradiating an exposed surface of the first therapeutic agent in at
least one loaded hole with a first ion beam to form a first barrier
layer at the exposed surface in the at least one loaded hole.
15. The method of claim 14, wherein the one or more holes are
disposed on the surface in a predetermined pattern to distribute
the first therapeutic agent on the surface according to a
predetermined distribution plan.
16. The method of claim 14, wherein there are at least two holes,
one or more of the holes with a first therapeutic agent and one or
more holes loaded with a second therapeutic agent different from
the first therapeutic agent.
17. The method of claim 15, wherein at least one of the one or more
holes is loaded with a first quantity of the first therapeutic
agent that differs from a second quantity of the first therapeutic
agent loaded in at least another of the one or more holes.
18. The method of claim 14, wherein the first loading step does not
completely fill the at least one hole, and following the first
irradiating step further comprising the steps of: second loading
the at least one incompletely filled hole with a further
therapeutic agent overlying the first barrier layer; and second
irradiating an exposed surface of the further therapeutic agent in
at least one second loaded hole with a second ion beam to form a
second barrier layer at the exposed surface in the at least one
loaded hole.
19. The method of claim 18, wherein the first barrier layer and the
further barrier layer have different properties for controlling
elution rate of the first and second therapeutic agents.
20. The method of claim 14, wherein the first ion beam is a first
gas cluster ion beam.
21. The method of claim 18, wherein the first ion beam is a first
gas cluster in beam and further wherein the second ion beam is a
second gas cluster ion beam.
22. A bone-implantable medical device having a surface, wherein at
least a portion of the surface comprises a shallow layer comprising
molecules and/or dissociation products of an osteoinductive agent
embedded into the at least a portion of the surface.
23. The medical device of claim 22, wherein the shallow layer is a
GCIB infused surface layer.
24. The medical device of claim 23, wherein the surface of the
medical device comprises a material selected from the group
consisting of titanium, titania, and zirconia.
25. The medical device of claim 23, further comprising: one or more
holes containing a therapeutic agent in the surface of the medical
device; and at least one or more barrier layers at one or more
surfaces of the therapeutic agent contained in the one or more
holes; wherein the at least one or more barrier layers constructed
to control at least one elution rate of therapeutic agent.
26. A bone-implantable medical device having a surface, wherein at
least a portion of the surface comprises: one or more holes
containing a therapeutic agent in the surface of the medical
device; and at least one or more barrier layers at one or more
surfaces of the therapeutic agent contained in the one or more
holes; wherein the at least one or more barrier layers control at
least one elution rate of therapeutic agent.
27. The medical device of claim 26, wherein the surface of the
medical device comprises a material selected from the group
consisting of titanium, titania, and zirconia.
28. The medical device of claim 26, wherein the one or more holes
one are disposed on the surface in a predetermined pattern to
distribute the therapeutic agent on the surface according to a
predetermined distribution plan.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Patent Application Ser. No. 61/086,986, filed Aug. 7, 2008 and
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates generally to an implantable medical
device for implantation into or onto a bone of a mammal and to a
method for producing such an implantable medical device. More
specifically, it relates to an implantable medical device made from
a biocompatible material, preferably titanium (with a titania
surface) or zirconia, with at least a portion of its surface parts
modified to facilitate improved integration with bone. The
invention also relates to a method for producing such an implant
that includes the use of ion beam technology, preferably gas
cluster ion beam technology.
BACKGROUND OF THE INVENTION
[0003] As used herein the term "titania" is intended to include
oxides of titanium, and the titanium metal itself (or an alloy
thereof) together with a surface coating of native oxide or other
oxide comprising the element titanium (including without limitation
TiO.sub.2, and or TiO.sub.2 with imperfect stoichiometry).
[0004] As used herein the term "zirconia" is intended to mean
zirconium dioxide (even with imperfect stoichiometry) in any of its
various forms (treated or untreated to toughen it for use in a bone
implant) and any materials or ceramics that are at least 50%
zirconium dioxide.
[0005] As used herein, the term "tricalcium phosphate" is intended
to include without limitation beta tricalcium phosphate.
[0006] As used herein, the term "nutrient material" is intended to
include any material that encourages osteoblasts to grow and
produce bone components on a surface by providing a local nutrient
source. Nutrient material examples include, without limitation,
calcium phosphate-containing materials such as hydroxyapatite
[Ca.sub.5(PO.sub.4).sub.3(OH)].sub.x (HA) or tricalcium phosphate
Ca.sub.3(PO.sub.4).sub.2 (TCP); or other minerals or compounds
having a composition similar to natural bone components including
Bioglass 45S5 and Bioglass 58S; or compounds related to the
foregoing but having imperfect stoichiometry; or other sources of
Ca, Ca.sup.++, P, O, PO.sub.4, or P.sub.2O.sub.5; or molecular
dissociation products including Ca, P, O, and H atoms, as well as
larger fragments of the HA or TCP molecules.
[0007] As used herein, the term "BMP" is intended to include any of
the bone morphogenic proteins that are useful in promoting the
formation and/or attachment of new bone growth when applied in
contact with or in proximity to a bone-implantable medical
device.
[0008] As used herein, the term "bone growth-stimulating agent" is
intended to include any material that stimulates and encourages the
development and functional maintenance of mature osteoblasts. Bone
growth-stimulating agents include, without limitation: growth
factors; cytokines and the like, such as members of the
Transforming Growth Factor-beta (TGF-.beta.) protein superfamily
including any of the Bone Morphogenic Proteins (BMP) and members of
Glycosylphosphatidylinositol-anchored (GPI-anchored) signaling
proteins including members of the Repulsive Guidance Molecule (RGM)
protein family; and other growth regulatory proteins.
[0009] As used herein the term "osteoinductive agent" is intended
to mean a nutrient material and/or a bone growth-stimulating
agent.
[0010] As used herein, the term "hole" is intended to mean any
hole, cavity, crater, trough, trench, or depression penetrating a
surface of a bone-implantable medical device and may extend through
a portion of the device (through-hole), or only part way through
the device (blind-hole, or cavity) and may be substantially
cylindrical, rectangular, or of any other shape.
[0011] As used herein, the term "bone-implantable medical device"
is intended to include, without limitation, dental implants, bone
screws, interference screws, buttons, artificial joint prostheses
(as for example femoral ball prostheses or an acetabular cup
prostheses) that attach to a bone, and endosseus implants,
prostheses and supports or any implant that required the
integration of bone with the implant, and ceramic, polymeric,
metallic, or hybrid materials that are meant to affix ligaments,
tendons, rotator cuffs, and the like soft skeletal tissues to bony
tissues.
[0012] As used herein, the term "therapeutic agent" is intended to
mean a medicine, drug, antibiotic, anti-inflammatory agent,
osteoinductive agent, BMP, or other material that is bioactive in a
generally beneficial way.
[0013] Bone implantable medical devices intended for implant into
or onto the bones of a mammal (including human) are employed as
anchors for dental restoration, fasteners and/or prostheses for
repair of bone fractures, joint replacements, and other
applications requiring attachment to bone. It is known that titania
and zirconia are among preferred materials for such
bone-implantable medical devices because of the biocompatibility of
the material and its ability to accept attachment of new bone
growth, however other materials including stainless steel alloys,
cobalt-chrome alloy, cobalt-chrome-molybdenum alloy, other ceramics
in addition to zirconia, and other materials are also utilized.
Bone-implantable medical devices are often fabricated from titanium
metal (or alloy) that typically has a titania surface (either
native oxide or otherwise). Bone-implantable medical devices may be
coated (or partially coated) with (A) one or more nutrient
materials or (B) one or more bone growth-stimulating agents. Such
materials may be applied as a coating by a variety of techniques.
Bone growth-stimulating agents may be introduced into a surgical
implantation site or applied as coatings for implantable medical
devices and also may serve to facilitate new bone growth and
attachment for integration of the device into the bone. Bone
growth-stimulating agents may be used as an alternative to or in
combination with nutrient material coatings. Coatings of nutrient
materials may be partial, and if totally contiguous on the surface,
may actually discourage adhesion of the cells and bone integration
by leaving exposed gaps on the surface as consumed.
[0014] Other problems exist, in that when such medical devices are
being implanted into bone, the surfaces of the devices most
intimately in contact with the preexisting bone often experience
considerable mechanical abrasion and/or wiping by the bone. For
example, an anchor for a dental implant often consists of a
threaded screw portion that is screwed into a drilled bone hole
and, which effectively becomes a self-tapping screw during implant,
cutting its own threads in the drilled hole. Similarly, orthopedic
bone screws for repairing fractures or attaching prostheses to
immobilize fractures, also experience considerable abrading forces
on the threaded surfaces during their surgical placement. An
artificial hip joint prosthesis has a stem for insertion into a
hole in a femur, and may be forcibly hammered into the opening
during surgical implantation, undergoing abrading forces on the
inserted stem. In such procedures, the aggressive abrasion of the
surfaces of the medical devices during their implantation tends to
abrade away or otherwise result in premature removal or release of
attached osteoinductive agents. This results in reduced benefit
from the osteoinductive coatings, which in turn results in longer
times for complete integration of the implant into the bone. Longer
integration times often correspond to delayed healing and increased
costs and greater suffering for the mammal receiving the
implant.
[0015] Bone-implantable medical devices having holes or grooves for
retaining and delivering osteoinductive agents are known. This
approach provides relief for some of the problems described above.
However, in general, medicines so delivered may not be adequately
retained and may migrate or elute out of the holes more rapidly
than is desired for optimal effect. One response to this problem
has been to mix the medicine with a polymer prior to loading it
into the holes. This can result in slowed release of the medicine
as the polymer biodegrades and/or erodes. Another response has been
to load the medicine and then cover it with a polymer layer. This
can result in delayed or slowed release. In either case the intent
and effect is to delay and/or control the elution of the medicine
from the hole, extending its therapeutic lifetime and
effectiveness. There remain a number of problems associated with
this polymer technology. Because of the mechanical forces involved
in the implantation of a bone-implantable medical device, the
polymeric material has a tendency to crack and sometimes
delaminate. This modifies the medicine release rate from that which
is intended and additionally the polymeric flakes can migrate
through the osteosurgical site and cause unintended side effects.
There is evidence to suggest that the polymers themselves cause a
toxic reaction that may interfere with proper healing and with
long-term success. Additionally, because of the volume of polymer
required to adequately contain the medicine, the total amount of
medicine that can be loaded may be undesirably reduced.
[0016] Gas cluster ion beams (GCIB) are generated and transported
for purposes of irradiating a workpiece according to known
techniques as taught for example in the published U.S. Patent
Application 2009/0074834A1 by Kirkpatrick et al., the entire
contents of which are incorporated herein by reference.
[0017] GCIB have been employed to smooth or otherwise modify the
surfaces of implantable medical devices such as stents, joint
prostheses and other implantable medical devices. For example, U.S.
Pat. No. 6,676,989C1 issued to Kirkpatrick et al. teaches a GCIB
processing system having a holder and manipulator suited for
processing tubular or cylindrical workpieces. In another example,
U.S. Pat. No. 6,491,800B2 issued to Kirkpatrick et al. teaches a
GCIB processing system having workpiece holders and manipulators
for processing other types of non-planar medical devices, including
for example, hip joint prostheses. In view of the increasing use of
surgical implants into or onto bone, the value of the use of
osteoinductive agents, and the problems associated with state of
the art practice, it is desirable to have bone-implantable medical
devices that can be loaded with osteoinductive agents and which are
resistant to the forces and abrasions encountered during the
implantation process, thus providing superior retention for greater
post-implant effectiveness.
[0018] It is therefore an object of this invention to provide
bone-implantable medical devices having surfaces with improved
retention of osteoinductive agents.
[0019] It is further an objective of this invention to provide
methods of attaching and/or retaining osteoinductive agents on
surfaces of bone-implantable medical devices.
[0020] Yet another objective of this invention is to provide
bone-implantable medical devices and methods for their production
that retain medicines or other therapeutic agents in holes with
controlled release or elution rates and without the undesirable
effects associated with the use of polymers by employing gas
cluster ion beam technology.
SUMMARY OF THE INVENTION
[0021] The objects set forth above as well as further and other
objects and advantages of the present invention are achieved by the
invention described herein below.
[0022] The present invention is directed to the use of gas cluster
ion beam processing to form one or more surface regions on
bone-implantable medical devices, the surface regions having
shallow layers including materials that are promoters of bone
growth and adhesion. It is also directed to the use of holes in the
medical device for containing a therapeutic agent such as for
example a BMP. The shallow surface layers and the holes are
resistant to abrasion and damage during implant into a bone.
[0023] Beams of energetic conventional ions, electrically charged
atoms or molecules accelerated through high voltages, are widely
utilized to dope semiconductor device junctions, to smooth or
roughen surfaces by sputtering, and to enhance the properties of
thin films. Unlike conventional ions, gas cluster ions are formed
from clusters of large numbers (having a typical distribution of
several hundreds to several thousands with a mean value of a few
thousand) of weakly bound atoms or molecules of materials that are
gaseous under conditions of standard temperature and pressure
(commonly oxygen, nitrogen, or noble gases such as argon or xenon,
for example, but any condensable gas can be used to generate gas
cluster ions) sharing common electrical charges and which are
accelerated together through high voltages (on the order of from
about 3 kV to 70 kV or more) to have high total energies. Being
loosely bound, gas cluster ions disintegrate upon impact with a
surface and the total energy of the accelerated gas cluster ion is
shared among the constituent atoms. Because of this energy sharing,
the atoms are individually much less energetic than as is the case
for conventional ions or ions not clustered together and, as a
result, the atoms penetrate to much shorter depths, despite the
high energy of the accelerated gas cluster ion.
[0024] Because the energies of individual atoms within a gas
cluster ion are very small, typically a few eV to some tens of eV,
the atoms penetrate through, at most, only a few atomic layers of a
target surface during impact. This shallow penetration (typically a
few nanometers or less to about ten nanometers, depending on the
beam acceleration) of the impacting atoms means all of the energy
carried by the entire cluster ion is consequently dissipated in an
extremely small volume in a very shallow surface layer during a
time period less than a microsecond. This is different from using
conventional ion beams where the penetration into the material may
be much greater, sometimes several hundred nanometers, producing
changes and material modification deep below the surface of the
material (depending on ion beam energy). Because of the high total
energy of the gas cluster ion and extremely small interaction
volume due to shallow penetration, the deposited energy density at
the impact site is far greater than in the case of bombardment by
conventional ions. Accordingly, at the point of impact of a gas
cluster ion on a substrate such as a metal, oxide, or ceramic,
there is a momentary (less than a microsecond) high temperature and
high pressure transient condition that results in dissociation of
the gas cluster and can result in dissociation of molecules, as for
example HA or other osteoinductive agent or agents, that may be on
the surface of the metal, oxide, or ceramic. The transient extreme
conditions can drive the molecular dissociation products and
perhaps entire molecules from their positions on the surface into
the surface of the metal, oxide, or ceramic substrate in a process
referred to as "infusion" or "infusing". The molecules of
osteoinductive agent and/or dissociation products of the molecules
of osteoinductive agent thereby become embedded in and incorporated
into the surface and shallow subsurface of the substrate. The more
volatile and less chemically reactive dissociation products and the
volatile and unreactive components of the gas cluster ions may tend
to escape to a greater degree, while the less volatile and/or more
reactive dissociation products tend to become infused (and
therefore embedded or partially embedded) into a very shallow
surface layer (about 1 to about 10 nanometers thick) of the
substrate, with many of the dissociation products exposed at the
surface where they are available for chemical reaction with both
the substrate surface and with surrounding materials from the
surgical site and thus are positioned to be able to promote new
bone growth and attachment to the substrate. Such a surface layer
is referred to as an "infused surface layer" or a "GCIB infused
surface layer". For HA (as an example), dissociation products may
include Ca, P, O, and H atoms, as well as larger fragments of the
HA molecule. The infused surface may also have its crystallinity
modified from that of the original pre-infusion substrate surface
by the action of the GCIB cluster impacts, typically resulting in
conversion to a more amorphous or less crystalline structure.
[0025] For this reason, the GCIB is capable of transforming a
titania or zirconia surface which has a thin coating of
osteoinductive agent into a surface that is primarily titania or
zirconia, but having a very thin infused layer containing for
example, Ca, P, O, and H atoms (and/or ions) as well as larger
fragments osteoinductive agent molecules, and possibly also
embedded and/or partially embedded osteoinductive agent molecules.
These infusion products are intimately embedded (wholly and/or
partially) in the metal, oxide, or ceramic substrate subsurface to
a depth of up to about 10 nanometers and many are exposed at the
surface and available for promotion of and attachment to new bone
growth. Such a surface is said to be infused with osteoinductive
agent. An osteoinductive agent-infused titania or zirconia surface
inherits beneficial characteristics of the osteoinductive agents
that are infused into the surface, especially so in the case of
nutrient materials. A unique characteristic of an osteoinductive
agent-infused surface of a surgical implant of for example titania
or zirconia is that in addition to the availability of the infusion
products at the surface, considerable amounts of the original
substrate material (for example titania or zirconia) are also
exposed at the surface of the infused region, thus the implant site
sees both the availability of the osteoinductive agent and its
fragments as well as the biocompatibility features of the titania
or zirconia. By controlling the portion of the implant that is
coated, more or less of the surface can be processed. In one
embodiment, more of the original titania or zirconia is exposed at
the surface than is the osteoinductive agent.
[0026] The metal, oxide, or ceramic surface can optionally also be
provided with small holes that are loaded with a medicine such as
BMP or an antibiotic, or other medicine that promotes the
effectiveness of a bone implant.
[0027] Osteoinductive agent coatings may be applied to a
bone-implantable medical device by any of several methods,
including for examples, spraying a suspension of ultra-fine
particles, spraying a solution, precipitation from solution,
dipping, electrostatic deposition, ultrasonic spraying, plasma
spraying, and sputter coating. When coating, a conventional masking
scheme may be employed to limit deposition to selected locations. A
coating thickness of from about 0.01 to about 5 micrometers may be
utilized.
[0028] In one embodiment, the bone-implantable medical device (or
portions of the bone-implantable medical device) may be cleaned by
GCIB irradiation prior to applying the osteoinductive agent
coating.
[0029] After the titania or zirconia has been coated with an
osteoinductive agent, it is processed by ion beam (preferably GCIB)
irradiation to form an osteoinductive agent-infused surface.
[0030] Optionally, the titania or zirconia surface may have holes,
and the holes may additionally be loaded with a therapeutic agent.
Holes may be of selected size or sizes and pattern to control the
dose of the medicine and the distribution of the medicine on the
titania or zirconia surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] For a better understanding of the present invention,
together with other and further objects thereof, reference is made
to the accompanying drawings, wherein:
[0032] FIG. 1 is a view of a prior art bone-implantable medical
device, a dental implant device;
[0033] FIG. 2A is a view of a dental implant device with holes for
loading an osteoinductive agent or other medicine as may be
employed in embodiments of the invention;
[0034] FIG. 2B is a view of a dental implant device with selected
portions of its surface coated with an osteoinductive agent
according to an embodiment of the invention;
[0035] FIG. 2C shows an ion beam irradiation step in the formation
of a GCIB infused layer in portions of the surface of a dental
implant device according to an embodiment of the invention;
[0036] FIG. 2D shows a view of a dental implant device having a
surface with an infused osteoinductive agent according to an
embodiment of the invention;
[0037] FIG. 2E shows a view of a dental implant device with an
infused osteoinductive agent on a portion thereof, further having
holes that are loaded with a medicine and/or an osteoinductive
agent according to an embodiment of the invention;
[0038] FIG. 2F shows a GCIB irradiation step in the formation of a
thin barrier layer in the surface of therapeutic agent loaded in
holes in a dental implant device according to an embodiment of the
invention;
[0039] FIGS. 3A, 3B, 3C, and 3D show detail of the steps for
loading a hole in a bone-implantable medical device with a
therapeutic agent, and forming a thin barrier layer thereon using
ion beam irradiation according to embodiments of the invention;
[0040] FIG. 4 shows a bone-implantable hip joint prosthesis
employing embodiments of the invention; and
[0041] FIG. 5 shows a cross sectional view of the surface of a
bone-implantable medical device having a variety of therapeutic
agent-loaded holes according to the invention and pointing out the
diversity and flexibility of the invention.
DETAILED DESCRIPTION OF THE DRAWINGS
[0042] Reference is now made to FIG. 1, which shows a view 100 of a
prior art bone-implantable medical device in the form of a prior
art dental implant 102. The prior art dental implant 102 is used
for insertion into and implantation into a hole in a jawbone to
form a basis for attaching a dental prosthesis, such as a
prosthetic tooth or a dental restoration, for example. Drilling or
other surgical techniques are typically employed to form the
jawbone hole. The prior art dental implant 102 has a post 110 for
attachment of a dental prosthesis (not shown). It has an
implantable portion consisting of a threaded portion 104 and an
unthreaded portion 106. A neck 108 connects the implantable portion
with the post 110. The prior art dental implant 102 may be a single
piece, or a composite of two or more pieces joined by any of a
variety of known fastening techniques. In general the materials of
the outer surfaces of the implantable portion are formed from
biocompatible materials, often metal, oxide, or ceramic, preferably
titanium with a titania (native or otherwise) surface or zirconia.
Prior art dental implants are manufactured according to numerous
different configurations, but in general they all have an
implantable portion intended to be implanted into a hole or
otherwise attached to a bone. The prior art dental implant 102 has
a threaded portion 104 intended to intimately engage a hole in a
bone, where if the implant is successful, it eventually becomes
integrated with the bone by regrowth of new bone material.
[0043] FIG. 2A is a view 200A of a bone-implantable medical device
in the form of a dental implant 202 as may be employed in an
embodiment of the present invention. Dental implant 202 is an
improved form of the prior art dental implant 102 (as shown in FIG.
1). Referring again to FIG. 2A, the implantable portion of the
dental implant 202 preferably has a titania surface and has a
multiplicity of holes (examples indicated by 204, not all holes
labeled). Although shown in a particular pattern for explaining the
invention, the particular pattern shown is not essential to the
invention and it is understood that many and varied patterns can be
employed in various embodiments of the invention. The relative
sizes of the dental implant 202 and the holes 204 are not
necessarily shown to scale. The holes may have a wide range of
sizes and shapes. The holes 204 can be formed by a variety of
techniques, but the methods of laser machining and focused ion beam
machining are preferable because they can be controlled with great
precision and can produce small, deep holes. The holes 204 may be,
for example from about 50 micrometers to about 500 micrometers in
diameter (or width) and may have an aspect ratio (diameter or width
to depth) of about 0.5 to about 10 or even more. The holes 204 may
be circular as indicated in FIG. 2 or in the form of grooves,
trenches, other shapes, or combinations. The holes 204 may be of a
variety of different diameters (or widths) and aspect ratios and
(if grooves or trenches) lengths and shapes, so as to have
differing volumes. The holes 204, empty at this process step, are
provided for holding one or more therapeutic agents as for example
BMP and/or antibiotics, anti-inflammatory agents, etc.
[0044] FIG. 2B is a view 200B of the dental implant 202, after
additional processing according to an embodiment of the invention.
A portion of the surface of the dental implant is shown as coated
with an osteoinductive agent, for example HA. The coated surface
portion 210 (indicated in the figure by coarse stippling), in this
case corresponds with the surface of the implantable portion of the
dental implant 202, but could alternatively be one or more smaller
regions of the implantable portion of the dental implant 202, with
other regions uncoated. The osteoinductive agent coating may be
applied by any of several methods, including for examples, spraying
or suspension of ultra-fine particles, precipitation from solution,
dipping, electrostatic deposition, ultrasonic spraying, plasma
spraying, and sputter coating. During coating, a conventional
masking scheme may be employed to limit deposition to a selected
location or locations. A coating thickness of from about 0.01 to
about 5 micrometers may preferably be utilized. At this step of the
process, the coating of osteoinductive agent is still susceptible
to the problems described above--it can be abraded away or
otherwise undesirably removed during the mechanical stresses of
implantation into bone.
[0045] FIG. 2C shows a view 200C of the dental implant 202 after a
portion of the surface has been coated with osteoinductive agent.
An ion beam, preferably GCIB 220 is now employed to irradiate the
coated surface portion 210 of the dental implant 202 to form a thin
osteoinductive agent-infused layer in the preferably titania or
zirconia surface of the implantable portion of the dental implant
202 wherever the coated surface portion 210 previously existed.
However, if for any reason it is not desired to form an
osteoinductive agent-infused layer at any portion of the
osteoinductive agent-coated surface, a conventional masking scheme
or controlled direction of the GCIB 220 may be employed to limit
irradiation to selected locations. Although the infused layer has
been described, for example, as an HA-infused layer it will be
readily understood, that if a different osteoinductive agent is
used to form the coated surface portion 210, then the infused layer
will be an infused layer of the different agent. In infusing the
osteoinductive agent into the surface of the dental implant 202, a
GCIB 220 comprising preferably argon cluster ions or oxygen cluster
ions may be employed. The GCIB 220 may be accelerated with an
accelerating potential of from 5 kV to 70 kV or more. The coating
may be exposed to a GCIB dose of at least about 1.times.10.sup.14
gas cluster ions per square centimeter. The GCIB irradiation step
produces an osteoinductive agent-infused layer within the immediate
surface of the titania or zirconia that is on the order of from
about 1 to about 10 nanometers thick. While performing the ion beam
irradiation, it is preferable to rotate the dental implant 202
about its axis with a rotary motion 222 during irradiation to
assure that the desired ion dose is achieved on the entire coated
surface portion 210. U.S. Pat. No. 6,676,989C1 issued to
Kirkpatrick et al. teaches a GCIB processing system having a holder
and manipulator suited for rotary processing tubular or cylindrical
workpieces such as vascular stents and with routine adaptation,
that system is also capable of the rotary irradiation required for
this invention. In certain cases it may be desirable to infuse
larger quantities of osteoinductive agent than can conveniently be
done in a single coating and GCIB irradiation. In such cases, it is
within the scope of the invention to repeat (one or more times) the
steps of (a) coating the desired areas of the dental implant 202
with osteoinductive agent, and (b) irradiating the coated areas
with GCIB to infuse the additional osteoinductive agent (using the
techniques described herein in the descriptions of FIGS. 2B and
2C.
[0046] FIG. 2D shows a view 200D of the dental implant 202
following the HA infusion step. The osteoinductive agent-coated
portion has been fully converted to an osteoinductive agent-infused
surface region 230 according to an embodiment of the invention.
[0047] FIG. 2E shows a view 200E of a dental implant 202, having an
osteoinductive agent infused surface region. At this step, the
holes 204 (as shown in FIG. 2A) are now loaded with a therapeutic
material, forming loaded holes 240 (again referring to FIG. 2E).
The loading of the therapeutic material may be done by any of
numerous methods, including spraying, dipping, wiping,
electrostatic deposition, ultrasonic spraying, vapor deposition, or
by discrete droplet-on-demand fluid jetting technology. When
spraying, dipping, wiping, electrostatic deposition, ultrasonic
spraying, vapor deposition, or similar techniques are employed, a
conventional masking scheme may be beneficially employed to limit
deposition to a hole or to several or all of the holes in the
dental implant 202. For liquids and solutions, discrete
droplet-on-demand fluid-jetting is a preferred deposition method
because it provides the ability to introduce precise volumes of
liquid materials or solutions into precisely programmable
locations. Discrete droplet-on-demand fluid jetting may be
accomplished using commercially available fluid-jet print head
jetting devices as are available (for example, not limitation) from
MicroFab Technologies, Inc., of Plano, Tex. When the therapeutic
material is a liquid, liquid suspension, or a solution, it is
preferably dried or otherwise hardened before proceeding to the
next step. The drying or hardening step may include baking, low
temperature baking, or vacuum evaporation, as examples.
[0048] FIG. 2F is a view 200F showing an ion irradiation step in
the formation of a thin barrier layer in the surface of the
therapeutic agent loaded in the holes in the dental implant 202. An
ion beam, preferably GCIB 250 is now employed to irradiate the
surface of the therapeutic agent in the loaded holes 240 (see FIG.
2E) in the dental implant 202 to form a thin barrier layer at the
surface to the therapeutic agent, forming loaded holes with thin
barrier layers 254 at the exposed surface. The GCIB 250 forms a
thin barrier layer at the surface of the therapeutic agent in the
holes by modification of a thin upper region of the therapeutic
agent. The thin barrier layer consists of therapeutic agent
modified so as to densify, carbonize or partially carbonize,
denature, cross-link, or polymerize molecules of the therapeutic
material in the thin uppermost layer of the therapeutic material.
The thin barrier layer may have a thickness on the order of about
10 nanometers or even less. Additional details on the thin barrier
layer and the process of its formation are described hereinafter in
the discussion of FIGS. 3C and 3D.
[0049] FIGS. 3A, 3B, 3C, and 3D show detail of the steps for
loading holes in a bone-implantable medical device with a
therapeutic agent, and forming a thin barrier layer thereon for
controlling retention and elution of the therapeutic agent by using
GCIB irradiation.
[0050] FIG. 3A shows a view 300A of a portion 304 of a surface 302
of a dental implant 202 (as shown in at the stage indicated in FIG.
2D, i.e., having an osteoinductive agent-infused surface region
according to the invention), wherein the surface 302 represents a
portion of the osteoinductive agent-infused surface region. Again
referring to FIG. 3A, the portion 304 of the surface 302 of the
dental implant 202 has a hole 204 having a diameter 306 and a depth
308. In this instance the hole 204 is intended to represent a
substantially cylindrical hole, but as previously explained, other
hole configurations are expected within the scope of the invention
and the cylindrical nature of the hole is not intended to be
limiting, but rather for clear explanation of the invention. The
hole 204 is at a stage of readiness for loading with a therapeutic
agent.
[0051] FIG. 3B shows a view 300B of a portion 304 of a surface 302
of a dental implant 202 with an osteoinductive agent-infused
surface region. In this stage, the hole 204 has been loaded with a
therapeutic agent 310, forming a loaded hole 240, corresponding to
the loaded hole of FIG. 2E.
[0052] FIG. 3C shows a view 300C of a portion 304 of a surface 302
of a dental implant 202 with an osteoinductive agent-infused
surface region and a loaded hole 240 loaded with therapeutic agent
310. An ion beam, preferably GCIB 250 is directed at the surface of
the therapeutic agent 310 for the purpose of modifying the
uppermost part of the surface of the therapeutic agent 310 to form
a barrier layer. The therapeutic agent 310 is irradiated by the
GCIB 250 modify of a thin upper region of the surface of the
therapeutic agent 310. In modifying the surface, a GCIB 250
comprising preferably argon cluster ions or cluster ions of another
inert gas may be employed. The GCIB 250 is may be accelerated with
an accelerating potential of from 5 kV to 50 kV or more. The upper
surface of the therapeutic agent 310 is may be exposed to a GCIB
dose of at least about 1.times.10.sup.13 gas cluster ions per
square centimeter.
[0053] FIG. 3D shows a view 300D of a portion 304 of a surface 302
of a dental implant 202 with an osteoinductive agent-infused
surface region and a hole 254 that is loaded with a therapeutic
agent 310 upon which has been formed a thin barrier layer 320 by
ion irradiation of the uppermost surface of the therapeutic agent
310. The thin barrier layer 320 consists of therapeutic agent 310
modified so as to densify, carbonize or partially carbonize,
denature, cross-link, or polymerize molecules of the therapeutic
agent in the thin uppermost layer of the therapeutic agent 310. The
thin barrier layer 320 may have a thickness on the order of about
10 nanometers or even less. By selecting the dose and/or
accelerating potential of the GCIB 250 (FIGS. 2F and 3C), the
characteristics of the thin barrier layer 320 may be adjusted to
permit control of the elution rate and/or the rate of inward
diffusion of water and/or other biological fluids when the dental
implant 202 is implanted in bone. In general, increasing
acceleration potential increases the thickness of the thin barrier
layer that is formed, and modifying the GCIB dose changes the
nature of the thin barrier layer by changing the degree of cross
linking, densification, carbonization, denaturization, and/or
polymerization that results. This provides means to control the
rate at which the therapeutic agent 310 will subsequently release
or elute through the barrier and/or the rate at which water and/or
biological fluids my diffuse into the drug from outside the dental
implant 202.
[0054] FIG. 4 shows a bone-implantable medical device in the form
of an artificial hip joint prosthesis 400 for replacement of a
femoral ball. The prosthesis 400 has a ball 402 for replacement of
the ball portion of the natural joint and has a stem 404 for
insertion into and for integration with the femur. According to the
invention, a portion 408 of the surface of the stem 404 has been
osteoinductive agent-infused by osteoinductive agent-coating
followed by ion irradiation (preferably GCIB irradiation) and has a
pattern of holes 406 that are loaded with a therapeutic agent and
which have been ion irradiated (preferably GCIB irradiated) to form
thin barrier layers for control of elution rate of the therapeutic
agent.
[0055] FIG. 5 shows a cross sectional view 700 of the surface 704
of a portion 702 of a bone-implantable medical device having a
variety of therapeutic agent loaded holes 706, 708, 710, 712, and
714 shown to point out the diversity and flexibility of the
invention. The bone-implantable medical device could, for example,
be any of a dental implant, a bone screw, an artificial joint
prosthesis, or any other bone-implantable medical device. The holes
all have thin barrier layers 740 formed according to the invention
on one or more layers of therapeutic agent in each hole. For
simplicity, not all of the thin barrier layers in FIG. 5 are
labeled with reference numerals, but hole 714 is shown containing a
first therapeutic agent 736 covered with a thin barrier layer 740
(only thin barrier layer 740 in hole 714 is labeled with a
reference numeral, but each cross-hatched region in FIG. 5
indicates a thin barrier layer, and all will hereinafter be
referred to by the exemplary reference numeral 740). Hole 706
contains a second therapeutic agent 716 covered with a thin barrier
layer 740. Hole 708 contains a third therapeutic agent 720 covered
with a thin barrier layer 740. Hole 710 contains a fourth
therapeutic agent 738 covered with a thin barrier layer 740. Hole
712 contains fifth, sixth, and seventh therapeutic agents 728, 726,
and 724, each respectively covered with a thin barrier layer 740.
Each of the respective therapeutic agents 716, 720, 724, 726, 728,
736, and 738 may be selected to be a different therapeutic agent
material or may be the same therapeutic agent materials in various
combinations of different or same. Each of the thin barrier layers
740 may have the same or different properties for controlling
elution or release rate and/or for controlling the rate of inward
diffusion of water or other biological fluids according to ion beam
processing (preferably GCIB processing) principles discussed herein
above. Holes 706 and 708 have the same widths and fill depth 718,
and thus hold the same volume of therapeutic agents, but the
therapeutic agents 716 and 720 may be different therapeutic agents
for different therapeutic modes. The thin barrier layers 740
corresponding respectively to holes 706 and 708 may have either
same or differing properties for providing same or different
elution, release, or inward diffusion rates for the therapeutic
agents contained in holes 706 and 708. Holes 708 and 710 have the
same widths, but differing fill depths, 718 and 722 respectively,
thus containing differing therapeutic agent loads corresponding to
differing doses. The thin barrier layers 740 corresponding
respectively to holes 708 and 710 may have either same or differing
properties for providing same or different elution, release, or
inward diffusion rates for the therapeutic agents contained in
holes 708 and 710. Holes 710 and 712 have the same widths 730, and
have the same fill depths 722, thus containing the same total
therapeutic agent loads, but hole 710 is filled with a single layer
of therapeutic agent 738, while hole 712 is filled with multiple
layers of therapeutic agent 724, 726, and 728, which may each be
the same or different volumes of therapeutic agent representing the
same or different doses and furthermore may each be different
therapeutic agent materials for different therapeutic modes. Each
of the thin barrier layers 740 for holes 710 and 712 may have the
same or different properties for providing same or different
elution, release, or inward diffusion rates for the therapeutic
agents contained in the holes. Holes 708 and 714 have the same fill
depths 718, but have different widths and thus contain different
volumes and doses of therapeutic agents 720 and 736. The thin
barrier layers 740 corresponding respectively to holes 708 and 714
may have either same or differing properties for providing same or
different elution, release, or inward diffusion rates for the
therapeutic agents contained in holes 708 and 714. The overall hole
(size, shape, and location) pattern on the surface 704 of the
implantable medical device and the spacing between holes 732 may
additionally be selected to control distribution of therapeutic
agent dose across the surface of the implantable medical device.
Thus there are many flexible options in the application of the
invention for controlling the types and doses and dose
distributions and release sequences and release rates of
therapeutic agents contained in the bone-implantable medical
devices of the invention.
[0056] Although the invention has been described with respect to
formation of exemplary HA-infused layers, it is recognized that
other osteoinductive agents can equally well be employed in forming
the infused layers within the scope of the invention. Although the
invention has particularly been described in terms of application
to titanium (with titania surface) and zirconia dental implants, it
is recognized that the scope of the invention includes
bone-implantable medical devices constructed of a wide variety of
other materials. Although the invention has been described with
respect to various embodiments and applications in the field of
bone-implantable medical devices (dental implants, joint
prostheses, etc.), it is understood by the inventors that its
application is not limited to that field and that the concepts of
GCIB infusion of surface coating materials into the surfaces upon
which they reside has broader application in fields that will be
apparent to those skilled in the art. It should be realized that
this invention is also capable of a wide variety of further and
other embodiments within the spirit and scope of the invention and
the appended claims.
* * * * *