U.S. patent application number 17/361582 was filed with the patent office on 2021-12-30 for medical implants and methods of manufacture.
The applicant listed for this patent is DiFusion, Inc.. Invention is credited to Joseph J. Crudden, Derrick Johns, Sriram Sankar.
Application Number | 20210402052 17/361582 |
Document ID | / |
Family ID | 1000005710556 |
Filed Date | 2021-12-30 |
United States Patent
Application |
20210402052 |
Kind Code |
A1 |
Johns; Derrick ; et
al. |
December 30, 2021 |
Medical Implants And Methods Of Manufacture
Abstract
Anti-biofilm osseointegrating and/or tissue-integrating
implantable biomaterial devices that optionally can elute
therapeutic ions such as magnesium, silver, copper and/or zinc. In
certain embodiments, the devices are engineered to produce
structures suitable as implants having a relatively high surface
population of zeolite. Methods of producing the devices are also
disclosed.
Inventors: |
Johns; Derrick; (Liberty
Hill, TX) ; Crudden; Joseph J.; (Hudson, NH) ;
Sankar; Sriram; (Austin, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DiFusion, Inc. |
Austin |
TX |
US |
|
|
Family ID: |
1000005710556 |
Appl. No.: |
17/361582 |
Filed: |
June 29, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
63046191 |
Jun 30, 2020 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2430/10 20130101;
A61K 33/30 20130101; A61L 2300/102 20130101; A61L 27/18 20130101;
A61K 33/00 20130101; A61L 27/025 20130101; A61L 2300/404 20130101;
A61K 33/34 20130101; A61L 2300/104 20130101; A61L 27/08 20130101;
A61K 33/06 20130101; A61K 33/38 20130101 |
International
Class: |
A61L 27/02 20060101
A61L027/02; A61L 27/18 20060101 A61L027/18; A61L 27/08 20060101
A61L027/08; A61K 33/38 20060101 A61K033/38; A61K 33/34 20060101
A61K033/34; A61K 33/30 20060101 A61K033/30; A61K 33/06 20060101
A61K033/06; A61K 33/00 20060101 A61K033/00 |
Claims
1. A medical implant comprising a thermoplastic polymer defining a
main body region and a surface region, said surface region being
configured to be exposed to bodily fluid or tissue of a host when
said medical implant is implanted in said host, said surface region
comprising zeolite in an amount greater than 12% by weight.
2. The medical implant of claim 1, wherein said surface region
contains a plurality of indentations containing said zeolite.
3. The medical implant of claim 1, wherein said surface region
comprises zeolite in an amount greater than 15% by weight.
4. The medical implant of claim 1, wherein said surface region
comprises zeolite in an amount greater than 20% by weight.
5. The medical implant of claim 1, wherein said surface region
comprises zeolite in an amount greater than 25% by weight.
6. The medical implant of claim 1, wherein said surface region
comprises zeolite in an amount greater than 30% by weight.
7. The medical implant of claim 1, wherein said surface region
comprises zeolite in an amount greater than 50% by weight.
8. The medical implant of claim 1, wherein said main body region
comprises zeolite in an amount of 12% by weight or less.
9. The medical implant of claim 1, wherein said implant is
configured as a member selected from the group consisting of an ACL
screw.
10. The medical implant of claim 1, wherein said implant is
configured as a spinal implant, a knee implant, a hip stem, a skull
flap, a dental implant or a trauma plate.
11. The medical implant of claim 1, wherein said thermoplastic
polymer comprises PEEK.
12. The medical implant of claim 1, further comprising carbon
fibers.
13. The medical implant of claim 1, wherein said zeolite comprises
one or more antimicrobial and/or therapeutic metal ions.
14. The medical implant of claim 13, wherein said one or more metal
ions is selected from the group consisting of silver, copper, zinc,
magnesium and strontium.
15. A method of making a medical implant having a main body region
and an exposed surface region and comprising a polymer, the method
comprising: a. heating the polymer to a molten state b. contacting
the polymer with a mixture of zeolite and indentation-forming agent
with the application of force to form indentations in said exposed
surface region and drive said mixture into the formed indentations
of the exposed surface region; c. cooling the polymer; an d.
washing the resulting composite.
16. The method of claim 15, wherein said polymer is PEEK.
17. A method of making a medical implant having a main body region
and an exposed surface region and comprising a polymer, the method
comprising: a. heating the polymer to a molten state; b. contacting
the polymer with an indentation-forming member and zeolite to form
indentations in said exposed surface region and drive the zeolite
into the indentations in the exposed surface region; and c. cooling
the resulting composite structure.
18. The method of claim 17, wherein said polymer is PEEK.
19. The method of claim 17, wherein said indentation-forming member
comprises sandpaper.
20. A method of making a medical implant having a main body region
and an exposed surface region and comprising a polymer, the method
comprising: a. injecting the polymer into the cavity of a mold at
elevated temperature sufficient to melt the resin, the mold
comprising a surface having a plurality of projections and a
coating of zeolite; b. causing the melted polymer to contact said
projections and driving the zeolite into the resin; c. removing the
resulting article from the mold and cooling it.
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 63/046,191 filed Jun. 30, 2020, the disclosure
of which is hereby incorporated by reference.
BACKGROUND
[0002] Implantable biomaterials may be surgically implanted into
the body for various reasons, including orthopedic applications
(e.g., hip replacement, skull flaps, dental implants, spinal
procedures, knee replacement, bone fracture repair, etc.), surgical
repair applications (e.g., ACL screws, surgical meshes, etc.). In
view of the structural integrity required by many such devices,
particularly those involving bone repair or replacement, materials
of fabrication are limited and generally consist of metal, plastic
and composites.
[0003] The benefits derived from these devices are often offset by
infection which in some cases can lead to sepsis and death. The
most common organisms causing infections are Staphylococcus
epidermidis and Staphylococcus aureus. Staphylococcus epidermidis
is a major component of the normal bacterial flora of human skin
and mucous membranes. It is a common pathogen that often colonizes
patients in hospital settings who have surgical implants due to the
microbes' ability to adhere to medical devices and form a biofilm.
Additionally, methicillin-resistant Staphylococcus aureus (MRSA) is
a type of staphylococcus bacteria that is resistant to many
antibiotics is therefore of particular concern. Other gram-positive
bacteria, gram-negative bacteria and fungal organisms also are
causative organisms that may be problematic.
[0004] As microorganisms come in close proximity to the surface of
the medical device, they will either be attracted or repelled by it
depending on the sum of the different non-specific interactions. In
biological systems, hydrophobic/hydrophilic interactions play an
important role in the pathogenesis of a wide range of microbial
infections.
[0005] The role of the neutralization of infectious agents, and the
host response to foreign materials such as surgical meshes,
orthopedic implants, and other devices, in normal tissue/organ
development and tissue regeneration is important. Immune cells such
as neutrophils, macrophages, and lymphocytes possess robust
plasticity with respect to phenotype. For example, macrophages
typically show a marked pro-inflammatory (M1-like) phenotype when
presented with certain antigens (e.g., synthetic foreign materials
or bacteria), but then transition to pro-healing, anti-inflammatory
and constructive phenotype (M2-like) when subsequently influenced
by alternative signaling molecules.
[0006] A "normal" response to injury involves an initial
pro-inflammatory cell response that must then switch to a
pro-healing phenotype lest there be continuous, non-healing
inflammation and tissue destruction. The phenotype of cells such as
macrophages can be determined, at least in part, by the expression
of certain markers that are detected by immunolabeling. Macrophage
phenotype during the early response (i.e., 7-14 days) to an
implanted foreign material is predictive of the downstream outcome.
An early M1-like response was associated with chronic inflammation
and fibrosis; whereas an early M2-like response was associated with
minimal fibrosis and constructive and functional tissue
remodeling.
[0007] It is therefore important, if not critical, that implantable
biomaterials be developed that promote activation of several genes
associated with an M2-like macrophage phenotype. A desirable M1/M2
macrophage phenotype balance, and in particular, the early
preferential polarization towards an M2 phenotype after
implantation, can lead to a shorter pro-inflammatory period and
earlier reparative process, which can be critical for effective
osseointegration and/or tissue integration and ultimately implant
success.
[0008] Certain polymeric materials, such as polyetherketoneketone
(PEKK) and polyetheretherketone (PEEK) have been found to be a
useful material for medical implants, particularly due to their
modulus of elasticity which closely matches that of bone. However,
in addition to strength characteristics, a suitable polymeric
material for implant applications should interact well with tissue,
and should osseointegrate with bone. The polymer should also be
recognized by the host as natural so as to minimize or avoid
becoming encapsulated by a fibrous apposition layer of soft tissue
rather than becoming bonded or fused to bone and tissue cells.
[0009] However, many resins including PEEK are hydrophobic
materials and bacteria tend to adhere easily to these types of
surfaces. They are also organic materials which do not carry
significant surface charges. Consequently, it would be desirable to
develop a medical implant composed of one or more thermoplastic
resins that has reduced hydrophobic properties, and/or that has a
net negative charge, particularly at an exposed surface when
implanted into a host.
[0010] The addition of ceramics such as zeolites to such resins
helps accomplish this. In addition, zeolites can provide
ion-exchange sites and can be loaded with antimicrobial metal ions
that elute when in contact with the bodily fluid or tissue of a
host, thereby imparting antimicrobial activity to the implant site.
Since conventionally the zeolite has been uniformly distributed in
the thermoplastic matrix, a composite with 10% loading, for
example, will have 10% of the surface occupied by zeolite
particles. While a higher concentration of zeolite at the surface
is desirable, the amount of zeolite that can be loaded into a resin
is limited in part by the desired or required biomechanical
properties of the resulting composite implant. For example, an
implant with more than about 12% uniformly distributed zeolite may
not have the load-bearing characteristics necessary for
load-bearing applications, such as spinal implantation.
[0011] It therefore would be beneficial to have a higher zeolite
surface occupancy of the composite in order to enhance the
therapeutic effects of the device, including osseointegration and
tissue integration, without compromising the biomechanical and
imaging properties of the device.
[0012] It therefore is an object of embodiments disclosed herein to
provide methods for increasing the amount of zeolite at the surface
of an implant, while maintaining the amount of zeolite, if any, in
the main body of the implant, at a level that does not compromise
the biomechanical properties of the implant.
[0013] It is a further object of embodiments disclosed herein to
provide composite implants with an increased amount of zeolite at
the surface of the implants.
SUMMARY
[0014] The shortcomings of the prior art have been overcome by
embodiments disclosed herein, which relate to anti-biofilm
osseointegrating and/or tissue-integrating implantable biomaterial
devices that optionally can elute therapeutic ions such as
magnesium, silver, copper and/or zinc. In certain embodiments,
medical devices such as implants are engineered to produce
structures suitable as implants having a relatively high surface
population of zeolite. The resulting device may be formed into the
shape of the desired implant, e.g., a hip stem; skull flap; spinal
implant (e.g., an intervertebral spacer); dental implant; joint
implant, e.g., a knee implant; screw, rod, hip stem; skull flap or
trauma plate. In certain embodiments, the implants are orthopedic
implants, such as spinal, knee and hip implants, and are so shaped
or configured. In certain embodiments, the implant is an ACL screw
such as an interference screw and is so shaped and configured.
[0015] In some embodiments, the biomaterial includes a polymer such
as PEKK, PEEK, polylactic acid (PLA) and/or polymethyl (meth)
acrylate.
[0016] In some embodiments, the biomaterial includes zeolite, and
the zeolite optionally may be loaded with one or more therapeutic
metal ions, such as magnesium, silver, copper and/or zinc, that
exhibit antimicrobial properties when implanted into a body and
exposed to bodily fluid or tissue. The devices, when implanted into
a body and exposed to bodily fluid, may elute antimicrobial metal
ions in a therapeutically effective amount. In certain embodiments,
the source of antimicrobial activity includes ion-exchangeable
cations contained in a zeolite. In certain embodiments, disclosed
are methods of imparting antimicrobial activity to devices by
controlling the delivery of certain cations through ion-exchange
via a zeolite incorporated in the device introduced in a patient.
Ceramics such as zeolite function as a cation cage, being able to
be loaded with silver and other cations having antimicrobial
properties. Metal zeolites can be used as an antimicrobial agent,
such as by being mixed with the resins used as thermoplastic
materials to make the implantable devices, or as coatings to be
applied to the devices, or incorporated into the surface of the
devices. The antimicrobial metal zeolites can be prepared by
replacing all or part of the ion-exchangeable ions in zeolite with
ammonium ions and antimicrobial metal ions. Such materials have
been seen to perform extremely well in ovine and rabbit implant
studies, showing high tissue compatibility, and bonding very well
to bone and soft tissues alike.
[0017] In some embodiments, the zeolite does not contain an
antimicrobial metal ion, yet imparts hydrophilicity and a negative
charge to the implant. This helps prevent biofilm formation and
enhances osseointegration and/or tissue integration. In embodiments
where antimicrobial ions are present, the polymer/zeolite
combination increases the ability of antimicrobial moieties to
permeate in and kill bacterial pathogens in vivo.
[0018] In certain embodiments, the device is configured for use in
spinal fusion (arthrodesis) which is often employed to stabilize an
unstable spinal column due to structural deformity, trauma,
degeneration, etc. Fusion is a surgical technique in which one or
more vertebrae of the spine are united together ("fused") to reduce
or eliminate relative motion between them or to fix the spatial
relationship between them. Spinal fusions include posterolateral
fusion, posterior lumbar interbody fusion, anterior lumbar
interbody fusion, anterior/posterior spinal fusion, cervical
fusion, thoracic fusion and interlaminar fusion. In certain
embodiments, the devices are for insertion in an intervertebral
space between adjacent vertebrae. In certain embodiments, a fusion
site is identified between adjacent vertebrae and a bone graft is
implanted at said site. In certain embodiments, the implant is a
spinal interbody cage.
[0019] The hydrophilicity imparted by the zeolite results in an
engineered biomaterial that interacts with the bone of a host and
induces a bone/biomaterial fusion, or that interacts with the
tissue of a host and induces tissue integration with the
biomaterial. The presence of an enhanced amount of zeolite at the
surface of the device results in a rapid transition from M1
proinflammatory macrophage phenotype to the M2 macrophage
phenotype, thereby minimizing fibrous encapsulation and
facilitating the deposition of site appropriate tissue ultimately
yielding constructive and functional tissue ingrowth and
remodeling. The negative charge imparted by the zeolite attracts
and adheres the required precursor proteins for bone growth to the
implant surface, and ultimately supports long term
osseointegration.
[0020] In certain embodiments, zeolite particles are incorporated
into the resin such that a negative charge is imparted to an
exposed surface of the resin. The term "exposed surface" is
intended to include one or more surfaces of an implantable device
that when implanted into the body of a host, is exposed to or in
contact with body tissue and/or bodily fluids of the host. The
incorporation of zeolite to the exposed surface reduces the immune
response, e.g., reduction of deleterious release of cytokines, such
as interleukin 2, etc. upon implantation.
[0021] Accordingly, disclosed is a medical implant comprising a
thermoplastic polymer defining a main body region and an exposed
surface region, the exposed surface region being configured to be
exposed to bodily fluid or tissue of a host when the medical
implant is implanted in the host, the surface region comprising
zeolite in an amount greater than 10% by weight. In some
embodiments, the surface region comprises zeolite in an amount
greater than 12% by weight. In some embodiments, the surface region
comprises zeolite in an amount equal to or greater than 15% by
weight. In some embodiments, the surface region comprises zeolite
in an amount equal to or greater than 20% by weight. In some
embodiments, the surface region comprises zeolite in an
amount-equal to or greater than 25% by weight. In some embodiments,
the surface region comprises zeolite in an amount equal to or
greater than 50% by weight. In some embodiments, the surface region
comprises zeolite in an amount equal to or greater than 75% by
weight. In some embodiments, the surface region comprises zeolite
in an amount as high as 95% by weight. The resulting implant
provides an excellent mechanical interlock with bone at the implant
site.
[0022] Embodiments include exposed surface regions that have
indentations or discontinuities, and are thus more porous than the
main body region, and wherein a plurality of indentations in the
surface region contain zeolite. In some embodiments, the main body
region is devoid of zeolite. In other embodiments, the main body
region contains between about 5 to about 12% zeolite.
[0023] In various embodiments, the medical implant may be
configured as an ACL screw, such as an interference screw, a
pedicle screw, a rod, a spinal implant such as an intervertebral
spacer, a joint implant or replacement such as a knee implant, a
hip stem, a skull flap, a dental implant or a trauma plate.
[0024] In certain embodiments, the thermoplastic polymer is PEEK.
In some embodiments, the device includes carbon fibers to enhance
mechanical strength. In some embodiments, the carbon fibers are in
the main body region of the device. In some embodiments, the carbon
fibers are in the surface region of the device. In some
embodiments, the carbon fibers are in both the main body region and
the surface region.
[0025] In various embodiments, a therapeutically effective amount
of one or more antimicrobial and/or therapeutic metal ions may be
added to the zeolite in the surface region to enable ion-exchange
at the implant site to cause effective antimicrobial activity. In
embodiments where the main body region includes zeolite,
antimicrobial metal ions optionally may be added to the zeolite in
the main body region. Suitable ions include silver, copper, zinc,
mercury, tin, magnesium, lead, gold, bismuth, cadmium, chromium,
strontium and thallium ions, calcium, silicon or combinations of
one or more of the foregoing.
[0026] Various methods may be used to form the indentations in the
surface region of the article and incorporate the zeolite in the
indentations formed, including creating the indentations with
particles of a salt, creating the indentations with sandpaper or
other substrate having indentation-forming members extending
therefrom, and creating indentations with injection molding or
press molding.
[0027] In a first exemplary embodiment, disclosed is a medical
implant comprising a thermoplastic polymer defining a main body
region and a surface region, said surface region being configured
to be exposed to bodily fluid or tissue of a host when said medical
implant is implanted in said host, said surface region comprising
zeolite in an amount greater than 12% by weight.
[0028] In a first aspect of the first exemplary embodiment, the
surface region contains a plurality of indentations containing said
zeolite.
[0029] In a second aspect of the first exemplary embodiment, the
surface region comprises zeolite in an amount greater than 15% by
weight.
[0030] In a third aspect of the first exemplary embodiment, the
surface region comprises zeolite in an amount greater than 20% by
weight.
[0031] In a fourth aspect of the first exemplary embodiment, the
surface region comprises zeolite in an amount greater than 25% by
weight.
[0032] In a fifth aspect of the first exemplary embodiment, the
surface region comprises zeolite in an amount greater than 30% by
weight.
[0033] In a sixth aspect of the first exemplary embodiment, the
surface region comprises zeolite in an amount greater than 50% by
weight.
[0034] In a seventh aspect of the first exemplary embodiment, which
may be based on any of the foregoing aspects, the main body region
comprises zeolite in an amount of 12% by weight or less.
[0035] In an eighth aspect of the first exemplary embodiment, which
may be based on any of the forgoing aspects, the implant is
configured as an ACL screw.
[0036] In a ninth aspect of the first exemplary embodiment, which
may be based on any of the first through seventh aspects, the
implant is configured as a spinal implant, a knee implant, a hip
stem, a skull flap, a dental implant or a trauma plate.
[0037] In a tenth aspect of the first exemplary embodiment, which
may be based on any of the first through ninth aspects, the
thermoplastic polymer comprises PEEK.
[0038] In an eleventh aspect of the first exemplary embodiment,
which may be based on any of the first through tenth aspects, the
medical implant further comprises carbon fibers.
[0039] In a twelfth aspect of the first exemplary embodiment, which
may be based on any of the first through eleventh aspects, the
zeolite comprises one or more antimicrobial and/or therapeutic
metal ions.
[0040] In a thirteenth aspect of the first exemplary embodiment,
which may be based on the twelfth aspect, the one or more metal
ions is selected from the group consisting of silver, copper, zinc,
magnesium and strontium.
[0041] In a second exemplary embodiment, disclosed is a method of
making a medical implant having a main body region and an exposed
surface region and comprising a polymer, the method comprising:
[0042] a. heating the polymer to a molten state; [0043] b.
contacting the polymer with a mixture of zeolite and
indentation-forming agent with the application of force to form
indentations in said exposed surface region and drive said mixture
into the formed indentations of the exposed surface region; [0044]
c. cooling the polymer; and [0045] d. washing the resulting
composite.
[0046] In a first aspect of the second exemplary embodiment, the
polymer is PEEK.
[0047] In a third exemplary embodiment, disclosed is a method of
making a medical implant having a main body region and an exposed
surface region and comprising a polymer, the method comprising:
[0048] e. heating the polymer to a molten state; [0049] f.
contacting the polymer with an indentation-forming member and
zeolite to form indentations in said exposed surface region and
drive the zeolite into the indentations in the exposed surface
region; and [0050] g. cooling the resulting composite
structure.
[0051] In a first aspect of the third exemplary embodiment, the
polymer is PEEK.
[0052] In a second aspect of the third exemplary embodiment, the
indentation-forming member comprises sandpaper.
[0053] In a third aspect of the second embodiment, which may be
based on the second aspect of the third exemplary embodiment, the
indentation-forming member comprises sandpaper.
[0054] In a fourth exemplary embodiment, disclosed is a method of
making a medical implant having a main body region and an exposed
surface region and comprising a polymer, the method comprising:
[0055] h. injecting the polymer into the cavity of a mold at
elevated temperature sufficient to melt the resin, the mold
comprising a surface having a plurality of projections and a
coating of zeolite; [0056] i. causing the melted polymer to contact
said projections and driving the zeolite into the resin; [0057] j.
removing the resulting article from the mold and cooling it.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] FIG. 1 is a photograph of a PEEK sample having increased
surface area at the exposed surface region in accordance with
certain embodiments.
DETAILED DESCRIPTION
[0059] A more complete understanding of the components, processes,
systems and apparatuses disclosed herein can be obtained by
reference to the accompanying drawings. The figures are merely
schematic representations based on convenience and the ease of
demonstrating the present disclosure, and are, therefore, not
necessarily intended to indicate relative size and dimensions of
the devices or components thereof and/or to define or limit the
scope of the exemplary embodiments.
[0060] Although specific terms are used in the following
description for the sake of clarity, these terms are intended to
refer only to the particular structure of the embodiments selected
for illustration in the drawings. In the drawings and the following
description below, it is to be understood that like numeric
designations refer to components of like function.
[0061] The singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise.
[0062] As used in the specification, various devices and parts may
be described as "comprising" other components. The terms
"comprise(s)," "include(s)," "having," "has," "can," "contain(s),"
and variants thereof, as used herein, are intended to be open-ended
transitional phrases, terms, or words that do not preclude the
possibility of additional components.
[0063] All ranges disclosed herein are inclusive of the recited
endpoint and independently combinable (for example, the range of
"from 2% to 10" is inclusive of the endpoints, 2% and 10%, and all
the intermediate values).
[0064] As used herein, approximating language may be applied to
modify any quantitative representation that may vary without
resulting in a change in the basic function to which it is related.
Accordingly, a value modified by a term or terms, such as "about"
and "substantially," may not be limited to the precise value
specified, in some cases. The modifier "about" should also be
considered as disclosing the range defined by the absolute values
of the two endpoints. For example, the expression "from about 2 to
about 4" also discloses the range "from 2 to 4."
[0065] It should be noted that many of the terms used herein are
relative terms. For example, the terms "upper" and "lower" are
relative to each other in location, i.e. an upper component is
located at a higher elevation than a lower component, and should
not be construed as requiring a particular orientation or location
of the structure. As a further example, the terms "interior",
"exterior", "inward", and "outward" are relative to a center, and
should not be construed as requiring a particular orientation or
location of the structure.
[0066] The terms "top" and "bottom" are relative to an absolute
reference, i.e. the surface of the earth. Put another way, a top
location is always located at a higher elevation than a bottom
location, toward the surface of the earth.
[0067] Certain embodiments disclosed herein relate to a biomaterial
formulated by incorporating a negatively charged zeolite into a
base polymer, such as PEEK. The zeolite changes the surface
topography, charging characteristics, and pH of the resulting
composite in a predictable, suitable manner for the surgical
environment and long-term healing of the host into whom the device
is implanted. Attributes imparted by the zeolite include bone
fusion, tissue fusion, biocompatibility, negative charge,
hydrophilicity and osseoconductivity. Attributes provided by the
PEEK base polymer include excellent imaging properties including
radiolucency; biocompatibility, durability and versatility. The
resulting combination provides a material construct having
excellent workability and functionality.
[0068] Particularly compelling is the ability of the zeolite to
mitigate or eliminate the immune response that is generated when
naked PEEK (or other polymeric material) is implanted. It is a
well-recognized problem that the human immune system reacts to the
presence of naked PEEK as a foreign, unnatural substance, and as a
damage/danger associated molecular pattern (DAMP). Consequently,
the human body responds to the presence of naked PEEK by
encapsulating it, causing bone resorption, and initiating a pain
response. This is believed to be directly related to the
hydrophobic, uncharged and water repellant nature of naked PEEK.
Adding zeolite to the PEEK polymer increases proliferation,
differentiation and transforms growth factor beta production in
normal adult human osteoblast-like cells. The hydrophilic surface
of the resulting implant down-regulates pro-inflammatory cytokines
interleukin 1 and 6, which modulates the immune response,
facilitates the enhanced bone would healing and osseointegration,
allows for early cell adhesion and ultimate osteoconduction, and
reduces pain. IL1-Beta upregulates inflammatory immune-response,
and IL6-Beta have been shown to have a direct relation to spinal
disc pain. Both have been shown to down regulate osteoblast cells
while up-regulating osteoclast cells, showing the increased
fibrosis and resorption of bone with which naked hydrophobic PEEK
has been well associated.
[0069] PEEK does not bond well to tissue and both PEEK and PEKK
materials are susceptible to microbial contamination and to the
support of bacterial biofilms. Composites of zeolite with PEEK
produce a more hydrophilic and negatively charged surface which is
less favorable to bacterial adhesion and more receptive to tissue
attachment and integration. The hydrophilicity imparted by the
zeolite results in an engineered biomaterial that interacts with
the bone of the patient and induces a bone/biomaterial fusion. The
presence of the zeolite also results in a rapid transition (e.g.,
faster than the transition that occurs in the absence of zeolite)
from M1 proinflammatory macrophage phenotype to the M2 macrophage
phenotype, thereby minimizing fibrous encapsulation and
facilitating the deposition of site appropriate tissue ultimately
yielding constructive and functional tissue remodeling. The
negative charge imparted by the zeolite attracts and adheres the
required precursor proteins for bone growth to the implant surface,
and ultimately supports long term osseointegration.
[0070] The implant may comprise one or more of titanium, carbon
fibers, biocompatible materials such as polyetheretherketone
(PEEK), polyetherketoneketone (PEKK), polylactic acid, or other
synthetic substances. Other suitable resins include low density
polyethylene, polypropylene, ultra-high molecular weight
polyethylene or polystyrene, polyvinyl chloride, ABS resins,
silicones, rubber, polymethylmethacrylate (which melts at about
320.degree. C.) and mixtures thereof, and reinforced resins, such
as ceramic or carbon fiber-reinforced resins, particularly carbon
fiber-reinforced PEEK. PEEK is particularly preferred, and melts at
between 385 and 400 degrees celsius.
[0071] In certain embodiments, zeolite particles may be
incorporated into the polymer interbody cage to form a composite
polymer resin/zeolite blend. In certain embodiments, the cage may
be loaded with bioagents such as osseoconductive and/or
osseoinductive agents to promote fusion. In some embodiments, the
implant includes PEEK resin, and ceramic particles such as zeolite
are uniformly incorporated into the main body region of the
resin.
[0072] In order to increase the concentration of zeolite at the
surface of the implant, zeolite may be forced into one or more
surfaces of the implant. This may be applied to naked polymer
(i.e., polymer with no zeolite incorporated into the main body
region), or to a composite polymer resin/zeolite blend such as the
composite prepared as above. Numerous methods may be used to
accomplish the addition of zeolite to the exposed surface region of
the implant article. For example, the polymer resin may be heated
to a molten state, and the molten resin may be contacted with solid
particles of an indentation forming agent or member, such as sodium
chloride or sodium bicarbonate, with sufficient force to cause the
particles to penetrate the resin surface and form indentations for
occupation by zeolite. Suitable sodium chloride particles may have
an average particle size ranging from 2 to 10 microns, as large as
about 0.3-0.5 mm, or even larger. In some embodiments, the size of
the indentation forming agent or member is similar to or about the
same as the size of the zeolite particles. Other suitable
indentation forming agents include potassium chloride, calcium
phosphate, sulfate or silicate, sodium citrate, sodium tartrate,
ammonium bicarbonate, ammonium chloride, sodium fluoride, potassium
fluoride, sodium iodide, sodium nitrate, sodium sulphate, sodium
iodate, and mixtures thereof. Residual exposed indentation forming
agent can be washed from the surface of the implant using pure
water. Preferably the salts are used in fine powder form and are
water soluble so that they easily can be removed from the device
such as after the device is cooled. Preferably the indentation
forming agent is micronized salt, preferably sodium chloride,
having an average particle size of about 0.3 mm. The depth of the
penetration of the agent into the resin depends in part on the size
of the solid particles. The resulting indentations creates a
roughened surface area which can then be contacted with zeolite to
load the zeolite into the indentations created by the agent. In
some embodiments, the molten resin can be contacted with the
zeolite and indentation forming agent simultaneously, such as by
mixing the zeolite with the agent prior to contacting with the
molten resin. Since the increased concentration of zeolite is only
at the exposed surface of the article, the mechanical integrity of
the article is not deleteriously compromised. As a result, zeolite
amounts much greater than the typical about 12% maximum amount that
can be tolerated in the case where zeolite is incorporated into the
resin uniformly (from the stand point of maintaining acceptable
mechanical integrity for purposes of implantation, particularly
load-bearing implantation) can be added. Amounts ranging from about
15-95% zeolite at the surface of the implant article can be
achieved. Preferred amounts include from 15-20 wt. % zeolite, 20-25
wt. % zeolite, 25-30 wt. % zeolite, 30-35 wt. zeolite, 35-40 wt. %
zeolite, 45-50 wt. % zeolite, 50-55 wt. zeolite, 55-60 wt. %
zeolite, 60-65 wt. % zeolite, 65-70 wt. zeolite, 70-75 wt. %
zeolite, 75-80 wt. % zeolite, 80-85 wt. zeolite, 85-90 wt. %
zeolite, and 90-95 wt. % zeolite at the surface region of the
article.
[0073] In some embodiments, the surface region is non-planar in
view of the formed indentations, and the indentations have a depth
of from about 4 to about 10 microns.
[0074] In another embodiment, the enhanced concentration of zeolite
at the exposed surface region can be carried out by contacting the
molten polymer with an indentation-forming member comprising a
substrate having rigid protrusions or discontinuities extending
therefrom. In the case of a flat or planar substrate, the angle of
extension can be perpendicular to the axis defined by the planar
substrate, or at an angle less than 90.degree. to the axis defined
by the planar substrate, such as 80.degree., 75.degree.,
70.degree., 65.degree., 60.degree. or less. The rigid protrusions
can be integral to the substrate, or can be attached to the
substrate by any suitable means such as with a suitable adhesive.
They can be randomly oriented, or oriented in a uniform, equally
spaced array. The protrusions can have various shapes, including
spike-like or conical, cylindrical, pyramidal, etc. Preferably the
rigid protrusions remain attached to the substrate and do not
detach from the substrate and remain in the molten polymer.
[0075] One suitable indentation-forming member is sandpaper or any
coated abrasive comprising a backing with abrasive grit attached
thereto. Suitable abrasive grits include garnet, emery, aluminum
oxide, silicon carbide, zirconium alumina, alumina and diamond.
Suitable grit sizes are not particularly limited, and depend in
part on the size of the indentations desired. Grit sizes ranging
from about 40 to about 220 may be suitable, with grit sizes of 60
and 80 grit being preferred.
[0076] In some embodiments, the molten polymer may be contacted
with the indentation-forming member coated with zeolite. For
example, zeolite powder may be dusted or otherwise introduced onto
the sandpaper or indentation-forming member substrate. Force may
then be applied to assist or enhance the penetration of the rigid
protrusions and zeolite into the molten resin. The force applied
may be manual or automatic. Suitable amounts of force may include
from about 10 to about 20 psi for about 30 seconds. This creates a
roughened surface area which can then be contacted with zeolite to
load the zeolite into the indentations in the exposed surface
region created by the indentation-forming member. The process may
be carried out multiple times with the same size grit size or with
different size grits.
[0077] In yet a further embodiment, a molding operation can be used
to form the implant and make one or more surfaces of the implant
roughened or having an increased surface area due to formed
indentations, such as injection molding. Thus, the mold itself may
have a suitable profile such as one or more projections or
discontinuities integral to it. Zeolite can be applied to the
profiled mold surface, and as the molten resin (or molten blend of
resin and zeolite) is injected into the cavity of the mold, it
forms around the projections creating indentations in the surface
once it is ejected from the mold, and forcing the zeolite into
those indentations. One suitable method of applying the zeolite to
the mold surface is by electrostatic deposition, as deposition of
zeolite particles on the mold substrate is enhanced by attractive
electrostatic forces between particles and the surface. The
injection molding process allows for a controlled, reproducible
operation for producing the structure loaded with zeolite in the
exposed surface region. The configuration, size (e.g., diameter and
length) and spacing of the surface profile of the mold can be
chosen based upon the desired exposed surface contour of the
article. A combination of micro and macro channels or indentations
can be formed, of dimensions suitable for promoting
osseointegration and/or tissue integration when implanted into a
host. Projections can be randomly oriented, or can be oriented in a
uniform spaced array. Projections can be perpendicular to the mold
surface, or can be oriented at an angle less than 90.degree., or
both. Projections can have various shapes, including spikes or
cones which taper axially to a sharp point, pyramidal, cylindrical,
etc. Thus, the molding operation can be used to both form the
article into the desired shape for the implant, and create the
desired surface contour and introduction of large amounts of
zeolite to the exposed surface region. A zeolite slurry can be
introduced into the mold in the same manner as a suitable release
agent is added to aid in release of the mold piece from the
mold.
[0078] In a still further embodiment, the implant may be press
molded in metal molds. A profiled or flat surfaced mold can be
evenly coated with zeolite and naked resin or a resin/zeolite
composite can be press molded, thereby coating the casting with a
high level of imbedded zeolite in the exposed surface region.
[0079] In some embodiments, either natural zeolites or synthetic
zeolites may be used to make the zeolites used in the embodiments
disclosed herein. "Zeolite" is an aluminosilicate having a
three-dimensional skeletal structure that is represented by the
formula: XM.sub.2/nO.Al.sub.2O.sub.3.YsiO.sub.2.ZH.sub.2O, wherein
M represents an ion-exchangeable ion, generally a monovalent or
divalent metal ion, n represents the atomic valency of the (metal)
ion, X and Y represent coefficients of metal oxide and silica
respectively, and Z represents the number of water of
crystallization. Examples of such zeolites include A-type zeolites,
X-type zeolites, Y-type zeolites, T-type zeolites, high-silica
zeolites, sodalite, mordenite, analcite, clinoptilolite, chabazite
and erionite. A-type zeolites are particularly preferred, such as
4A zeolite having particle size ranges from 1 to 10 microns with a
narrow distribution of about 4 microns.
[0080] Other ceramics and metal glasses are also envisaged instead
of zeolite and are within the scope of the embodiments disclosed
herein. For example, zirconium phosphate, bioglass or silver glass
could be used.
[0081] In certain embodiments where the main body region of the
article also is to include zeolite, fine zeolite powder may be
incorporated into a powder of the thermoplastic polymer. For
example, 4 micron powder of a 4A zeolite may be incorporated into
molten PEEK powder that has a particle diameter of between about 10
to about 100 microns. In some embodiments, the incorporation of the
zeolite into the polymer is carried out by thorough mixing the dry
components at room temperature until the resulting composition is
uniform by visual inspection. In some embodiments a drum roller can
be used to carry out the mixing process.
[0082] The powder formulation may include the polymer, such as
PEEK, and metal-loaded zeolite, such as silver zeolite. Other
bioactive agents also may be included.
[0083] In certain embodiments, when metal cation is used, the metal
cation is present at a level below the ion-exchange capacity in at
least a portion of the zeolite particles. In some embodiments, the
amount of zeolite mixed with the polymer may range from about 5 to
50 wt. %, more preferably about 10 to 20 wt. %. The amount of metal
ions, if present, in the zeolite should be sufficient such that
they are present in an antimicrobial effective amount when
implanted into the body of a patient. For example, suitable amounts
can range from about 0.1 to about 20 or 30% of the exposed zeolite
(w/w %). These levels can be determined by complete extraction and
determination of metal ion concentration in the extraction solution
by atomic absorption. Preferably the ion-exchanged antimicrobial
metal cations, if present, are present at a level less than the
ion-exchange capacity of the ceramic particles. The amount of
ammonium ions is preferably limited to from about 0.5 to about 15
wt. %, more preferably 1.5 to 5 wt. %. For applications where
strength is not of the utmost importance the loading of zeolite can
be taken as high as 50%. At such loadings the permeation of metal
ions can permeate well below the surface layer due to interparticle
contact, and much greater loadings of metal ions are possible.
[0084] In some embodiments, zeolite can be post-loaded with metal
ions after it has been incorporated into the resin. Metal ion salt
solutions, such as nitrates, acetates, benzoates, carbonates,
oxides, etc., can be used to accomplish this. Addition of nitric
acid to the infusion solution also may be advantageous in that it
can etch the surface of the implant, providing additional surface
area for ion exchange. That is, the zeolite may be charged with
metal ions at a temperature between about 0 and 100.degree. C.,
preferably about room temperature) from a metal ion source such as
an aqueous metal ion solution, such as silver nitrate, copper
nitrate and zinc nitrate, alone or in combination. Cooling to lower
temperatures gives lower loading rates but higher stability.
Loading at even higher temperatures can be carried out at a faster
rate by maintaining the system under pressure, such as in a
pressure cooker or autoclave. The content of the ions can be
controlled by adjusting the concentration of each ion species (or
salt) in the solution.
[0085] For example, the zeolite can be loaded with metal ions by
bringing the composite material into contact with an aqueous mixed
solution containing ammonium ions and antimicrobial and/or
therapeutic metal ions such as silver, copper, zinc, strontium,
etc. These materials will strongly inhibit attachment of
microorganisms and can accelerate healing and reduce inflammation.
By loading metal ions at these temperatures, deleterious oxidation
of the metal ions that occurs at higher processing temperatures is
reduced or eliminated. The most suitable temperatures at which the
infusion can be carried out range from 5.degree. C. to 75.degree.
C., but higher temperatures may also be used even above 100.degree.
C. if the reaction vessel is held under pressure. Higher
temperatures will show increased infusion rates but lower
temperatures may eventually produce more uniform and higher
loadings. The pH of the infusion solution can range from about 2 to
about 11 but is preferably from about 4 to about 7. Suitable
sources of ammonium ions include ammonium nitrate, ammonium sulfate
and ammonium acetate. Suitable sources of the metal ions include: a
silver ion source such as silver nitrate, silver sulfate, silver
perchlorate, silver acetate, diamine silver nitrate and diamine
silver nitrate; a copper ion source such as copper(II) nitrate,
copper sulfate, copper perchlorate, copper acetate, tetracyan
copper potassium; a zinc ion source such as zinc(II) nitrate, zinc
sulfate, zinc perchlorate, zinc acetate and zinc thiocyanate.
[0086] In some embodiments, the mechanical strength of the device
may be reinforced by incorporating carbon fiber into the
formulation. For example, milled carbon fiber may be added to the
powder mixture of zeolite and polymer. The carbon fiber may also
result in greater inter-layer adhesion and integrity of the device.
The incorporation of fibers or other suitable reinforcing
material(s) provides high wear resistance, a Young's modulus of 12
GPa (matching the modulus of cortical bone) and providing
sufficient strength to permit its use in very thin implant designs
which distribute the stress more efficiently to the bone. The
amount of reinforcing material such as carbon fiber incorporated
into the resin such as PEEK can be varied, such as to modify the
Young's modulus and flexural strength. One suitable amount is 30 wt
% carbon fiber.
[0087] In some embodiments, one or more biological agents can be
added to the implant. Preferably they are incorporated after the
implant has been cooled, since such agents typically do not
tolerate high temperatures. Suitable biological agents include
peptides, stem cells and growth factors such as bone morphogenetic
proteins (BMPs). The BMPs are bioactive proteins that naturally
occur in the human body and are regulated by various transcription
and translation mechanisms. The BMPs belong to a family of growth
factors that contribute to developmental processes such as pattern
formation and tissue specification; in addition to inducing bone
and cartilage formation, these proteins also regulate cell
proliferation, migration, differentiation, and apoptosis in a
number of tissues and organs. The BMPS have also been shown to
promote wound healing and repair processes in adult tissues as
well. A number of BMPs have been identified in humans and other
animals including BMP-2, BMP-3 (osteogenin), BMP-3b (GDF-10), BMP-4
(BMP-2b), BMP-5, BMP-6, BMP-7 (osteogenic protein-1 or OP-1), BMP-8
(OP-2), BMP-8B (OP-3), BMP-9 (GDF-2), BMP-10, BMP-ii (GDF-11,
BMP-12 (GDF-7), BMP-13 (GDF-6, CDMP-2), BMP-15 (GDF-9), BMP-16,
GDF-1, GDF-3, GDF-5 (CDMP-1), and GDF-8 (myostatin). More recently,
certain recombinant human BMPs have been approved by the Food and
Drug Administration for limited clinical applications. For
instance, INFUSE.RTM. is a commercially available product that
delivers rhBMP-2 in an absorbable collagen sponge which may be
placed into titanium spacers for the purpose of interbody fusion in
the lumbar spine.
[0088] The resulting device may be introduced into the body
surgically. Suitable hosts include mammals, including humans,
canines, felines, livestock, primates, etc. The rate of release of
antimicrobial metal ions, if present, is governed by the extent of
loading of the polymer with zeolite and the extent to which the
exposed zeolite is charged with metal ions. The electrolyte
concentration in host blood and body fluids is relatively constant
and will cause ion exchange with ions such as silver, copper and
zinc, etc. from the surface of the implant, which deactivate or
kill gram positive and gram negative organisms, including E. coli
and Staphylococcus aureus. Effective antibacterial control (e.g., a
six log reduction of microorganisms) is achieved even at low metal
ion concentrations of 40 ppb.
[0089] Surface occupancy of zeolite can be determined indirectly by
post loading the zeolite with a therapeutic metal ion, removing non
absorbed metal by thorough rinsing and determining the amount which
can be extracted into a 1% sodium nitrate solution by ICP OES.
Comparison elution from a composite without the enhanced zeolite
addition to the exposed surface region will give an indication of
the extent of the surface enhancement of zeolite concentration.
Formulation Example 1
TABLE-US-00001 [0090] Component Composition (w/w) % Average
particle size (Microns) PEEK 88 60 4A Zeolite 12 4
Formulation Example 2
TABLE-US-00002 [0091] Component Composition (w/w) % Average
particle size (Microns) PEEK 88 10 4A Zeolite 12 4
Formulation Example 3
TABLE-US-00003 [0092] Component Composition (w/w) % Average
particle size (Microns) PEEK 73 10 4A Zeolite 12 4 Carbon Fiber 15
Milled strand
Formulation Example 4
TABLE-US-00004 [0093] Component Composition (w/w) % Average
particle size (Microns) PEEK 73 10 4A Zeolite 12 4 Carbon Fiber 15
Milled strand
Formulation Example 5
TABLE-US-00005 [0094] Component Composition (w/w) % Average
particle size (Microns) PEEK 43 10 Sodium Chloride 3 4 4A Zeolite
12 4 Carbon Fiber 15 Milled strand
Example 1
[0095] Crystalline sodium chloride was mixed with Type 4A
zeolite.
[0096] The mix ratio is not critical but in this Example, 7 grams
of 4A Zeolite was mixed with 93 grams crystalline sodium chloride.
The bottom of a metal container 60 mm diameter was covered with a
layer of the salt/zeolite mixture. The container was placed in a
furnace at 525.degree. C. until it reached thermal equilibrium,
which was about 20 minutes. The furnace may be flooded with inert
gas to minimize the potential for oxidation.
[0097] A coupon of PEEK zeolite composite having 12% zeolite, 30 mm
in diameter and 2 mm thick, was placed onto the surface of the
heated salt. The system was rapidly placed back into the furnace
and retained at temperature until the polymer softened.
[0098] The container was removed from the furnace and pressure
applied to the top surface of the softened composite with a metal
plunger 10 to 20 psi for 30 seconds. The system was allowed to cool
and the coupon was removed and rinsed under running water, followed
by immersion in distilled water until residual sodium chloride
embedded in the surface was fully dissolved.
Example 2
[0099] A PEEK coupon, devoid of zeolite, 30 mm in diameter was
heated for 90 seconds at about 525.degree. C. in a furnace. A sheet
of 80 mesh sandpaper was coated with 4A zeolite powder in an amount
sufficient to cover the surface of the sandpaper. The softened PEEK
coupon was removed from the furnace with tweezers and laid on the
zeolite-coated sandpaper. Pressure of about 10 to 20 psi was
applied to the softened PEEK for 30 seconds using a plunger.
[0100] On cooling the PEEK coupon was lifted from the surface and
residual unattached zeolite was thoroughly rinsed from the surface.
Visual observation indicated that a considerable amount of zeolite
was bound to the surface.
Example 3
[0101] A coupon of a PEEK/zeolite composite containing 12% zeolite
was evenly coated with a slurry of 4A zeolite in propanol and
allowed to dry onto the surface. The coupon was heated to
525.degree. C. in a furnace and pressed onto a sheet of 60 mesh
sandpaper. The sample was rinsed as in Example 2. The surface of
the polymer which was exposed to the sandpaper showed an indented
profile as seen in FIG. 1.
Example 4
[0102] A continuous layer of zeolite slurry was applied to the
surface of a PEEK coupon and allowed to air dry at room temperature
to produce an adherent film of dried zeolite. Sodium chloride
crystals were heated in the furnace as before and the
zeolite-coated coupon was placed on the heated salt for 90 seconds
and pressure applied as before for 30 seconds at 10 to 20 psi. The
coupon was removed from the salt bed and allowed to cool and rinsed
free of residual salt and residual unbonded zeolite with distilled
water.
Example 5
[0103] A PEEK coupon, devoid of zeolite, 30 mm in diameter was
heated in a furnace for 90 seconds at about 525.degree. C. A sheet
of 80 mesh sandpaper was coated with 4A zeolite powder.
[0104] The softened PEEK coupon was removed from the furnace with
tweezers and laid on the zeolite-coated sandpaper. Pressure was
applied to the softened PEEK using a plunger, about 10 to 20 psi
for about 30 seconds.
[0105] On cooling, the PEEK coupon was lifted from the surface and
residual unattached zeolite was thoroughly rinsed from the surface.
Visual observation showed that a considerable amount of zeolite was
bound to the surface.
Example 6
[0106] The inside surface of an injection molding mold engraved or
etched with a suitable profile for application to the surface of a
surgical implant to enhance osseointegration is used.
[0107] A spray slurry of 4A zeolite, in a suitable solvent such as
water, is sprayed into the cavity of the mold in such as a way as
to evenly coat the profiled surface of the mold, prior to injection
of the shot of resin. The surface is allowed to dry and the resin
is injected into the cavity of the mold. The melt presses hard into
the profile of the mold and strongly bonds the zeolite particles to
its surface.
[0108] During an injection molding run the mold is hot enough for
the water to rapidly evaporate, leaving a uniform layer of zeolite
on the mold surface.
[0109] While various aspects and embodiments have been disclosed
herein, other aspects, embodiments, modifications and alterations
will be apparent to those skilled in the art upon reading and
understanding the preceding detailed description. The various
aspects and embodiments disclosed herein are for purposes of
illustration and are not intended to be limiting. It is intended
that the present disclosure be construed as including all such
aspects, embodiments, modifications and alterations insofar as they
come within the scope of the appended claims or the equivalents
thereof.
* * * * *