U.S. patent application number 15/813176 was filed with the patent office on 2018-04-05 for dimensionally stable molded bone replacement element with residual hydraulic activity.
The applicant listed for this patent is Innotere GmbH. Invention is credited to Berthold Nies.
Application Number | 20180093009 15/813176 |
Document ID | / |
Family ID | 51685310 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180093009 |
Kind Code |
A1 |
Nies; Berthold |
April 5, 2018 |
Dimensionally Stable Molded Bone Replacement Element with Residual
Hydraulic Activity
Abstract
Dimensionally stable molded bone replacement elements made of
mineral bone cement with residual hydraulic activity that contain
at least one share of hardened mineral bone cement and at least one
share of unconverted or unhardened reactive mineral bone cement,
wherein the share of hardened mineral bone cement is 5% to 90% by
weight. The dimensionally stable molded bone replacement elements
have at least 5% of the maximum value of the strength of a
completely hardened bone cement comprised of the same mineral
components and with the same structural characteristics and reach
compressive strengths in the range of 2 to 200 MPa. They are
substantially free of water and can be converted under biological
conditions.
Inventors: |
Nies; Berthold;
(Frankisch-Crumbach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Innotere GmbH |
Radebeul |
|
DE |
|
|
Family ID: |
51685310 |
Appl. No.: |
15/813176 |
Filed: |
November 15, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15021354 |
Mar 11, 2016 |
9849211 |
|
|
PCT/EP2014/072784 |
Oct 23, 2014 |
|
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15813176 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2430/02 20130101;
A61L 27/56 20130101; A61L 24/0042 20130101; A61L 24/0015 20130101;
A61L 24/02 20130101; A61L 24/0036 20130101; A61L 27/12 20130101;
A61L 27/58 20130101; A61L 27/54 20130101; A61L 27/02 20130101 |
International
Class: |
A61L 24/00 20060101
A61L024/00; A61L 27/02 20060101 A61L027/02; A61L 27/58 20060101
A61L027/58; A61L 24/02 20060101 A61L024/02; A61L 27/12 20060101
A61L027/12; A61L 27/54 20060101 A61L027/54; A61L 27/56 20060101
A61L027/56 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 2013 |
DE |
102013221575.4 |
Claims
1. Dimensionally stable molded bone replacement elements made of
mineral bone cement with residual hydraulic activity, comprising a.
at least one share of hardened mineral bone cement, b. at least one
share of unconverted or unhardened reactive mineral bone cement,
wherein the dimensionally stable molded bone replacement elements
have at least 5% of the maximum value of strength of a completely
hardened bone cement made of the same mineral components and with
the same structural characteristics, wherein the dimensionally
stable molded bone replacement elements, which can be converted
under biological conditions, 37.degree. C. and water saturation,
contain a share of hardened mineral bone cement of 5% to 90% by
weight, wherein the dimensionally stable molded bone replacement
elements have compressive strengths in the range of 2 to 200 MPa
and wherein physically bound and condensed water has been
completely withdrawn from the dimensionally stable molded bone
replacement elements.
2. Dimensionally stable molded bone replacement elements according
to claim 1, wherein the at least one share of unconverted or
unhardened reactive mineral bone cement contains at least one
unconverted or unhardened reactive mineral bone cement component
with a share of at least 10% by weight.
3. Dimensionally stable molded bone replacement elements according
to claim 1, wherein the dimensionally stable molded bone
replacement elements have an overall porosity between 20% and
90%.
4. Dimensionally stable molded bone replacement elements according
to claim 1 in the form of granules, wherein the individual granules
have a size of >100 .mu.m and <10 mm.
5. Dimensionally stable molded bone replacement elements according
to claim 1, wherein they have the shape of a printed 3D molded
element.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. Ser. No. 15/021,354,
filed on Mar. 11, 2016, which is the U.S. national stage of
International Application No. PCT/EP2014/072784, filed on Oct. 23,
2014, and claims the priority thereof. The international
application claims the priority of German Application No. DE 10
2013 221 575.4 filed on Oct. 23, 2013; all applications are
incorporated by reference herein in their entirety.
BACKGROUND
[0002] The invention relates to dimensionally stable molded bone
replacement elements made of mineral bone cement with residual
hydraulic activity, a method and a set for producing it, as well as
its use as a technical, bioengineering and/or pharmaceutical
product, especially as an alloplastic bone implant.
[0003] Only a temporary retention of the implant material in the
body is frequently required when medical implants are used.
Research has been done for several years on the development of
bioresorbable implant materials so that an elaborate operation to
remove utilized implant materials that cannot be broken down by the
body can be dispensed with in implantation processes of that type.
Bioresorbable materials have the characteristic that they are
gradually broken down after being implanted in the body. The
decomposition products that arise in the process are reabsorbed by
the body to a great extent.
[0004] Implant materials can be broken down actively or passively.
In the case of an active breakdown by the organism, the implant
material is broken down via enzymatic or cellular mechanisms. This
applies, as an example, to implant materials made of collagen or
mineral bone cements based on calcium phosphates. An active
breakdown of implant materials is especially desired when the
breakdown takes place within the framework of natural metabolism
and not on the basis of an inflammatory reaction.
[0005] Previous solutions for providing alloplastic molded bone
replacement elements are mostly based on calcium phosphates that
are manufactured via precipitation or through high-temperature
processes (sintering of suitable starting materials at temperatures
>500.degree. C.). Production through high-temperature processes
does in fact supply materials with a substantial similarity to bone
minerals, but it leads to a heavy coarsening of the structure; the
bioactivity and resorbability of a molded bone replacement element
are negatively impacted because of that.
[0006] Mineral bone cements that harden in situ via a hydraulic
setting reaction are a special form.
[0007] U.S. Pat. No. 6,642,285 B1 discloses a hydraulic cement for
manufacturing bone implants that is comprised of three components
that are matched to one another, which are supposed to harden into
a macro-porous solid immediately after mixing to the extent
possible. The first component is a calcium source that completely
hardens within 60 minutes as a preference in combination with an
aqueous solution and a hydrophobic liquid; the product no longer
has any hydraulic activity after hardening.
[0008] WO 2008 148 878 A3 discloses pastes, suspensions or
dispersions comprised of a resorbable mineral bone cement component
and a carrier liquid that are substantially free of water. The
pastes, suspensions or dispersions that are disclosed have a liquid
to pasty consistency and are implanted in this form as bone cements
or bone replacement materials; the setting reaction completely
takes place after implantation as a preference.
[0009] Lode et al. (J. Tissue Eng. Regen. Med. 2012) disclose that
water-free, pasty preparations made of mineral bone cements can be
printed via a printing process into porous molded elements that can
subsequently be hardened into solid molded elements by putting them
in aqueous solutions (to the extent described in the
literature).
[0010] Surprisingly, it was found that molded elements that are
manufactured in that way have especially good mechanical
characteristics when the hardening does not take place in aqueous
solutions, but instead in a saturated steam atmosphere at ambient
temperatures or slightly increased temperatures (25-75.degree. C.),
especially below the sintering temperature.
[0011] The known solution suggestions have the situation in common
that none of them involve residual hydraulic activity. Residual
hydraulic activity is above all desirable based on biological
conditions, because then part of the setting reaction of the
cement-type mineral preparation takes place under biological
conditions after implantation. Greater bioactivity can be achieved
in this way.
[0012] Moreover, a stimulating effect on the osteogenic cells,
which can be supported by an individualized adaptation to the bone
defect of the patient, is desirable.
[0013] The instant invention is therefore based on the object of
providing dimensionally stable molded bone replacement elements
manufactured without using a ceramic-sintering step that are shaped
under controlled conditions and that are solidified via a hydraulic
setting process to the degree that adequate dimensional stability
is ensured for storage, transport and the respective implantation
conditions; the molded bone replacement elements are only
completely hardened during and/or after the implantation,
though.
SUMMARY
[0014] The invention relates to dimensionally stable molded bone
replacement elements made of mineral bone cement with residual
hydraulic activity that contain at least one share of hardened
mineral bone cement and at least one share of unconverted or
unhardened reactive mineral bone cement, wherein the share of
hardened mineral bone cement is 5% to 90% by weight. The
dimensionally stable molded bone replacement elements have at least
5% of the maximum value of the strength of a completely hardened
bone cement comprised of the same mineral components and with the
same structural characteristics and reach compressive strengths in
the range of 2 to 200 MPa. They are substantially free of water and
can be converted under biological conditions.
DETAILED DESCRIPTION
[0015] The problem is solved as per the invention by dimensionally
stable molded bone replacement elements made of mineral bone cement
with residual hydraulic activity that are comprised of [0016] a) at
least one share of hardened mineral bone cement, [0017] b) at least
one share of unconverted or unhardened reactive mineral bone
cement, wherein the dimensionally stable molded bone replacement
element has at least 5% of the maximum strength value of a
completely hardened mineral bone cement made of the same components
and with the same structural characteristics, in particular the
same porosity, wherein the dimensionally stable molded bone
replacement elements that can be converted under biological
conditions -37.degree. C. and water saturation--contain a share of
hardened mineral bone cement of 5 to 90 percent by weight, from 10
to 80 percent by weight as a special preference, and from 30 to 70
percent by weight as a very special preference, wherein the
dimensionally stable molded bone replacement elements have a
compressive strength in the range of 2 to 200 MPa and wherein the
dimensionally stable molded bone replacement elements are
substantially free of water.
[0018] Mineral bone cements are made up of at least one reactive
mineral or organo-mineral solid component (bone cement component)
that can harden into a solid with low solubility when coming into
contact with an aqueous solution or after being put into an aqueous
solution in a hydraulic setting process. Reactive mineral bone
cements exclusively mean here that the at least one reactive
mineral bone cement component has not yet been chemically converted
with water to form a hardened mineral bone cement. The reactive
mineral bone cement components are advantageously used in the form
of powder mixtures that are intensively mixed; the formation of a
dimensionally stable molded bone replacement element with a
homogeneous composition is encouraged by that.
[0019] Residual hydraulic activity means, in the sense of the
invention, the qualitative capability of a synthetic molded bone
replacement element as per the invention to enter with the addition
of water and/or a component containing water into a chemical
reaction, i.e. a setting process, that can be interrupted by
withholding water before the complete conversion of the reactive
components has been achieved; a hydration of the residual reactive
mineral bone cement component takes place once again via renewed
contact of a synthetic molded bone replacement element as per the
invention with water, which causes the interrupted setting process
to be continued. The renewed contact with water and/or a component
containing water of a synthetic molded bone replacement element as
per the invention with residual hydraulic activity only takes place
immediately before its use or during or after its use, and thus
during or after implantation in the body.
[0020] As a preference, the dimensionally stable molded bone
replacement element has at least 5% of the maximum value of the
strength of a completely hardened, dimensionally stable molded bone
replacement element made up of the same mineral bone cement
components and with the same structural characteristics, especially
the same porosity. They have enough dimensional stability at that
point in time to be able to withstand the mechanical loads involved
in storage and transport, for instance. As a preference, the
dimensionally stable molded bone replacement elements have 15%, 25%
as a special preference, 50% of the maximum value of the strength
as a very special preference, and even more preferred >75% of
the maximum value of the strength of a completely hardened,
dimensionally stable molded bone replacement element made of the
same mineral bone cement components and with the same structural
characteristics, especially the same porosity.
[0021] The dimensionally stable molded bone replacement elements,
which can be converted under biological conditions -37.degree. C.
and water saturation--preferably contain a share of hardened
mineral bone cement of 5 to 90 percent by weight, 10 to 80 percent
by weight as a special preference and 30 to 70 percent by weight as
a very special preference.
[0022] The dimensionally stable molded bone replacement elements
with residual hydraulic activity have compressive strengths of 2 to
200 MPa, from 5 to 200 MPa as a special preference, and from 10 to
200 MPa as a very special preference, and they are therefore
comparable to a molded bone replacement element without residual
hydraulic activity.
[0023] The dimensionally stable molded bone replacement elements
with residual hydraulic activity have compressive strengths in a
range of 2 to 100 MPa, in a range of 3 to 50 MPa as a special
preference, in a range of 5 to 25 MPa as a very special preference,
and they are therefore comparable to a molded bone replacement
element without residual hydraulic activity.
[0024] Surprisingly, it turned out that dimensionally stable molded
bone replacement elements that contain a share of approx. 80% of a
reactive mineral bone cement component that has not yet been
chemically converted (with reference to the starting content)
already achieves 75% of the maximum compressive strength of a
molded bone replacement element with a complete chemical conversion
of the mineral bone cement component. As a particular surprise, it
turned out that the dimensionally stable molded bone replacement
elements that contain a share of approx. 50% of a reactive mineral
bone cement component that has not yet been chemically converted
already achieves the maximum compressive strength of a molded bone
replacement element with a complete chemical conversion of the
mineral component.
[0025] A universal testing machine such as that of the company
Hegewald & Peschke, utilizing a load cell of 20 kN, for
instance, with a feed rate of 1 mm/min, for example, can be used to
determine the compressive strength of the molded bone replacement
element as per the invention. The material conversion can be
determined via x-ray diffractometry (XRD) in dependence upon the
hardening duration at a certain temperature and humidity. The
Rietveld method can be used for quantification. The Rietveld method
serves to provide a quantitative phase analysis, and thus the
quantitative determination of the crystalline components of a
powdery sample.
[0026] The dimensionally stable molded bone replacement elements
are substantially free of water as per the invention.
[0027] As a preference, the at least one share of reactive mineral
bone cement that has not been converted or hardened contains a
reactive mineral bone cement component that has not been converted
or hardened with a share of at least 10 percent by weight, at least
20 percent by weight as a special preference, at least 30 percent
by weight as a very special preference, and at least 50 percent by
weight as even more of a preference.
[0028] It is advantageous that the dimensionally stable molded bone
replacement element has a high level of biological activity.
Biological activity designates, as per the invention, the
characteristic of the dimensionally stable molded bone replacement
element to advantageously form a crystal structure that is more
similar to the bone during hardening under biological conditions. A
bone-like nanocrystalline structure of the mineral structures that
are formed in the setting process is an essential prerequisite for
their interaction with the organic and cellular elements of the new
bone being formed. That is why hardening of the dimensionally
stable molded bone replacement element that goes as far as possible
after implantation in the body under biological conditions is
strived for. The greater the share of a reactive mineral bone
cement component that has not been converted or hardened, the
greater the biological activity. A dimensionally stable molded bone
replacement element with the appropriate strength and biological
activity can be provided in that way that is coordinated to the
requirements of the respective clinical application area.
[0029] The dimensionally stable molded bone replacement elements
preferably have an overall porosity of between 20% and 90%.
[0030] The overall porosity is the sum of the macro-porosity
(macroscopically visible pores, >approx. 100 pm) and the micro
and nano-porosity (only microscopically visible pores, <approx.
10 .mu.m or <approx. 1 .mu.m) of the dimensionally stable molded
bone replacement elements. The macro-pores, as contained in
printed, dimensionally stable 3D molded bone replacement elements,
as an example, are particularly significant for growth of cells and
tissue structures into the molded element. The micro and nano-pores
are a result of bringing together the reactive mineral bone cement
that has not been converted or hardened and its processing
conditions. They are crucial for the specific surface of the
dimensionally stable molded bone replacement elements and therefore
for the absorption capability for biological molecules and the
interaction with bone cells.
[0031] In one embodiment, the dimensionally stable molded bone
replacement elements exist in the form of granules; the individual
granules have a size of >100 .mu.m and <10 mm.
[0032] The granules with biological activity can be advantageously
used to fill out bone defects. The granules form a crystal
structure that is more similar to the bone after implantation in
the body with a setting reaction that takes place under biological
conditions to a very great extent.
[0033] Larger molded bone replacement elements, adapted to the
corresponding defect location, can be advantageously prepared from
the granules via shaping processes (e.g. pressing them in a mold).
In addition, the ease of manufacturing the granules, their high
level of bioactivity and their relatively high compressive strength
are advantageous.
[0034] The dimensionally stable molded bone replacement element
will preferably have the shape of a printed 3D molded element.
Printed 3D molded elements will preferably obtain their structure
via a 3D printing process; both the external shape and the pore
structure can be specified in very broad areas because of that. As
a preference, they will have a geometric external shape, especially
in the form of a cylinder or rectangular block. Other preferred
shapes are wedges, disks, cones anatomically adapted to the bones
or shapes that are known from the implantation of cages for the
spinal column, for instance. A 3D molded bone replacement element
as per the invention is preferably made up of several successive
layers (stacked) that can accommodate various shapes, for instance
circular, oval and angular shapes. The individual layers are
comprised of sections that are arranged in such a way that spaces
arise between the sections; a contiguous (interconnecting)
macro-porosity arises because of that, wherein the macro-porosity
is in a range of 20% to 90%.
[0035] Specific pore arrangements and specific pore volumes can be
advantageously produced via 3D printing processes. This
advantageously makes the design of directional pores possible, in
particular, so the path for the new bones growing in to bridge over
a bone defect can be reduced to a minimum.
[0036] The problem is solved as per the invention via a method for
manufacturing dimensionally stable molded bone replacement elements
with residual hydraulic activity comprised of the following steps:
[0037] a) Mixing a reactive mineral bone cement to create a
moldable bone cement substance, [0038] b) Shaping the bone cement
substance to form a molded bone replacement element, [0039] c)
Putting the molded bone replacement element into contact with an
aqueous solution or a water (steam) saturated environment so that a
setting process is initiated and the molded bone replacement
element achieves at least 5% of the maximum value of the strength
of a completely hardened bone replacement material made of the same
components and with the same structural features, especially the
same porosity, [0040] d) Terminating the setting process by
substantially withdrawing water so that the dimensionally stable
molded bone replacement element will contain a share of hardened
mineral bone cement of 5 to 90 percent by weight, from 10 to 80
percent by weight as a special preference, and from 30 to 70
percent by weight as a very special preference, and that the
dimensionally stable molded bone replacement element is
substantially free of water. [0041] e) If necessary, drying the
molded bone replacement element, i.e. removing auxiliary materials,
residual water and/or water-soluble solvents contained in it that
were used to substantially withdraw the water.
[0042] The problem is solved via a method for manufacturing
dimensionally stable molded bone replacement elements with residual
hydraulic activity comprised of the following steps: [0043] a)
Mixing a reactive mineral bone cement to create a moldable bone
cement substance, [0044] b) Shaping the bone cement substance to
form a molded bone replacement element, [0045] c) Putting the
molded bone replacement element into contact with an aqueous
solution or a water (steam) saturated environment so that a setting
process is initiated and the molded bone replacement element
achieves at least 5% of the maximum value of the strength of a
completely hardened bone replacement material made of the same
components and with the same structural features, especially the
same porosity, [0046] d) Terminating the setting process by
substantially withdrawing water so that the dimensionally stable
molded bone replacement element will contain a share of hardened
mineral bone cement of 5 to 90 percent by weight, from 10 to 80
percent by weight as a special preference, and from 30 to 70
percent by weight as a very special preference, and that the
dimensionally stable molded bone replacement element is
substantially free of water.
[0047] As a special preference, the molded bone replacement element
is dried via the removal of auxiliary materials, residual water
and/or water-soluble solvents contained in it that were used to
substantially withdraw the water.
[0048] Surprisingly, it turned out that the hydraulic setting
process and the hardening of a synthetic molded bone replacement
element associated with that can be interrupted by the substantial
withdrawal of water (i.e. the complete removal of the share of
physically bound and condensed water) from a molded bone
replacement element as per the invention. A molded bone replacement
element as per the invention exists in the form of a dimensionally
stable structure that has residual hydraulic activity because of
the interruption of the setting process.
[0049] A major advantage is that the molded bone replacement
elements as per the invention can be subjected to plastic
deformation before the first time they are brought into contact
with water or a water (steam) atmosphere, but a dimensionally
stable molded bone replacement element with residual hydraulic
activity arises after the first time they are brought into contact
with water or a water (steam) atmosphere and the premature
interruption of the setting reaction whose hardness and brittleness
can still be significantly below that of a completely hardened
molded bone replacement element of the same mineral composition and
with the same structural features, especially the same porosity.
The molded bone replacement element as per the invention has
sufficient mechanical strength for transport, storage and
implantation. The shaping and/or structuring of a synthetic molded
bone replacement element as per the invention into structured
preforms with residual hydraulic activity advantageously makes it
easier for the final user (e.g. surgeon) to adapt an implant based
on a synthetic molded bone replacement element as per the invention
to the defect of the bone in a positive-locking way, because it
turned out that incompletely hardened molded elements as per the
invention (with residual hydraulic activity) can be reworked
especially well during an operation, for instance via carving with
surgical instruments (e.g. scalpel), which, as experience has
shown, is very difficult or impossible under OP conditions with
commercially available molded ceramic elements.
[0050] The reactive mineral bone cements are obtained via intensive
mixing of at least one powdery, reactive mineral bone cement
component with a carrier liquid so that a homogeneous, moldable
bone cement substance is obtained in the form of a pasty
dispersion.
[0051] The pasty dispersions for manufacturing the dimensionally
stable molded bone replacement element can be subjected to various
methods of shaping; the composition of dispersions and their
physical characteristics are matched to the shaping method. As an
example, dispersions with a lower viscosity are used for casting
methods than is the case for 3D printing methods. Preferred methods
are oriented towards the desired shape and function of the molded
bone replacement elements that are strived for.
[0052] As a preference, a paste capable of plastic deformation and
containing at least one reactive mineral bone cement component that
is dispersed in a carrier liquid is shaped by the effects of
tensile and/or compressive forces in the form of rolling, printing
(e.g. flatbed printing, porous printing, relief printing, intaglio
printing, in accordance with DIN 16500, screen printing, offset
printing, ink-jet printing, among others), extrusion, casting,
coating with a doctor knife, granulation and other shaping methods
that are known to a person skilled in the art.
[0053] Cylinders, blocks or wedges are preferred shapes of the
molded bone replacement elements. They can be obtained, as an
example, via casting or pressing in a corresponding negative mold.
They can be hardened in the mold (see below), removed from the mold
after reaching adequate post-removal strength and, if necessary,
processed further until the desired degree of hardening is
obtained.
[0054] Porous molded elements with different external geometries
and randomly distributed macro-porosity are a further preferred
type of molded bone replacement elements. Molded elements of that
type can be obtained in a different way by putting a pasty bone
cement dispersion containing a filler (e.g. sugar, salt, ammonium
carbonate, polymer particles) that are readily soluble in water
into a specified mold. The filler can be removed during or after
the hardening via extraction or evaporation, and it can leave a
porous structure behind in the process. The shaping can also take
place after the hardening by first producing a larger molded
element and creating the desired molded element in the implant size
via subsequent processing (e.g. milling, sawing etc.).
[0055] Porous molded elements with a defined and especially
interconnected porosity are an especially preferred form of molded
bone replacement elements. Molded bone replacement elements of that
type are of special clinical interest, because the goal of the bone
integration that is to be complete and as quick as possible can
only be achieved with an interconnecting porosity, and this bone
integration can only take place in an especially quick manner when
the path for the bone in-growth is as short as possible, and thus
when the pores are in a straight line to the extent possible and
run in a targeted way through the molded element. This goal can be
achieved with the material and method as per the invention,
especially via the 3D printing.
[0056] The paste that can be subjected to plastic deformation or,
more specifically, the molded element created from that in the
shaping step is brought into intimate contact in a subsequent step,
preferably in a gradual way, with an aqueous solution or pure water
or, as a special preference, a water (steam) atmosphere, to
initiate the setting process. Surprisingly, it turned out that
dispersions made of bone cement powder in a water-free carrier
liquid with a high level of solid content can be processed to
become large molded elements in one shaping step via 3D printing,
as an example, without changing their geometric shape during the
production and further processing. It is possible to first
manufacture any number of molded elements and to jointly subject
them in a subsequent step to the initiation of the setting
process.
[0057] As a preference, the dimensionally stable molded bone
replacement element is put into contact with an aqueous solution or
a water (steam) saturated environment so that it achieves at least
5%, preferably 15%, very preferably 25%, especially preferably 50%,
even more preferably >75% of the maximum value of the strength
of a completely hardened bone replacement material made of the same
components and with the same structural features, especially the
same porosity.
[0058] The dimensionally stable molded bone replacement element is
preferably put into contact with an aqueous solution or a water
(steam) saturated environment for a period of time of 0 to 672
h.
[0059] The aqueous solution contains, as a preference, at least one
additive selected from a buffer solution, an organic and/or an
inorganic salt, a cell preparation (preferably stem cells,
osteoprogenitor cells), an active biological, recombinant or
pharmacological substance, nucleic acid (RNA or DNA), mixtures of
nucleic acids, an amino acid, a modified amino acid, a vitamin and
mixtures of them.
[0060] The aqueous solution advantageously contains a buffer
solution; a pH value is set in a fixed way in the aqueous solution
because of that. Various buffer solutions are known to a person
skilled in the art. He will select a suitable buffer solution
comprised of physiologically compatible components in dependence
upon the pH value to be set. In addition, the aqueous solution can
contain other inorganic and/or organic salts that do not have a
buffer effect themselves. As a preference, the buffer solution and
the other salts are selected from phosphates, citrates, acetates,
chlorides, sulfates and borates. Preferred cations are alkali and
alkaline earth metal ions, ammonium ions and guanidine.
[0061] As a special preference, the aqueous solution contains a
solution of amino acids and/or modified amino acids, especially
phosphorylated amino acids, and phosphoserine as a very special
preference.
[0062] The hardening advantageously takes place in that way under
defined (similar to those of the human body) biological conditions
and nevertheless outside of the body by incubating the molded bone
replacement element in a (defined biological) solution before
implantation.
[0063] The active pharmacological substances are advantageously
absorbed by the molded elements and/or adsorbed in dependence upon
the type of active substance. The adsorption is dependent upon the
specific surface of the molded elements. A more effective and more
practical method is provided by the addition of active substances
in the hardening phase instead of to molded elements that have set
with finality. Some preferred active (biological and
pharmacological) substances advantageously influence the
nanostructure and therefore the specific surface of the molded
elements. They are, on the one hand, specifically bound and lead,
on the other hand, to a finer nanostructure, which, among other
things, improves the mechanical characteristics, increases the
resorbability and, in the case of active substances, additionally
controls the delivery.
[0064] Water that can be substantially withdrawn is understood to
mean, as per the invention, physically bound or condensed water. As
a preference, the water is substantially withdrawn via the
variation of physical environmental parameters (e.g. a reduction in
pressure and/or increase in temperature or freeze drying) and/or
via contact with a water-soluble solvent, preferably short-chain
alcohols such as methanol, ethanol, isopropanol and/or propanol.
Ketones, e.g. acetone, lactones such as y-butyrolactone, lactames
such as N-methyl-2-pyrrolidone, nitriles such as acetonitrile,
nitro compounds such as nitromethane, tertiary carboxylic acid
amides such as dimethylformamide, urea derivatives such as
tetramethylurea or dimethyl propylene urea (DMPU), sulfoxides such
as dimethylsulfoxide (DMSO), sulfones such as sulfolane, and
carbonates such as dimethyl carbonate or ethylene carbonate can
likewise be used to withdraw water.
[0065] In contrast to the substantial withdrawal of water via the
variation of physical environmental parameters (e.g. reduction in
pressure and/or increase in temperature or freeze drying) or via
contact of the synthetic bone replacement material with a
water-soluble solvent (e.g. solvent replacement of water with
acetone), the water can also be substantially withdrawn via its
consumption in the chemical setting reaction. In that case, the
complete conversion of the existing share of physically bound water
into chemically bound water suffices; less water is available in a
defined way than would be necessary for a complete conversion in a
complete setting reaction.
[0066] As a preference, not only water will be substantially
withdrawn via the contact of the dimensionally stable molded bone
replacement element with a water-soluble solvent; the carrier
liquid and other auxiliary materials will also be washed out
depending on the type of water-soluble solvent that is used. A
person skilled in the art will preferably select the water-soluble
solvent in accordance with the solubility characteristics of the
carrier liquid and auxiliary materials that are used. The carrier
liquid and the auxiliary materials will preferably be completely
washed out of the dimensionally stable molded bone replacement
element. A partial residue of the carrier liquid and/or the
auxiliary materials in the dimensionally stable molded bone
replacement element as per the invention is not ruled out because
of that. Through the use of biocompatible materials as the carrier
liquid and auxiliary materials, the use of dimensionally stable
molded bone replacement elements of that type is also made possible
in the human body.
[0067] The water is substantially withdrawn as a preference when
the dimensionally stable molded bone replacement element contains a
share of hardened mineral bone cement of 5 to 90 percent by weight,
10 to 80 percent by weight as a special preference and 30 to 70
percent by weight as a very special preference.
[0068] The dimensionally stable molded bone replacement element is
put into contact or washed with a water-soluble solvent until the
dimensionally stable molded bone replacement element is
substantially free of water. According to a special design form of
the invention, the dimensionally stable molded bone replacement
element is put into contact or washed with different solvents
(mixed).
[0069] The molded element with residual hydraulic activity that is
obtained can be dried after the substantial withdrawal of water via
the variation of physical environmental parameters (e.g. an
increase in temperature and/or a reduction in pressure, freeze
drying) to remove auxiliary materials, residual water and
water-soluble solvents contained in it that were used to
substantially withdraw water.
[0070] As a basic principle, the water removal, washing and drying
can also take place under different conditions and with other
solvents. The selection of a suitable solvent for the water removal
and washing of the molded element will be obvious to a person
skilled in the art in dependence upon the selected carrier liquids
and auxiliary materials and in an appropriate way for the planned
usage. Suitable washing and drying conditions likewise result from
technical considerations regarding the auxiliary materials that are
chosen (including safety-related and industrial-safety-related
considerations), and a person skilled in the art will be familiar
with them.
[0071] In a special design form of the invention, the setting
reaction of the molded elements is carried out in several steps
and/or with various aqueous solutions and/or a steam atmosphere.
The mineral bone cement is first subjected to a shaping process for
this; the shape of the bone implant is roughly specified or the
final shape (net shape) is already established. After that, the
setting process of the molded element for a dimensionally stable
molded bone replacement element takes place via contact with an
aqueous solution and/or a steam atmosphere. The setting process is
interrupted at a specified point in time (or after reaching a
defined degree of conversion)--before the complete conversion--by
the withdrawal of water as per the invention. At a later point in
time, the setting process is continued via renewed contact with an
environment containing water or steam. This procedure makes it
possible to carry out the setting process in successive steps while
changing the reaction conditions, especially in different aqueous
solutions. The setting reaction can consequently be carried out in
an advantageous way under different and/or defined conditions. The
dimensional stability of the molded element can be achieved in a
first step for that. The interruption and resumption of the setting
process can take place as frequently as desired. The dimensionally
stable molded bone replacement element can finally be completely
hardened in a last setting reaction. In particular, the
manufacturer of the molded element can create a low-grade hardened
molded bone replacement element in a first step. Starting from this
pre-product, a processor taking it further can carry out a partial
or complete hardening, for instance in the presence of defined
active biological (cells, tissues), recombinant and/or
pharmacological substances and therefore create the final
product.
[0072] In accordance with the invention, the dimensionally stable
molded bone replacement element is both a low-grade hardened molded
bone replacement element and a partially or completely hardened
molded bone replacement element, in so far as it was converted into
a dimensionally stable state or molded element in an intermediate
step via water withdrawal before the a complete setting
reaction.
[0073] Low-grade hardening means, in the sense of the invention, a
dimensionally stable molded element whose setting reaction was
interrupted at an earlier point in time, especially at a point in
time at which less than 30% of the hydraulically active components
were converted. The point in time is preferably chosen in such a
way that the molded element can be further processed without
damage.
[0074] As a preference, a substance from the group of silicates,
phosphates, sulfates, carbonates, oxides and/or hydroxides in
combination with calcium ions, magnesium ions and/or strontium
ions, which can set in a hydraulic setting process to form a solid
of low solubility when put into contact with an aqueous solution or
after addition to an aqueous solution, is used as at least one
reactive mineral bone cement component for mixing the reactive
mineral bone cement. Bone cement components that set to form
calcium phosphates and/or magnesium phosphates are especially
preferred.
[0075] As a preference, the reactive mineral bone cement component
contains calcium and/or magnesium sales of orthophosphoric
acid.
[0076] Reactive mineral bone cement components containing mixtures
of calcium phosphates and/or magnesium phosphates with carbonates,
oxides or hydroxides of calcium, magnesium or strontium are
likewise especially preferred.
[0077] Reactive mineral bone cement components containing mixtures
of carbonates, oxides or hydroxides of calcium, magnesium or
strontium with alkali phosphates (mono, di and tri-alkali
phosphates), mono and di-ammonium phosphates or alkali
silicates.
[0078] As a preference, the reactive mineral bone cement is mixed
with a carrier liquid to form a moldable bone cement substance. As
a preference, the carrier liquid is an organic, water-free
substance into which the at least one reactive mineral bone cement
component has been dispersed.
[0079] As a preference, the organic carrier liquid is selected in
such a way that it does not react itself with the at least one
powdery reactive mineral bone cement component. As a basic
principle, carrier liquids that are both water-soluble and that
have low solubility, as well as those that are water-insoluble, are
suitable. Low solubility in water in the sense of the invention is
understood to mean carrier liquids whose maximum solubility in
water is 1.0 mol/l, preferably 0.1 mol/l. Organic carrier liquids
with a maximum solubility in water of more than 1 mol/l (preferably
more than 3 mol/l) are designated as water-soluble here. Carrier
fluids with low solubility in water are preferred, however.
Hydrophobic, practically water-insoluble carrier liquids are
especially preferred. The carrier fluid contained in the water-free
preparation is preferably bio-compatible.
[0080] Additives are preferably used when mixing the reactive
mineral bone cement to form a moldable bone cement substance.
Surfactants (tensides), active pharmacological substances and
fillers, as examples, are additives.
[0081] In a preferred design form of the invention, the carrier
liquid of the dispersion of the at least one reactive mineral bone
cement component for manufacturing a synthetic molded bone
replacement element contains surfactants that support or enable the
penetration of water or steam or air moisture to initiate and
continue the setting reaction; that especially applies when
hydrophobic carrier liquids are used. As a preference, the
surfactants are selected from the group of tensides and, as a
special preference, from the group of nonionic and anionic
tensides.
[0082] A further component of the moldable bone cement substance is
preferably at least one setting accelerator. The setting kinetics
are advantageously adjusted and controlled during the hardening of
the dispersion as per the invention because of that. Phosphate
salts, organic acids or salts of organic acids are preferred
setting accelerators. Phosphates containing sodium ions and/or
potassium ions or ammonium ions, or salts of organic acids
containing sodium ions or potassium ions or ammonium ions, and
their mixtures among one another are preferred.
[0083] In a particular design form of the invention, the setting
accelerator a component of the aqueous solution that initiates the
setting process.
[0084] In addition, active pharmacological substances can be worked
into the moldable bone cement substance. Active pharmaceutical
substances with a (bone) growth-stimulating effect or antimicrobial
effect are preferred. Active substances selected from antibiotics,
antiseptics, antimicrobial peptides, nucleic acids (preferably
siRNA), active antiresporbtive substances (preferably
bisphosphonates, corticoids, fluorides, proton pump inhibitors),
PTH and its derivatives, active bone-growth-stimulating substances,
preferably growth factors, vitamins, hormones, morphogenes, with a
preference for bone-morphogenetic proteins and peptides, as well as
active angiogenetic substances and, especially preferred among
them, fibroblast growth factors (aFGF, bFGF, FGF18 etc.),
anti-inflammatory substances and anti-tumor substances are
especially preferred.
[0085] The nucleic acids (especially the siRNA) advantageously
exercise a regulatory effect on cells in the proximity of the
implanted molded element.
[0086] The synthetic molded bone replacement elements as per the
invention are especially well suited to being carriers for active
pharmacological substances. This is because, on the one hand, the
synthetic molded bone replacement element as per the invention is
provided at low temperatures (preferably under 80.degree. C., with
a special preference for <60.degree. C., and a further
preference for <37.degree. C.). This permits active
temperature-sensitive substances to be worked in without problems.
On the other hand, the method for manufacturing synthetic molded
bone replacement elements as per the invention offers improved
release of active substances, because the active substances are
successively released via the resorption of the mineral bone
cement. The method for manufacturing dimensionally stable molded
bone replacement elements as per the invention therefore permits a
controlled release of active substances in a broad range and is
suitable in an especially advantageous way for the use of active,
temperature-sensitive substances.
[0087] Further preferred components of the moldable bone cement
substance, preferably with water-free preparation, are fillers.
Water-soluble, particulate fillers made of mineral or organic
substances are preferred. The porosity of the solid formed during
hardening with water can be advantageously adjusted by the use of
water-soluble particles. Water-soluble fillers preferably have a
particle size of 10 pm to 2000 .mu.m, and from 100 .mu.m to 1000
.mu.m as a further preference. The water-free preparation
preferably contains water-soluble fillers in a proportion of 5 to
90% by volume, with a further preference for 10 to 80% by volume
(with reference to the total volume of the water-free
preparation/dispersion). Preferred water-soluble fillers are
selected from sugars (preferably sucrose), sugar alcohols
(preferably sorbitol, xylitol, mannitol), and water-soluble salts
(preferably sodium chloride, sodium carbonate, ammonium carbonate
or calcium chloride). The proportion of pores of the hardened
mineral bone cement is preferably 10 to 90% by volume, with a
special preference for 10 to 75% by volume. The pores preferably
have a mean pore width (maximum inner extension of a pore) of
100-2000 .mu.m, with a special preference for 100-1000 .mu.m.
[0088] As a special preference, all of the components of the
dimensionally stable molded bone replacement element can be
absorbed into the body. The combination of resorbable metallic or
mineral fibers and the reactive mineral bone cement to create the
synthetic molded bone replacement elements as per the invention to
manufacture composite fiber materials is especially preferred for
the invention.
[0089] As an option, the moldable bone cement substance contains
polymeric additives, preferably selected from chitosan, hyaluronic
acid, gelatins, collagen, chondroitin sulfate, cellulose
derivatives, starch derivatives, alginate, water-soluble acrylates,
polyethylene glycol, polyethylene oxide, PEG-PPG copolymers,
polyvinylpyrrolidone, and copolymers made of water-soluble
acrylates with polyethylene glycol and/or polyethylene oxide.
[0090] As previously mentioned, commercially available cements
sometimes contain large amounts of fillers that only superficially
participate in the reaction (and thus bind to the cement matrix in
particular), but only indirectly participate in the setting
process. The participation can, as an example, also consist in a
filler acting as a seed crystal for the mineralization during the
setting process and therefore influencing the setting kinetics, in
particular, but not being converted itself. That applies, for
example, in the case of calcium phosphate cements to the addition
of precipitated hydroxyl apatite. Cost-effective additives are
frequently also added for dilution for economic reasons in
technical cements.
[0091] As a preference, the setting process is initiated in a
saturated steam atmosphere at >90% relative humidity,
advantageously controlled by the portion-by-portion supply of a
defined amount of water particles, at a temperature between 0 and
100.degree. C., and between 25 and 75.degree. C. as a special
preference.
[0092] Surprisingly, it was found that the preferred temperature
range is significantly below the sintering temperature and an
increase in the temperature is associated with neither a quicker
setting reactor nor with a quicker increase in compressive
strength.
[0093] The setting process takes place, as a preference, in a water
(steam) atmosphere at >90% relative humidity and a temperature
between 0 and 100.degree. C.
[0094] The setting process can advantageously take place in
multiple steps by first, as an example, having the setting process
initiated at a high humidity-->90%--after the shaping step and
subsequently carrying out one or more further hardening step(s)
under different conditions. In that case, one of the hardening
steps can also take place in an aqueous solution. One of the
hardening steps (preferably the final one) can also take place
under an increased temperature (>100.degree. C.) and under
increased pressure (>1 bar) in autoclaves and thus
simultaneously serve in the sterilization of the molded elements.
Likewise, it is possible to carry out one or more of the setting
steps after the interruption of the setting process via withdrawal
of water and the washing of the molded elements (and subsequent
drying). It is also advantageous in this case to carry out the last
setting step via autoclaving, possibly with simultaneous
sterilization, advantageously in the final packing It is crucial
for the residual hydraulic activity to survive after the execution
of all of the setting steps in the final molded bone replacement
element as per the invention.
[0095] As a preference, the termination of the setting process via
a substantial withdrawal of water will take place at a temperature
between 0 and 100.degree. C. The substantial withdrawal of water
will preferably take place by putting the dimensionally stable
molded bone replacement element into contact with an aqueous
solvent.
[0096] The shaping of the bone cement substance will preferably
take place via a (3D) printing process. As a preference, a paste
containing reactive mineral bone cement components in a water-free
carrier liquid is extruded in the form of sections, put in order
and laid down in successive layers (stacked) so that spaces remain
between the sections and a 3D molded element with contiguous
(interconnecting) porosity arises via the arrangement of the
layers, and the dimensionally stable molded bone replacement
elements obtained in this way have an overall porosity between 20
and 90%.
[0097] The 3D printing process can take place, for instance, in
such a way (without being limited by this description in principle)
that a previously described dispersion in the form of paste
containing a reactive mineral bone cement powder in a water-free
carrier liquid is extruded in the form of thin (e.g. 0.3-0.6 mm
diameter) sections, put in order and laid down in successive layers
(stacked); the successive layers are offset by a pre-specified
angle between 0.degree. and 90.degree., so spaces remain between
the sections and a 3D molded element with contiguous
(interconnecting) porosity arises via the arrangement of the
layers, and the dimensionally stable molded bone replacement
elements obtained in this way have an overall porosity between 20
and 90%. Molded elements with almost any desired dimensions and
pore arrangements can be printed with this method. Surprisingly, it
turned out that a high level of dimensional accuracy of the molded
elements is achieved with this method and the subsequent hardening
of the printed molded elements in a steam-saturated atmosphere and
neither fractures of the sections nor surface changes arose in the
individual sections (with most of the other 3D printing methods
that are described for ceramic molded elements as bone implants,
both shrinkage and other damage in the manufacturing process are
described and, in particular, significantly narrower limitations
with small land thicknesses and small pore dimensions).
[0098] As a preference, the complete hardening of the synthetic
molded bone replacement element with residual hydraulic activity or
of a preform will take place--after the first partial hardening and
water withdrawal--via renewed contact with an aqueous liquid
containing biological components and/or active pharmacological
substances and/or isolated or cultivated cells.
[0099] The bone cement mass will preferably be shaped via a
granulation process in which the dimensionally stable molded bone
replacement element is obtained in the form of granules consisting
of individual granules or agglomerations of granules. The granules
are produced in a known way, for instance via fluidized bed
granulation or granulation via an extrusion process. During the
granulation via an exclusion process, the pasty dispersion
comprised of a reactive mineral cement powder and a water-free
carrier liquid is pressed out of a cartouche through a calibrated
outlet opening. The extruded section is sheared off at short
intervals, and cylindrical segments of the paste are obtained in
this way that can subsequently be rounded off on a dish granulator.
The granules obtained in this way can be hardened and
compacted.
[0100] The invention also relates to the use of a dimensionally
stable molded bone replacement element for manufacturing an
alloplastic implant.
[0101] Use of a dimensionally stable molded element as a carrier
material in the cell culture, the tissue culture and/or the tissue
engineering.
[0102] Molded elements with residual hydraulic activity as per the
invention can be used in a variety of ways, especially as a
cell-culture carrier for the cultivation of bone cells in research
or for tissue engineering. Further preferred applications are as
carrier materials in biotechnology; the cultivated bacteria or
yeast cells can, for instance, already be put into the carrier
material in the manufacturing process. A further preferred
application is the purification of (waste) water from heavy metals
and organic substances.
[0103] Use as an alloplastic implant material for filling in bone
defects that can be congenital, that can arise as a result of
accidents or that can arise after surgical procedures--especially
after the removal of bone tumors or cysts, change of a prosthesis,
corrective osteotomies etc.--is a special preference. The use of
the molded bone replacement elements as per the invention in
mouth/jaw surgery to build new bone, e.g. alveolar ridge
augmentation, a sinus lift or filling in extraction holes, is a
special preference.
[0104] Another special preference is the use of the molded bone
replacement elements as per the invention in orthopedics, trauma
surgery and spinal column surgery to fill in all types of bone
defects. In comparison with other biological and alloplastic bone
replacement materials currently in use, the molded bone replacement
elements as per the invention offer the advantage of defined
porosity, increased bioactivity, defined mechanical
characteristics, simple intra-operative processing capability and
ease of combination with biological substances, bone cells and
active pharmacological substances.
[0105] Use of the molded bone replacement elements as per the
invention within the framework of therapeutic tissue engineering is
a special preference. Molded bone replacement elements as per the
invention are incubated in vitro with bone cells (preferably
autologous bone cells or stem cells) under sterile conditions for
this; the dimensionally stable molded bone replacement elements are
populated with the cells, and the cells can be reproduced. After
the conclusion of the cultivation, an autologized bone replacement
implant is obtained that is indicated for the regeneration of major
bone defects, in particular.
[0106] The combination of molded elements with bone cells or stem
cells preferably takes place in a bioreactor; the molded elements
as per the invention bring along especially good prerequisites for
this, in particular--aside from the above-mentioned
characteristics--variable shaping without a technological size
limitation with, at the same time, completely interconnected
porosity that is a crucial requirement for good perfusion with a
culture medium in the bioreactor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0107] The invention is to be explained in more detail with the aid
of the descriptions and examples that are provided without limiting
it to them; the figures show the following:
[0108] FIG. 1A) X-ray diffractogram of a porous, printed molded
element made of paste CPC that was hardened for 2 days under steam
saturation at 50.degree. C. and whose hardening was subsequently
stopped via removal of water with acetone (3.times.20 min. acetone
washing in the ratio 1:5 w/w) and drying at 80.degree. C. The
reflexes show, as the predominant crystalline phase, .alpha.-TCP
(.circle-solid.) and a broad reflex for nanocrystalline hydroxyl
apatite (.box-solid.) that arises as a reaction product of the
hydraulic setting reaction. A further reactive component is the
monetite (.diamond-solid.). whose reflexes can still be clearly
recognized. The reaction was stopped before the complete hydraulic
setting.
[0109] FIG. 1B) X-ray diffractogram of a porous, printed molded
element made of paste CPC that was hardened for 14 days under steam
saturation at 50.degree. C. and whose hardening was subsequently
stopped via removal of water with acetone (3.times.20 min. acetone
washing in the ratio 1:5 w/w) and drying at 80.degree. C. The
reflexes show the presence of only slight amounts of .alpha.-TCP
(.circle-solid.) and monetite (.diamond-solid.) as a sign of almost
completely concluded hydraulic conversion. The dominant phase is
nanocrystalline hydroxyl apatite (.box-solid.), which is
characterized by the broad reflex between 31.5 and
33.5.degree..
[0110] FIG. 2) Strength progression after different incubation
times in different aqueous media of the dimensionally stable molded
bone replacement elements manufactured according to Example
1.6.
[0111] FIG. 3) Compressive strength (CS) of the molded elements in
dependence upon the pH value of the incubation solution.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Example 1
1.1 Mixing a Reactive Mineral Bone Cement to Create a Moldable Bone
Cement Substance
[0112] A calcium phosphate cement powder based on .alpha.-TCP was
manufactured by mixing 60 g of .alpha.-tricalcium phosphate, 26 g
of calcium hydrogen phosphate (water free), 10 g of calcium
carbonate and 4 g of hydroxyl apatite and then finely grinding it.
2.5 g of ground dibasic potassium phosphate was added to 82 g of
this powder mixture, and this was then dispersed in 15.5 g of an
oil-emulsifying agent mixture comprised of short-chain
triglycerides (Milyol 812), caster oil ethoxylate (Cremophor ELP)
and cetyl phosphate (Amphisol A) (ratio of ingredients w/w
82:13:5). The mixture that was obtained was mixed to form a
plastically deformable paste and ground up. After the conclusion of
the grinding process, the paste was filled into commercially
available 5 ml PE cartouches and stored until further use.
1.2 Shaping
[0113] The 5 ml PE cartouches filled with the paste that was
described were connected via their Luer Lock connector to a
stainless steel cannula with an internal diameter of 0.3 mm and
mounted in a commercially available 3D printer (regenHU,
Switzerland). A section of the plastically deformable paste was
pressed through the cannula with compressed air and set down in
layers on a glass plate according to a computer-controlled system.
The porosity of the printed molded elements was specified by the
choice of the section spacing. The successive layers were offset by
an angle of 90.degree.. The consistency of the paste that was
described made it possible to print molded elements with a height
of 15 mm without a recognizable deformation of the lower sections.
Molded elements with the dimensions 10.times.10.times.5 mm were
manufactured in the chosen example. The overall porosity was
approx. 60%.
1.3 Hardening of the Molded Elements
[0114] After the conclusion of the printing process, the glass
plate with the printed molded element was put into a Petri dish.
The Petri dish was put into a waterproof foil bag that additionally
contained a water-saturated sponge. The foil bag was tightly
closed. The water-saturated sponge and the printed molded element
did not have direct contact. The molded elements that were packed
in this way were incubated in an incubator at 50.degree. C. for
various periods of time.
1.4 Termination of the Setting Reaction
[0115] To terminate the setting reaction, the molded elements were
removed from the incubator at different points in time and put into
a glass vessel with water-free acetone for 20 in. (ratio of acetone
to the molded element: 5:1 (w/w)) and lightly shaken. The process
was repeated 3.times. to remove both water and the oil-emulsifying
agent mixture. After the last washing in acetone, the molded
elements were dried at 80.degree. C. in the drying cabinet and then
packed in foil bags in an airtight manner.
1.5 Analysis of the Dimensionally Stable Molded Elements With
Regard to Their Compressive Strength and Material Conversion in
Dependence Upon the Duration of the Setting Reaction
[0116] The table below shows the compressive strength of the molded
elements that were manufactured in dependence upon the hardening
duration at 50.degree. C. and saturated air moisture. The
compressive strength was determined for molded elements with the
dimensions 10.times.10.times.5 mm (horizontal). The molded elements
of the example had a density of approx. 1.1 g/cm.sup.3 on average.
The measurement took place in a universal testing machine of the
company Hegewald & Peschke using a 20 kN load cell at a feed
rate of 1 mm/min. The material conversion in dependence upon the
hardening duration at 50.degree. C. and saturated air moisture was
investigated via XRD measurements (x-ray diffractograms).
TABLE-US-00001 TABLE 1 Compressive strength values (CS-MV) of 7
test specimens each that were hardened at 50.degree. C. and
saturated air moisture. CS-MV Time [MPa] 6 h 1.72 16 h 5.25 24 h
5.85 38 h 6.40 48 h 11.44 4 d 10.38 7 d 10.64 14 d 11.50
[0117] The joint analysis of the progression of compressive
strength and the material conversion of the mineral phases in the
course of the setting reaction shows that the increase in
mechanical strength takes place in a substantially quicker way than
would be expected after the material conversion of the mineral
starting components into hydroxyl apatite, the reaction product of
the setting reaction. In particular, the compressive strength
values already show the maximum value of the compressive strength
after 48 h, whereas the material conversion of the reactive
starting components has not come anywhere close to being concluded
and is at <50% based on the X-ray diffractogram.
[0118] The degree of conversion in this comparison is determined
with the aid of the content of .alpha.-TCP determined via X-ray
diffractometry or more specifically the ratio of .alpha.-TCP to
hydroxyl apatite at the respective points in time of the
measurements (FIGS. 1A and 1B). The starting content of all of the
reactive mineral components was 96%; the starting content of
.alpha.-TCP in the reactive mineral powder mixture was 60%. After
48 h, the content of .alpha.-TCP was determined to be approx. 45%,
whereas the remaining overall content of all of the reactive
mineral powder components was approx. 50%. After 14 days, the
material conversion to hydroxyl apatite was almost completely
concluded under the selected conditions; only traces of .alpha.-TCP
were able to be verified via X-ray diffractometry (FIG. 1b). A
further increase in strength is not associated with the continuing
conversion, though.
[0119] The analysis of the progression of compressive strength
makes a targeted selection of product characteristics possible with
respect to the intended application. The hardening was stopped via
water withdrawal at an early point in time for the simplest
possible processing capabilities that were desired and the greatest
conversion under biological conditions that was strived for. In the
case of the molded elements of the example, that could already take
place after approx. 6 h, because sufficient dimensionally stability
of the printed molded element has already been achieved at this
point in time; a strength of approx. 2 MPa is strived for. A
termination of the setting reaction after approx. 16 h is
preferred, when the strength is approx. 50% of the maximum
strength. A termination of the setting reaction in the case of the
molded elements of the example after approx. 48 h, when the
strength has reached 100% or nearly 100% of the maximum strength,
is especially preferred. In so doing, the point in time of the
termination of the setting reaction is chosen in such a way that a
value for the material conversion that is as small as possible
exists at this point in time. Experimental data have shown that
this circumstance is reached for the molded element in the example
at approx. 48 h. An optimal compromise can be achieved between
strength and biological activity in that way.
1.6. Conversion of the Molded Elements With Residual Hydraulic
Activity After Incubation in Different Media
[0120] Molded elements with the dimensions 10.times.10.times.5 mm
with the material composition according to Example 1.1 were
manufactured in a 3D printing process according to Example 1.2 and
hardened over 24 h according to Example 1.3 and the hardening was
terminated via water withdrawal according to Example 1.4 in such a
way that the average density was 1.5 g/cm.sup.3. After that, the
molded elements were packed in an air-tight way in foil bags and
stored for further investigation at room temperature. The molded
elements manufactured in that way had a compressive strength of 7.8
MPa. Three of the molded elements each (per medium and
investigation point in time) were put into different media (NaCl,
DMEM (cell culture medium) and SBF (simulated body fluid) to
investigate the influence of the media composition on the further
hardening of the molded elements; the incubation took place at
37.degree. C. FIG. 2 shows the strength progression after different
incubation times. The strength of the molded elements already
increases strongly in all of the media after a short period of
incubation. The increase continues over the entire investigation
period of 168 days and reaches unexpectedly high values at approx.
30-35 MPa. There are no significant differences with regard to the
progression of strength between the different incubation media that
differ significantly in terms of composition. The results show that
the setting reaction interrupted via water withdrawal is continued
after being put into an aqueous medium once again and that the
further reaction is independent of the composition of the medium to
a great extent (in so far as the composition of the medium is
within the biologically relevant framework).
Example 2
Study Involving Implantation in a Sheep
[0121] Printed molded elements according to Example 1 after 4 days
of hardening were shaped via milling into half spheres with a
radius of 5 mm, subsequently washed in water and acetone, dried,
and, after that, individually packed in plastic tubes and
sterilized with 25 kGy via gamma irradiation. In the technique
according to Busenlechner (Biomaterials 29 (2008) 3195-3200), the
half spheres from the printed molded elements were put in a
positive-locking way into titanium half spheres with an inner width
of 10 mm and, after placing 11 small drill holes each of 1 mm
diameter and 2 mm depth, set on the calvarias of full-grown sheep.
The control group received half spheres that were filled with
porous .beta.-TCP (bone replacement material according to the prior
art). After 8 and 16 weeks, the implants were removed and evaluated
on a histological basis. The group with the printed molded elements
showed a significantly stronger formation of new bone than the
group with .beta.-TCP. Although practically all of the pores of the
printed molded elements were filled with new bone and all of the
surfaces of the material as per the invention were covered with new
bone, this was only sporadically the case with the .beta.-TCP.
These in vivo results show the exceptionally high bioactivity of
the material as per the invention in comparison with a molded bone
replacement element used on a standard basis in orthopedics and
traumatology. The results of the study confirm that the formation
of nanocrystalline hydroxyl apatite leads under biological
conditions to a material with an especially high level of
bioactivity. This high level of bioactivity is reflected in a
significantly increased rate of new bone formation in a clinically
relevant model for bone healing. A .beta.-TCP that is comparable to
the implant material as per the invention with regard to the molar
calcium/phosphate ratio (approx. 1.5) and the overall porosity
served as a comparative implant. The significantly increased
formation of new bone and bone integration that was likewise
significantly quicker and more complete can therefore be causally
traced back to the greater bioactivity by the composition as per
the invention and the method of manufacturing the molded element
with residual hydraulic activity that was described.
Example 3
Molded Element With Residual Hydraulic Activity on the Basis of
Magnesium Calcium Phosphate Cement (MgPCP)
[0122] In a manner analogous to Example 1, cement pastes based on
MgCPC were produced by creating, with the same organic phase, the
mineral phase from MgCPC powder with the composition
(Ca.sub.0.5Mg.sub.2.5(PO.sub.4).sub.2) in a ratio of 84% by weight
powder to 16% by weight carrier liquid. The shaping likewise took
place in a manner analogous to Example 1 via a 3D printer to create
molded elements with the dimensions 10.times.10.times.5 mm with a
mean density of 1.4 g/ml. The initial hardening of the molded
elements took place in a saturated steam atmosphere at 37.degree.
C. over 24 h. After that, the molded elements were incubated in
various media to investigate the influence of the medium
composition. The compressive strength of the molded elements is
presented in FIG. 3 in dependence upon the pH value of the
incubation solution. The result shows that MgCPC molded elements
with residual hydraulic activity can be manufactured with a
relatively high level of initial strength that can subsequently
(after termination of the hardening via water withdrawal) be
further strengthened by incubation over 24 h in a defined buffer
solution (the reference had a compressive strength of 17 MPa).
Example 4
Setting of Molded Elements Over Several Stages
[0123] CPC molded elements with the dimensions 6.times.6.times.12
mm are prepared by plastering paste in CPC into a divisible metal
mold and holding it over 24 h at 37.degree. C. in a 0.9% NaCl
solution. After removal from the mold, the molded elements are
washed in distilled water and dried. The compressive strength is
approx. 12 MPa. Cylinders dimensioned with the diameter 5 mm and
the height 12 mm are manufactured from these low-grade hardened
molded elements on a lathe. After that, the cylinders are incubated
for 2 days at 37.degree. C. in 1% CaCl2 solution, washed with
acetone and dried. The compressive strength is 32 MPa. The molded
elements that are obtained in this way are subsequently put into
simulated body fluid at 37.degree. C. for 7 days, water is
subsequently withdrawn from them in acetone and they are dried. The
compressive strength is 56 MPa. The degree of conversion according
to the XRD analysis is approx. 85%.
[0124] The molded elements can--depending on the intended use--be
used as a product after each of the steps that were described.
* * * * *