Patent Grant
11185475
The present invention is related to new biomaterials, in particular bone foams, a process for preparing such materials as well as an applicator for applying the biomaterials directly to the patient's application site. Further, the present invention is directed to the use of a composition comprising water, a surfactant and a propellant in the preparation of a bone foam.
The natural capability of the human body to regenerate bone defects is not sufficient. Therefore, for the human body is typically not possible to restore a fracture on its own. Medical implants are useful in providing sufficient stability for the fracture and support the curing process.
In cases where the bone damage is too severe, bone cements may also be applied to stabilize implants and thereby support the curing of the defect.
Bone cements may act as an artificial “linker” between the natural bone and the implant. Usually, bone cements are classified into two general classes, so called PMMA bone cements (Poly Methyl Methacrylates) and calcium phosphate based cements.
Since the discovery of the calcium phosphate based cements in the mid 1980ies, various formulations have been developed. The underlying principle of these materials is that a mixture of one or more calcium salts with water or an aqueous solution forms a cement which due to a dissolution and precipitation process sets. The setting typically takes place under physiological conditions. The final reaction product (after setting) is typically a hydroxyapatite that is very similar to the biological material in terms of crystallinity and non-stoichiometry.
One of the main advantages of the calcium phosphate foams is their excellent biocompatibility and bioactivity. Moreover, the foam is capable of adapting to the geometry of the defect.
The properties of the resulting calcium phosphate foam (bone foam) can be adjusted by modifying various parameters such as the chemical composition of the starting material, the relative proportion of the constituents, additives (such as seeds, accelerants, retardants, etc.), particle size, pH value, liquid to powder ratio, temperature, humidty or the like.
The porosity of the bone foam is a further important parameter and is also important for the durability of e.g. implants. On the one hand, a high porosity is desired to allow for space for newly formed bone tissue. On the other hand, the higher the porosity of the resulting material, the smaller is its breaking strength.
Moreover, the handling of the current products is far from ideal. The application of bone cements into a void for example of an osteoporotic bone is very difficult as the cement paste is made outside the application site and subsequently applied into the damaged bone. Therefore, it is very difficult to apply the foam into small cavities which cannot be reached by the instrument with which the paste is applied to the damaged bone.
EP 1 787 626 describes an injectable self setting calcium phosphate foam for use as biomaterial. The foam is prepared by agitation and mechanical whipping and may subsequently be applied.
Particles for incorporation of particulate components in a calcium phosphate cement are for example known from U.S. Pat. No. 5,525,148 issued to Chow et al, U.S. Pat. No. 5,820,632 issued to Constantz et al, or JP 5,023,387 issued to Hirano et al.
One of the problems associated with the calcium phosphate bone foams of the prior art is that they are prepared extra corporally and only after preparation applied to the corresponding site of application in the body by manually controlled means, e.g. a syringe. For small application sites or complex geometric forms there is a need for an improved application of the foams and/or foams which are instantly applied to the application site after preparation (“direct to patient application”).
It would be desirable to provide an improved calcium phosphate foam, process for the preparation of a calcium phosphate foam, use of a composition, solid state structure, calcium phosphate cement foam and bone foam applicator.
The invention provides calcium phosphate foam, process for the preparation of a calcium phosphate foam, use of a composition, solid state structure, and calcium phosphate cement foam and a bone foam applicator according to the subject matter of the independent claims. Further embodiments are incorporated in the dependent claims.
According to an exemplary embodiment of the invention, there is provided a process for the preparation of a calcium phosphate foam wherein the foam is obtainable by the mixture of at least two phases, a first phase comprising water and a second phase comprising one or more sources for calcium and/or phosphate, and wherein the foaming is performed during the mixture of the at least two phases. The first and/or the second phase may optionally further comprise a propellant. The term “during the mixture” of the at least two phases should be understood that the foaming of the cement starts just before, immediately when or substantially immediately when the first and the second phases are being contacted.
Thus, the process may provide a bone foam which is foamed in situ while mixing the first and the second phase so that no sequential foaming of the mixed cement paste or any precursors thereof is required any more. The optional propellant may be used for foaming the respective first and second phase.
According to another exemplary embodiment of the invention, the use of a composition comprising water, a surfactant and a propellant in the preparation of a calcium phosphate foam is provided, wherein the composition is contacted with at least one phase comprising one or more sources for calcium and/or phosphate.
Thus, the use of the composition allows for an in-situ foaming of the cement paste which is obtained upon mixing of the composition comprising water and the one or more sources for calcium and/or phosphate by the propellant, so that no additional step of foaming of the cement paste is required.
According to another exemplary embodiment of the invention the calcium phosphate foam obtainable by the above described process for use in bone regeneration, tissue engineering or as a bone substitute is provided.
According to an exemplary embodiment of the invention the solid state structure obtainable by the above described process after setting of the foam is provided. A solid state structure for use in bone surgery, bone regeneration, bone defect fillings, stabilization of bone fractures, fixing of implants, tissue engineering or as a bone substitute is also provided.
According to an exemplary embodiment of the invention there is provided a bone foam applicator, comprising a first container for storing a first composition having a first outlet, a second container for storing a second composition having a second outlet, a mixing arrangement having a first inlet and a second inlet, and an application outlet, an activation unit, wherein the first outlet is connected to the first inlet, and the second outlet is connected to the second inlet, wherein the activation unit is adapted to activate a convey of the first composition from the first container and the second composition from the second container to the mixing arrangement, wherein the mixing arrangement comprises a mixing volume being connected to the first inlet, the second inlet and the application outlet, wherein the mixing volume being adapted for mixing the first composition and the second composition within the mixing volume for foaming the mixed first composition and second composition when exiting the application outlet.
Thus, a bone foam applicator may be provided by which the first composition and the second composition may be mixed within the mixing volume before exiting the bone foam applicator. This allows a sufficient and reliable mixing process, in particular for medical compositions, like for example bone foam cement. In a medical application a reliable mixing process is of utmost importance, as for example bone foam cement is used during larger surgeries requiring save and reproducible processes. As a rule, the mixing process does not require further items or tools, as the mixing takes place within the bone foam applicator, i.e. within a mixing volume. This further allows providing the bone foam applicator as a simple single or multiple use device, which the surgeon may take from a storage when required during the surgery. In addition the first and second composition may be compositions which are activated when being mixed, so that this activation may take place on demand when applying the bone foam to the application site. Before activation, the compositions may be stored, without being activated. It should be noted that also more than two composition may be used, which as a rule requires more than two containers.
According to an exemplary embodiment of the invention at least one of the first container and the second container are adapted to store a propellant for blowing out the respective first and second compositions.
Thus, no further drive is required for conveying the mixture of the first and second composition. The bone foam applicator may be designed such that only a low force application is required for activation.
According to an exemplary embodiment of the invention the activation unit is integrally formed with the mixing arrangement and adapted to activate at least one valve positioned in the respective first and second outlet of the respective first and second container.
Thus, the number of movable parts may be reduced. A reduced number of movable parts as a rule lead to a higher reliability of the entire device.
According to an exemplary embodiment of the invention, the first container comprises water and optionally a propellant, and the second container comprises one or more sources for calcium and/or phosphate.
Thus, the bone foam may be obtained in situ by activation the bone foam applicator. The water from the first container and the sources for calcium and/or phosphate from the second container each enter the mixing volume. Within the mixing volume the bone foam will be generated in-situ. The generated bone foam may exit the mixing volume via the application outlet so that the bone foam may be directly applied to the patient's application site, when directing the application outlet directly to the patient's site. The application outlet may be provided with an extension like a tube or a conduit for an easier application. The tip of the application exit or the extension may be provided with an application head. The application head may have a plurality of openings and/or nozzles each pointing into different directions. The fmalization of the chemical process of foam generation may also take place at the patient's site, i.e. at least a part of the chemical reaction, the final expansion and/or the hardening of the bone foam.
It should be noted that the above features may also be combined. The combination of the above features may also lead to synergetic effects, even if not explicitly described in detail.
These and other aspects of the present invention will become apparent from and elucidated with reference to the embodiments described hereinafter.
Exemplary embodiments of the present invention will be described in the following, at least a part of it with reference to the following drawings.
According to an exemplary embodiment of the invention, there is provided a process for the preparation of a calcium phosphate foam wherein the foam is obtainable by the mixture of at least two phases, a first phase comprising water and a second phase comprising one or more sources for calcium and/or phosphate, and wherein the foaming is performed during the mixture of the at least two phases. The first phase may optionally further comprise a propellant. The second phase may also optionally further comprise a propellant.
In one preferred embodiment of the invention, the first phase further comprises a propellant which allows for the foaming of the first and the second phase when the at least two phases are mixed. Upon mixing of the at least two phases, the cement paste is formed by the reaction of the first phase comprising water and the second phase comprising one or more sources of calcium and/or phosphate. The in-situ foaming of the cement paste formed from the at least two phases allows for the omission of an additional foaming step (e.g. performed by mechanical agitation) required by cement pastes described in the art.
In another exemplary embodiment of the invention, the first phase further comprises a stabilizing agent. The stabilizing agent supports the bubbles formed during foaming and thereby allow for a preparation of solid state structures exhibiting a higher macroporosity. A high macroporosity of the resulting solid state structure is desirable for bone regeneration and further conditions of interest of the present invention since it facilitates angiogenesis.
The stabilizing agent is preferably biocompatible.
The stabilizing agent is preferably selected from the group consisting of a surfactant, gelling agents, soluble phosphate salts, organic acids, and any mixtures thereof and more preferably is a surfactant.
The surfactant may be selected from the group consisting of a cationic, anionic or non-ionic surfactant and is preferably a non-ionic surfactant. In an alternative preferred embodiment of the present invention, the surfactant is a polymeric surfactant.
The surfactant that may be applied in the present invention are selected from the group consisting of substituted polyethylenglycols, PEGylated fatty acid derivatives, PEGylated glycerol fatty acid derivatives, PEGylated sorbitan fatty acid derivatives, and polypropylene glycol-PEG-blockpolymers derivatives and is preferably selected from the group consisting of PEG-glycerol rizinoleate, PEG-gycerol-hydroxystearate, polypropylene glycol-PEG-blockpolymer, PEG-hydroxystearate, and PEG-sorbitan-monooleate. In particluar, PEG-35-glycerol rizinoleates, PEG-40-gycerol-hydro xystearates, PEG-15-hydroxystearates, PEG-20-sorbitan-monooleates are preferred. Suitable surfactants that may be applied in the present invention are for example Cremophor EL®, Cremophor RH40®, Poloxamer 188®, Solutol HS 15®, or Tween 80®.
In case a stabilizing agent is present in the first composition, the stabilizing agent is present between 0,1% and 10% by weight, 0,5% to 7,5% or 0,5% to 3% based on the first phase. In a preferred embodiment, wherein the stabilizing agent is a surfactant, the surfactant is present between 0,1% and 10% by weight, 0,5% to 7,5% or 0,5% to 3% based on the first phase.
In an exemplary embodiment of the invention, the first phase further comprises a propellant. The propellant may be selected from the group consisting of propane, butane, iso-butane, heptafluorpropane, pentafluorobutane, and tetrafluoroethan and any mixtures of the foregoing. In a preferred embodiment, the propellant may be present between 5% and 25% by weight/weight based on the first phase.
The properties of foam may also be adjusted by the vapor pressure of the propellant in the first phase. In a preferred embodiment of the invention, the vapor pressure of the propellant is from about 1,1 to about 8 bar, preferably from about 1,3 to about 6 bar, and more preferably from about 1,5 to about 5 bar.
The compositions of the present invention may further comprise components selected from the group consisting of binders, accelerators, cohesion promotors, and any mixtures of the foregoing.
Binders suitable for use in the present invention are selected from the group consisting of sodium alginate, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl starch, soluable starch, cyclodextrin, dextran sulphate, polyvinylpyrrolidone, chitosan, hyaluronic acid and any mixtures of the foregoing. The binders are preferably present in the range from 0,1% to 10% by weight, more preferably from 0,5% to 5% by weight based on the first phase. Polyvinylpyrrolidone is preferred.
Accelerators of the setting reaction may be selected from the group consisting of Na2HP04, NaH2P04, tri-sodiumcitrate-dihydrate, KH2P04, or K2HP04 or any mixtures thereof. Preferably, the accelerator is present in the range from 0,1 to 10% (by weight), preferably in the range from 0,5% to 5% based on the first composition.
The reagents of the second phase of the cement include a source of calcium and a source of phosphate, which can be present as a single component or as two or more components. In case of a single source both calcium and phosphate are comprised therein. In case two or more components are applied as the source for calcium and/or phosphate, either each of them comprises calcium and phosphate or the sources for calcium and phosphate are present in separate components. The second phase comprises a calcium and/or a phosphate source selected from the group consisting of
a) at least a source of calcium and/or phosphate selected from tetracalcium phosphate, dicalcium phosphate anhydride, dicalcium phosphate dihydrate, alpha tricalcium phosphate, beta tricalcium phosphate, monocalcium phosphate monohydrate, hydroxyapatite, calcium deficient hydroxyapatite, fluorapatite, amorphous calcium phosphate, calcium-sodium- and potassium-phosphate, calcium- and sodium-phosphate, calcium- and potassium-phosphate, and calcium pyrophosphate; or alternatively,
b) at least a compound of calcium selected from calcium carbonate, calcium sulphate, calcium sulphate hemi hydrate, calcium oxide, and calcium hydroxide, and at least a compound of phosphate selected from phosphoric acid and all the soluble phosphates; or alternatively
c) a mixture of at least a compound defined in option a) and at least a compound defined in option b).
From these sources of calcium and/or phosphate tetracalcium phosphate, dicalcium phosphate anhydride, dicalcium phosphate dihydrate, alpha tricalcium phosphate, beta tricalcium phosphate, monocalcium phosphate monohydrate, hydroxyapatite, calcium deficient hydroxyapatite, fluorapatite, amorphous calcium phosphate, calcium-sodium- and potassium-phosphate, calcium- and sodium-phosphate, calcium- and potassium-phosphate, and calcium pyrophosphate are preferred.
Even more preferably, the second phase comprises tetra-calcium phosphate, di-calciumphosphate or mixtures thereof, and preferably the ratio of tetra-calcium phosphate to di-calciumphosphate is between 1:5 and 5:1 and more preferably between 1:3 and 3:1. A suitable source for calcium and/or phosphate is e.g. the mixture of dicalcium phosphate dihydrate, tetracalcium phosphate comprising tri-sodium citrate sold under the tradename “HydroSet®” by Stryker®.
In a further preferred embodiment of the invention, the particle size of the calcium and/or phosphate source is in the range of 0,05 to 100 μm, and preferably is between 0,1 and 75 μm, more preferably is between 0,2 and 50 μm, and even more preferably between 0,5 and 10 μm.
The particle size distribution is determined by methods known to the person skilled in the art such as laser diffraction or photon correlation spectroscopy. In general, laser diffraction is used when determining particle size distribution of particles about 0,5 μm or larger. For example suitable apparatus such as a laser diffractometer “Helos” of the company Sympatec may be used. Photon correlation spectroscopy is applied for particle size distribution of 5 μm or less. A suitable apparatus for Photon correlation spectroscopy is the Malvern Zetasizer Nano-ZS. Particle size distributions between 0,5 μm and 5 μm may be analyzed by either of the two methods described above.
In a further exemplary embodiment of the invention, the second phase may preferably comprise a further component selected from the group consisting of an alcohol, a propellant, and any mixtures thereof.
The foam prepared by the process of the present invention may comprise an active agent (such as anticancer agents, antibiotics and/or antioxidans), a viable cell, or a growth factor or a combination of the foregoing. Preferably, these additional components are added in form of a solution or suspension. The use of an osteoblast suspension is preferred.
The process of the present invention allows for an in situ preparation of the bone foam. Thus, the foaming starts immediately when the first and the second phase are mixed. After formation of the foam it sets in less than 60 min, less than 50 min, less than 40 min, less than 30 min, less than 15 min, less than 10 min, less than 8 min, or less than 5 min at 37° C.
In an exemplary embodiment of the present invention, the ratio of the first phase and the second phase is between 10:1 and 1:10, and preferably between 8:1 and 1:8, and even more preferably 5:1 and 1:5.
The calcium phosphate foam according to the present invention comprises calcium phosphate cement and at least one stabilizing agent.
The stabilizing agent is preferably selected from the group consisting of a surfactant, gelling agents, soluble phosphate salts, organic acids, and any mixtures thereof and more preferably is a surfactant.
Suitable soluble phosphate salts are preferably selected from the group consisting of primary phosphates (dihydrogen phosphates), secondary phosphates (hydrogen phosphates) and tertiary phosphates, preferably alkaline or alkaline earth phosphates such as NaH2P04, KH2P04, Na2HP04, K2HP04, Na3P04, orK3P04.
Suitable organic acids are preferably selected from the group consisting of organic acid selected from oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoro acetic acid, ascorbic acid, fatty acids and the like. Citric acid is preferred.
The surfactant may be selected from the group consisting of a cationic, anionic or non-ionic surfactant and is preferably a non-ionic surfactant. In an alternative preferred embodiment of the present invention, the surfactant is a polymeric surfactant. With respect to the preferred surfactants, it is referred to the above mentioned preferred surfactants.
The calcium phosphate foam according to the present invention has preferably a viscosity which allows for a direct application of the calcium phosphate foam to the application site e.g. with the applicator of the present invention described above. The calcium phosphate foam is capable of being applied to and fill small cavities before setting. The viscosity of the calcium phosphate foam of the present invention (non hardened) is between 100 and 100.000 cP at 20° C.
Calcium phosphate foam of the present invention exhibits (after setting) a macroporosity in the range of 5 to 90 vol.-%, preferably in the range of 15 to 80 vol-%, more preferably between 20 and 80%, even more preferably between 25 and 80 vol.-% and more preferably 30 and 80%, and most preferably between 35 and 80%. Said set foam (a solid state structure) comprises pores having a diameter comprising between 10 and 1000 μm, preferably between 100 and 800 μm. The size of the pores may be adjusted by various parameters such as the concentration of the stabilizing agent or the particle size of the calcium and/or phosphate sources.
Preferably the macropores are interconnected. Interconnectivity of the pores may be induced by the foaming process. However, the interconnectivity of the pores may be increased by measures known to the skilled person such as incorporation of particulate components in the second phase. These particulate components should be insoluble in the cement but dissolve after being exposed to physiological conditions after the cement foam has set. Such particles are for example mentioned in U.S. Pat. No. 5,525,148 issued to Chow et al, U.S. Pat. No. 5,820,632 issued to Constantz et al, or JP 5,023,387 issued to Hirano et al, all incorporated herein by reference.
Preferably the calcium phosphate foam of the present invention exhibits a setting time measured by the Gillmore needles method less than 45 min, less than 35 min, less than 25 min, less than 15 min, less than 10 min, less than 8 min, or less than 5 min. Alternatively, a Zwick/Roell Materialprufer Z2.5 may also be applied for determination of the setting time.
In a further exemplary embodiment, the calcium phosphate foam preferably is stable for at least 15 min, at least 30 min, at least 40 min, at least 45 min, at least 50 min, or at least 60 min. The stability of the foam is measured by the so called “cylinder method”, in which a measuring cylinder is filled with foam and by determination of the respective foam and liquid volume at specific time points, the stability of the foam is determined. If the stability of the foam is sufficient, the foam sets in the foamed structure to form a corresponding solid state structure.
In a further exemplary embodiment of the invention, the calcium phosphate foam is self setting, preferably under physiological conditions (e.g. temperature, aqueous environment).
In yet another exemplary embodiment of the invention, the foam further preferably comprises a crosslinking agent. The crosslinking agent assists in the setting of the foam.
A further aspect of the present invention is directed to a use of a composition comprising water, a surfactant and a propellant in the preparation of a calcium phosphate foam comprising contacting said composition with at least one phase comprising one or more sources for calcium and/or phosphate. The use of the composition comprising water, a surfactant and a propellant allows for an in-situ foaming of the cement paste, once the composition has been brought in contact with one or more sources for calcium and/or phosphate. Thereby no additional foaming step of either the first or the second phase or the cement paste is required any more.
Suitable surfactant and propellants for the use have been described above.
The solid state structure and the calcium phosphate foam of the present invention may be used in bone surgery, bone regeneration, bone defects filling, stabilization of bone fractures, fixing of prostheses or implants, and tissue engineering scaffolds.
In all described devices the first container may comprise water and optionally a propellant, and the second container may comprise one or more sources for calcium and/or phosphate. Thus, the bone foam may be obtained in situ by activation the bone foam applicator. The water from the first container and the sources for calcium and/or phosphate from the second container each may enter the mixing volume. Within the mixing volume the bone foam will be generated in-situ. The generated bone foam may exit the mixing volume via the application outlet so that the bone foam may be directly applied to the patient's application site, when directing the application outlet directly to the patient's site. The application outlet may be provided with an extension like a tube or a conduit for an easier application (not shown). The tip of the application exit or the extension may be provided with an application head (not shown). The application head may have a plurality of openings and/or nozzles each pointing into different directions. This allows a better distribution of the applied foam. The fmalization of the chemical process of foam generation may also take place at the patient's site, i.e. at least a part of the chemical reaction, the final expansion and/or the hardening of the bone foam.
It has to be noted that embodiments of the invention are described with reference to different subject matters. In particular, some embodiments are described with reference to method type claims whereas other embodiments are described with reference to the device type claims. However, a person skilled in the art will gather from the above and the following description that, unless otherwise notified, in addition to any combination of features belonging to one type of subject matter also any combination between features relating to different subject matters is considered to be disclosed with this application. However, all features can be combined providing synergetic effects that are more than the simple summation of the features. It has to be noted that exemplary embodiments of the invention are described with reference to different subject matters. In particular, some exemplary embodiments are described with reference to apparatus type claims whereas other exemplary embodiments are described with reference to method type claims. However, a person skilled in the art will gather from the above and the following description that, unless other notified, in addition to any combination of features belonging to one type of subject matter also any combination between features relating to different subject matters, in particular between features of the apparatus type claims and features of the method type claims is considered to be disclosed with this application. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are re-cited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.
This application is a divisional of U.S. application Ser. No. 13/884,423, filed on Jul. 16, 2013, which is a national phase entry under 35 U.S.C. § 371 of International Application No. PCT/EP2010/067196 filed Nov. 10, 2010, published in English, the disclosures of which are incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2018410 | McDonald | Oct 1935 | A |
| 3318774 | Dingwall et al. | May 1967 | A |
| 3767085 | Cannon | Oct 1973 | A |
| 3968567 | Nevins | Jul 1976 | A |
| 4139599 | Tomlinson et al. | Feb 1979 | A |
| 4244931 | Jarvis et al. | Jan 1981 | A |
| 4312843 | Monty et al. | Jan 1982 | A |
| 4472365 | Michel | Sep 1984 | A |
| 4612053 | Brown et al. | Sep 1986 | A |
| 4690306 | Staheli | Sep 1987 | A |
| 4772468 | Pfirrmann | Sep 1988 | A |
| 4828823 | Li | May 1989 | A |
| 4843112 | Gerhart et al. | Jun 1989 | A |
| 4861733 | White | Aug 1989 | A |
| 4869906 | Dingeldein et al. | Sep 1989 | A |
| 4880610 | Constantz | Nov 1989 | A |
| RE33161 | Brown et al. | Feb 1990 | E |
| RE33221 | Brown et al. | May 1990 | E |
| 4973168 | Chan | Nov 1990 | A |
| 5024825 | Buhl et al. | Jun 1991 | A |
| 5047034 | Sohngen | Sep 1991 | A |
| 5053212 | Constantz et al. | Oct 1991 | A |
| 5129905 | Constantz | Jul 1992 | A |
| 5137534 | Sumita | Aug 1992 | A |
| 5149368 | Liu et al. | Sep 1992 | A |
| 5162430 | Rhee et al. | Nov 1992 | A |
| 5178845 | Constantz et al. | Jan 1993 | A |
| 5262166 | Liu et al. | Nov 1993 | A |
| 5336264 | Constanz et al. | Aug 1994 | A |
| 5342441 | Mandai et al. | Aug 1994 | A |
| 5398483 | Smith et al. | Mar 1995 | A |
| 5427756 | Dany et al. | Jun 1995 | A |
| 5434440 | Yoshitomi et al. | Jul 1995 | A |
| 5522893 | Chow et al. | Jun 1996 | A |
| 5525148 | Chow et al. | Jun 1996 | A |
| 5542973 | Chow et al. | Aug 1996 | A |
| 5545254 | Chow et al. | Aug 1996 | A |
| 5569442 | Fulmer et al. | Oct 1996 | A |
| 5605713 | Boltong | Feb 1997 | A |
| 5683496 | Ison et al. | Nov 1997 | A |
| 5697981 | Ison et al. | Dec 1997 | A |
| 5709742 | Fulmer et al. | Jan 1998 | A |
| 5782971 | Constantz et al. | Jul 1998 | A |
| 5797873 | Franz et al. | Aug 1998 | A |
| 5820632 | Constantz et al. | Oct 1998 | A |
| 5846312 | Ison et al. | Dec 1998 | A |
| 5900254 | Constantz | May 1999 | A |
| 5952010 | Constantz | Sep 1999 | A |
| 5954867 | Chow et al. | Sep 1999 | A |
| 5962028 | Constantz | Oct 1999 | A |
| 5968253 | Poser et al. | Oct 1999 | A |
| 5968999 | Ramp et al. | Oct 1999 | A |
| 6002065 | Constantz et al. | Dec 1999 | A |
| 6005162 | Constantz | Dec 1999 | A |
| 6030635 | Gertzman et al. | Feb 2000 | A |
| 6117456 | Lee et al. | Sep 2000 | A |
| 6117979 | Hendriks et al. | Sep 2000 | A |
| 6201039 | Brown et al. | Mar 2001 | B1 |
| 6206957 | Driessens et al. | Mar 2001 | B1 |
| 6235665 | Pickrell et al. | May 2001 | B1 |
| 6277151 | Lee et al. | Aug 2001 | B1 |
| 6318841 | Coleman et al. | Nov 2001 | B1 |
| 6340648 | Imura et al. | Jan 2002 | B1 |
| 6375935 | Constantz | Apr 2002 | B1 |
| 6379453 | Lin et al. | Apr 2002 | B1 |
| 6383519 | Sapieszko et al. | May 2002 | B1 |
| 6409972 | Chan | Jun 2002 | B1 |
| 6485754 | Wenz et al. | Nov 2002 | B1 |
| 6491900 | Chow et al. | Dec 2002 | B2 |
| 6511510 | de Bruijn et al. | Jan 2003 | B1 |
| 6521246 | Sapieszko et al. | Feb 2003 | B2 |
| 6547866 | Edwards et al. | Apr 2003 | B1 |
| 6558709 | Higham | May 2003 | B2 |
| 6585992 | Pugh et al. | Jul 2003 | B2 |
| 6616742 | Lin et al. | Sep 2003 | B2 |
| 6642285 | Bohner | Nov 2003 | B1 |
| 6648960 | Lin et al. | Nov 2003 | B1 |
| 6670293 | Edwards et al. | Dec 2003 | B2 |
| 6706690 | Reich et al. | Mar 2004 | B2 |
| 6713420 | Imura et al. | Mar 2004 | B2 |
| 6719993 | Constantz | Apr 2004 | B2 |
| 6733582 | Bohner et al. | May 2004 | B1 |
| 6793725 | Chow et al. | Sep 2004 | B2 |
| 6800360 | Miyanaga et al. | Oct 2004 | B2 |
| 6821916 | Myoi et al. | Nov 2004 | B2 |
| 6887488 | Cui et al. | May 2005 | B2 |
| 6929692 | Tas | Aug 2005 | B2 |
| 6979700 | Ma | Dec 2005 | B2 |
| 6994726 | Lin et al. | Feb 2006 | B2 |
| 7070722 | Gilchrist et al. | Jul 2006 | B1 |
| 7118705 | Lin et al. | Oct 2006 | B2 |
| 7151120 | Ma | Dec 2006 | B2 |
| 7163651 | Chern Lin et al. | Jan 2007 | B2 |
| 7189263 | Erbe et al. | Mar 2007 | B2 |
| 7258734 | Lin et al. | Aug 2007 | B2 |
| 7291345 | Winterbottom et al. | Nov 2007 | B2 |
| 7294187 | Chow et al. | Nov 2007 | B2 |
| 7318841 | Tofighi et al. | Jan 2008 | B2 |
| 7326426 | Nathan et al. | Feb 2008 | B2 |
| 7351280 | Khairoun et al. | Apr 2008 | B2 |
| 7407542 | Lemaitre et al. | Aug 2008 | B2 |
| 7416602 | Murphy et al. | Aug 2008 | B2 |
| 7459018 | Insley et al. | Dec 2008 | B2 |
| 7473312 | Barralet et al. | Jan 2009 | B2 |
| 7494950 | Armitage et al. | Feb 2009 | B2 |
| 7531004 | Bagga et al. | May 2009 | B2 |
| 7534451 | Erbe et al. | May 2009 | B2 |
| 7709029 | Chow et al. | May 2010 | B2 |
| 7858079 | Hadba et al. | Dec 2010 | B2 |
| 7892346 | Insley et al. | Feb 2011 | B2 |
| 7892347 | Insley et al. | Feb 2011 | B2 |
| 20020018797 | Cui et al. | Feb 2002 | A1 |
| 20020055143 | Bell et al. | May 2002 | A1 |
| 20020120351 | Tuomela et al. | Aug 2002 | A1 |
| 20020155167 | Lee et al. | Oct 2002 | A1 |
| 20030021824 | Lacout et al. | Jan 2003 | A1 |
| 20030049329 | Lee et al. | Mar 2003 | A1 |
| 20030078317 | Lin et al. | Apr 2003 | A1 |
| 20030152606 | Gerber | Aug 2003 | A1 |
| 20040048947 | Lidgren et al. | Mar 2004 | A1 |
| 20040064194 | Irie et al. | Apr 2004 | A1 |
| 20040137032 | Wang | Jul 2004 | A1 |
| 20040141903 | Zitelli et al. | Jul 2004 | A1 |
| 20040151751 | Cooper | Aug 2004 | A1 |
| 20040211794 | O'Jack | Oct 2004 | A1 |
| 20040244651 | Lemaitre et al. | Dec 2004 | A1 |
| 20040258729 | Czernuszka et al. | Dec 2004 | A1 |
| 20040266943 | Oriakhi | Dec 2004 | A1 |
| 20050008672 | Winterbottom et al. | Jan 2005 | A1 |
| 20050029701 | Lin et al. | Feb 2005 | A1 |
| 20050074415 | Chow et al. | Apr 2005 | A1 |
| 20050087903 | Farr et al. | Apr 2005 | A1 |
| 20050119746 | Lidgren | Jun 2005 | A1 |
| 20050184417 | Chern Lin et al. | Aug 2005 | A1 |
| 20050199156 | Khairoun et al. | Sep 2005 | A1 |
| 20050230870 | Oriakhi | Oct 2005 | A1 |
| 20050267592 | Lin et al. | Dec 2005 | A1 |
| 20050271740 | Lin et al. | Dec 2005 | A1 |
| 20050271741 | Lin et al. | Dec 2005 | A1 |
| 20050271742 | Chern Lin et al. | Dec 2005 | A1 |
| 20060205652 | Zamora et al. | Sep 2006 | A1 |
| 20060225620 | Murphy et al. | Oct 2006 | A1 |
| 20060263443 | Chow et al. | Nov 2006 | A1 |
| 20070041906 | Lidgren et al. | Feb 2007 | A1 |
| 20070092580 | Chow et al. | Apr 2007 | A1 |
| 20070092856 | Chow et al. | Apr 2007 | A1 |
| 20070128245 | Rosenberg et al. | Jun 2007 | A1 |
| 20070186818 | Bohner | Aug 2007 | A1 |
| 20070189951 | Constantz et al. | Aug 2007 | A1 |
| 20070202075 | Hadba et al. | Aug 2007 | A1 |
| 20070218144 | Lally | Sep 2007 | A1 |
| 20070260325 | Wenz | Nov 2007 | A1 |
| 20070282455 | Luginbuehl et al. | Dec 2007 | A1 |
| 20070283849 | Edidin et al. | Dec 2007 | A1 |
| 20080014242 | Overby et al. | Jan 2008 | A1 |
| 20080153784 | Zhang et al. | Jun 2008 | A1 |
| 20080194810 | Kim et al. | Aug 2008 | A1 |
| 20080206716 | Asgary | Aug 2008 | A1 |
| 20080208354 | Bohner et al. | Aug 2008 | A1 |
| 20080305517 | Griffin et al. | Dec 2008 | A1 |
| 20090048145 | Hellerbrand et al. | Feb 2009 | A1 |
| 20090054545 | Muratoglu et al. | Feb 2009 | A1 |
| 20090158964 | Insley et al. | Jun 2009 | A1 |
| 20090280179 | Neumann et al. | Nov 2009 | A1 |
| 20110062046 | Hadba et al. | Mar 2011 | A1 |
| Number | Date | Country |
|---|---|---|
| 2006201475 | Oct 2006 | AU |
| 2540927 | Oct 2006 | CA |
| 2669777 | Oct 2006 | CA |
| 1844010 | Oct 2006 | CN |
| 101264338 | Sep 2008 | CN |
| 0 627 899 | Dec 1994 | EP |
| 0 936 929 | Aug 1999 | EP |
| 1 237 585 | Sep 2002 | EP |
| 0 912 161 | Feb 2003 | EP |
| 1 443 981 | Aug 2004 | EP |
| 1712245 | Oct 2006 | EP |
| 1787626 | May 2007 | EP |
| 1787626 | May 2007 | EP |
| 1938844 | Jul 2008 | EP |
| 2260877 | Dec 2010 | EP |
| 2003516190 | May 2003 | JP |
| 2006130122 | May 2006 | JP |
| 2006-289902 | Oct 2006 | JP |
| 2006289092 | Oct 2006 | JP |
| 05-023387 | Sep 2012 | JP |
| 9316657 | Sep 1993 | WO |
| 9416951 | Aug 1994 | WO |
| 98016268 | Apr 1998 | WO |
| 00007639 | Feb 2000 | WO |
| 01041824 | Jun 2001 | WO |
| 0141824 | Jun 2001 | WO |
| 04000374 | Dec 2003 | WO |
| 04103419 | Dec 2004 | WO |
| 05009481 | Feb 2005 | WO |
| 2005084726 | Sep 2005 | WO |
| 2005117919 | Dec 2005 | WO |
| 2007090880 | Aug 2007 | WO |
| 2008014561 | Feb 2008 | WO |
| 2010116321 | Oct 2010 | WO |
| Entry |
|---|
| Abstract of: Desai et al. Drug Deliv. 2006, 13(1), 39-50) 1 page. |
| Barralet, Grover, Gbureck, ‘Ionic Modification of Calcium Phosphate Cement Viscosity. Part II: Hypodermic Injection and Strength Improvement of Brushite Cement.’, Biometerials, vol. 25, No. 11, pp. 2197-2203, May 2004. |
| Biotek, Inc.,“Hydroformed Microspheres as New Injectable Drug Vehicle”, 1994. |
| Boyce et al., J. Biomedic. Mater. Res., vol. 26,547-553 (1992). |
| Burguera EF, Xu HH, Weir MD, Injectable and rapid-setting calcium phosphate bone cement with dicalcium phosphate dihydrate, J Biomed Mater res B Appl Biomater, Sep. 23, 2005. |
| Burguera, Guitian, Chow, “A water setting tetracalcium phosphate-dicalcium phosphate dihydrate cement”, Wiley Periodicals, vol. 71A, No. 2, Oct. 2004. |
| Chow et al., AADR Abstract, No. 666, 1992. |
| Chow et al., IADR Abstract No. 2410, Apr. 1991. |
| Freche, M. & Heughebaert, J.C.; Calcium Phosphate Precipitation in the 60-80oC Range, Journal of Crsytal Growth, vol. 94 (1989), pp. 947-954. |
| Gbureck, Barralet, Spatz, Grover, Thull ‘Ionic Modification of Calcium Phosphate Cement Viscosity. Part I:Hypodermic Injection and Strength Improvement of Apatite Cement.’, Biometerials, vol. 25, No. 11, pp. 2187-2195, May 2004. |
| Gbureck, Dembski, Thull, Barralet, “Factors influencing calcium phosphate cement shelf-life”, Biomaterials, May 26, 2004. |
| Ginebra et al., Biomaterials 25:3453-3462 (2004). |
| Gisep, Kugler, Wahl, Rahn, ‘Mechanical Characterization of a Bone Defect Model Filled with Ceramic Cements’, J Mater Sci Mater Med, vol. 15, No. 10, pp. 1065-1071, Oct. 2004. |
| Grureck, U., et al., Inonic modification of calcium phosphate cement viscosity. Part I: hypodermic injection and strength improvement of appatite cement, Biomaterials, 2004, vol. 25, p. 2187-2195. |
| International Search Report and Written Opinion for PCT/EP2010/067196 dated Oct. 14, 2011. |
| International Search Report, PCT/US2010/060793, dated Apr. 18, 2011. |
| Japanese Office Action for Application No. 2012-276983 dated Feb. 28, 2014. |
| Japanese Office Action for Application No. 2012-508835 dated Apr. 20, 2012. |
| Jensen, Ooms, Verdonschot, Wolke, ‘Injectable Calcium Phosphate Cement For Bone Repair and Implant Fixation’, Orthop Clin North Am, vol. 36, No. 1, pp. 89-95, Jan. 2005. |
| Komath, Varma , “Development of a fully injectable calcium phosphate cement for Orthopedic and Dental Applications”, Bull Matter. Sci, Jun. 2003, pp. 415-422. |
| Komath, Varma and Sivakumar, “On the development of an apatitic calcium phosphate bone cement”, Bull. Matter. Sci, vol. 23, No. 2, Apr. 2000, pp. 135-140. |
| Lee at al., “A Critical Role for the Membrane-type-1 Matrix Metalloproteinase in Collagen Phagocytosis.” 2006, Mol Bioi Cell17: 4812-4826. |
| MacPhee et al., Curr. Opin. Solid State Mater Sci., vol. 8, 141-149 (2004). |
| Moreau et al., J. Biomed. Mater. Res. A., 91(2): 605-613 (2009). |
| Murphy, Clarkin & Insley,‘Calcium Phosphate Bone Cements of the Future: Towards the Understanding of their Chemistry’, Biomaterials Research Group, Sep. 2005. |
| nerac.com, “Injectable Calcium Phosphate Cement” Retro Search, p. 1-151, Printed Oct. 14, 2005. |
| Rocha et al., Biomaterials, vol. 23, 449-456 (2002). |
| Salem et al., Adv. Mater., vol. 15., No. 3, 210-213 (2003). |
| Segman-Magidovich et al., Adv. Mater., vol. 20, 2156-2161 (2008). |
| Tofighi A, Mounic S, Chakaravarthy P, Rey C, Lee D, “Setting Reactions Involved in Injectable Cements Based on Amorphous Calcium Phosphate”, Key Engineering Materials, vol. 192-195, pp. 769-772, 2001. |
| Wach et al. (nuclear instruments and Methods in Physics Research B 2003 211, 533-544. |
| Zhang et al., Semin. Cancer Bioi., vol. 15,413-420 (2005). |
| Number | Date | Country | |
|---|---|---|---|
| 20190105238 A1 | Apr 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13884423 | US | |
| Child | 16210189 | US |
