Abstract:
Bone cement mixing and delivery device and methods are disclosed. The device includes a first tube/barrel (e.g., a syringe barrel) containing a bone cement powder and a second tube/barrel that can be filled with or that contains a liquid; the first and second tubes/barrels can be fluidly connected end-to-end such that there is fluid communication between the tubes/barrels. Also disclosed are methods of preparing the device for use, methods for forming a bone cement using the device, and methods and device design to extend the shelf life of the device.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority under 35 U.S.C. §371 from international application PCT/US2008/010214, filed Aug. 28, 2008, which claims priority under 35 U.S.C. §119 from provisional application No. 60/966,579, filed Aug. 29, 2007. Both of these applications are incorporated by reference herein in their entirety. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to bone cement mixing devices, related systems, and methods of use thereof. 
     BACKGROUND OF THE INVENTION 
     Bone cements are used in orthopedic procedures for filling bone voids and repairing defects. They typically comprise a cement powder that is mixed with a liquid and manually applied to the defect site. The mixed cement may also be transferred into a delivery device and injected into the site. Current mixing and delivery systems rely on manual open mixing, such as a bowl and spatula, which can be messy and difficult to achieve uniformity. The open mixing and transfer steps also present contamination risk. Furthermore, the transfer step is messy and time consuming. Thus, there is a need for a better bone cement mixing and delivery system. 
     SUMMARY OF THE INVENTION 
     The present invention features an enclosed bone cement mixing and delivery system. The present mixing and delivery system is based on syringe-to-syringe mixing, which eliminates the open mixing and transfer steps and reduces contamination risk and preparation time. The system also improves cement injectability and includes a packaging design that promotes powder filling and extends shelf life. 
     Accordingly, the invention features a mixing and delivery system that includes first and second rigid tubes containing movable pistons, in which the tubes are joined end-to-end such that there is communication between the tubes that allows fluid to move between the tubes, and wherein at least one of the tubes includes a bone cement powder. The application of force to alternate pistons produces high shear during the mixing step. In one embodiment, the tubes and pistons are provided as disposable syringes. In yet another embodiment, the syringes have Luer tips. The pistons are capable of moving independent of one another. 
     Bone cement powder is filled into one of the two tubes. In one embodiment, the powder is a calcium phosphate composition. In preferred embodiments, the calcium phosphate composition includes amorphous calcium phosphate, poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, or tricalcium phosphate, or mixtures thereof. Alternatively, the calcium phosphate composition includes an amorphous calcium phosphate and a second calcium phosphate source, e.g., poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, or tricalcium phosphate, or mixtures thereof. In other embodiments, the calcium phosphate composition is a powder described in or prepared according to the methods disclosed in, e.g., U.S. Pat. No. 5,650,176, U.S. Pat. No. 5,783,217, U.S. Pat. No. 6,214,368, U.S. Pat. No. 6,027,742, U.S. Pat. No. 6,214,368, U.S. Pat. No. 6,287,341, U.S. Pat. No. 6,331,312, U.S. Pat. No. 6,541,037, U.S. Patent Application Publication No. 2003/0120351, U.S. Patent Application Publication No. 20040097612, U.S. Patent Application Publication No. 2005/0084542, U.S. Patent Application Publication No. 2007/0128245, and WO 2005/117919, all of which are incorporated herein by reference. 
     In other embodiments, the calcium phosphate composition has an average crystalline domain size of less than 100 nm (e.g., in the range of between about 1 nm to about 99 nm; preferably 50 nm or less; more preferably 10 nm or less). In another embodiment, the calcium phosphate composition has a tap density of between about 0.5 g/cm 3  to about 1.5 g/cm 3 , preferably the calcium phosphate composition has a tap density of greater than about 0.7 g/cm 3  (e.g., about 1.0 g/cm 3 ). 
     In another embodiment, the calcium phosphate composition includes a supplemental material, e.g., a biocompatible cohesiveness agent or a biologically active agent (see, e.g., the biocompatible cohesiveness agents and biologically active agents as described and defined in U.S. Patent Application Publication No. 2007/0128245; incorporated hereby by reference). In yet another preferred embodiment, the biocompatible cohesiveness agent is present in the calcium phosphate composition in an amount in the range of about 0.5 wt % to about 20 wt % (e.g., less than about 20 wt %, preferably less than about 10 wt %, more preferably less than about 5 wt %, and most preferably less than about 1 wt %). 
     In another embodiment, the powder is compressed to a desired density to enhance the wetting characteristics, optimize mixing forces, and minimize the amount of air in the mixed product. In a preferred embodiment, the powder has a density in the range of about 0.1 to about 1.2 g/cc, preferably, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, or 1.2 g/cc, and most preferably 1.0 g/cc. In another embodiment; the tube with powder has an affixed porous cap to aid powder filling and compaction by venting air; the porous cap allows air to escape from the tube, but prevents escape of the powder. In preferred embodiments, the porous cap has pores that are less than or equal to 1.0 mm in diameter, preferably less than or equal to 750, 500, 300, 250, 150, and 100 μm in diameter, and more preferably less than 75, 50, 25, 15, 10, and 5 μm in diameter, and most preferably less than or equal to 1, 0.5, 0.4, 0.3, 0.2, 0.1, and 0.05 μm in diameter. The cap also allows released moisture to exit the device, which extends shelf life and long term stability of the powder during storage by preventing degradation of the powder components. In another embodiment, the cap is composed of a porous polymer, ceramic, or metal material. 
     The second tube is filled with a liquid. In an embodiment, the liquid is a physiologically-acceptable fluid including but are not limited to water, saline, and phosphate buffers. In other embodiments, the fluid can be a biological fluid, e.g., any treated or untreated fluid (including a suspension) associated with living organisms, particularly blood, including whole blood, warm or cold blood, and stored or fresh blood; treated blood, such as blood diluted with at least one physiological solution, including but not limited to saline, nutrient, and/or anticoagulant solutions; blood components, such as platelet concentrate (PC), apheresed platelets, platelet-rich plasma (PRP), platelet-poor plasma (PPP), platelet-free plasma, plasma, serum, fresh frozen plasma (FFP), components obtained from plasma, packed red cells (PRC), buffy coat (BC); blood products derived from blood or a blood component or derived from bone marrow; red cells separated from plasma and resuspended in physiological fluid; and platelets separated from plasma and resuspended in physiological fluid. In a preferred embodiment, the calcium phosphate composition, once hydrated, forms a paste. Varying amounts of a liquid may be added to the powder to produce a paste having one or more desired characteristics. For example, in at least some embodiments, 0.3-2.0 cc of liquid per gram of powder is used to prepare a paste that is formable, i.e., capable of being molded and retaining its shape. In at least some embodiments, the paste is injectable, i.e., capable of passing through a 16- to 18-gauge needle. The paste can also be prepared for delivery through a catheter (e.g., a catheter having a 7-15 gauge needle, and more preferably a 7, 8, 9, 10, 11, 12, 13, 14, or 15 gauge needle). 
     The powder-containing tube and the liquid-containing tube can be joined end-to-end such that there is communication between the tubes that allows fluid to move between the tubes. In an embodiment, the tubes are joined using a Luer connector, which provides a tight seal to prevent leakage and contamination. 
     Mixing of the powder and liquid is initiated by pressing a piston in the liquid-containing tube, which forces the liquid through the connection into the powder present in the powder-containing tube. The liquid is allowed to soak into the powder. Preferably, the liquid is allowed to soak into the powder for 1, 2, 3, 4, 5, 10 seconds, preferably 30 seconds or 1, 2, 3, 4, or 5 minutes, or more preferably 10, 15, 20, or 30 minutes. Following the soak period, gas may be entrapped within the material. In preferred embodiments, the gas is selected from carbon dioxide, air, nitrogen, helium, oxygen, and argon. The gas can be removed by disconnecting the two tubes and repositioning the pistons until all gas is expelled, keeping the solid and liquid content within the tubes. This venting step improves the mixing and mechanical properties of the material. The two tubes are reconnected after venting the gas. 
     Mixing is resumed by alternately applying pressure to the pistons present in the tubes to transfer the hydrated and unhydrated material through the connector from one tube to the other. In a preferred embodiment, mixing continues until the material is substantially completely hydrated. If all material does not transfer, the material is alternately pressed back and forth between tubes until it all flows and is uniformly hydrated and mixed. In a preferred embodiment, the orifice formed from the joining of the two tubes is sized such that it breaks agglomerates and renders the cement more injectable. In several embodiments, the orifice is 5.0, 4.0, 3.0, 2.0, or 1.0 mm in diameter, preferably the orifice is 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm in diameter. 
     When mixing is completed (e.g., after approximately 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 or more depressions), the hydrated material, which is preferably in a paste form, is dispensed substantially completely into one of the two tubes for delivery. At this time, the second tube is disconnected from the first tube. In a preferred embodiment, one of the two tubes used for mixing is a delivery syringe, which is used to deliver the hydrated powder material once it is substantially mixed (e.g., to a site in a human patient requiring bone cement). A delivery tip, such as a needle, can be attached to the end of the delivery syringe to deliver the material (e.g., using a Luer connector). In a preferred embodiment, the substantially completely mixed and hydrated material is sterile. 
     In an embodiment, the calcium phosphate material, after hydration and hardening, has a porosity of about 5%, more preferably the material is about 10, 20, or 30% porous, and most preferably the material is about 40, 50, or 60% porous. In a preferred embodiment, the calcium phosphate material is at least about 20% porous. In other embodiments, the hydrated material has a Ca/P ratio of less than 1.67. In particularly preferred embodiments, the hydrated material is a paste that hardens to form a calcium phosphate having an overall Ca/P molar ratio in the range of 1.0-1.67, preferably 1.3-1.65, more preferably 1.4-1.6, and most preferably close to that of naturally-occurring bone, that is in the range of 1.45 to 1.67. In a preferred embodiment, the hardened calcium phosphate composition has a Ca/P molar ratio of equal to or less than about 1.5. 
     In yet other embodiments, the hardened calcium phosphate composition exhibits a compressive strength of equal to or greater than about 1 or 2 MPa. In other embodiments, the compressive strength is in the range of about 1 MPa to about 150 MPa (e.g., 20, 30, 40, 50, 60, 70, 80, 90, or 100 MPa). In yet other embodiments, the compressive strength is 120 MPa or greater (e.g., 120 to 150 MPa). In another embodiment, the compressive strength is in the range of about 20-30 MPa. 
     A second aspect of the invention features a method of bone repair that includes administering the hydrated material prepared using the mixing system of the first aspect of the invention. In an embodiment, the hydrated material is a formable, self-hardening, paste, which is moldable and cohesive when applied to an implant site in vivo, and hardens to form a calcium phosphate composition. In at least some embodiments, the paste hardens to form a calcium phosphate composition (e.g., a poorly crystalline apatitic (PCA) calcium phosphate) having significant compressive strength. The hydrated material may be implanted in vivo in paste form or as a hardened calcium phosphate. The composition can be used to repair bone, e.g., damaged bone, or as a delivery vehicle for biologically active agents. All of the embodiments of the first aspect of the invention apply to the composition utilized in the method of the second aspect of the invention. 
     As used herein, the term “about” means±10% of the recited value. 
     As used herein, the term “substantial” or “substantially” means sufficiently to accomplish one or more of the goals, applications, functions and purposes described herein. For example, “substantially mixed” means that one or more powder components used in conjunction with the mixing devices of the invention are mixed with one or more other components (one or more of which may be an aqueous fluid) to near homogeneity such that the mixture is relatively or nearly uniform in composition. In an embodiment, the mixture forms a slurry, paste, or cement, and is injectable. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention is described with reference to the following figures, which are presented for the purpose of illustration only and which are not intended to be limiting of the invention. 
         FIG. 1  is a plan view of the packaged device with powder and porous cap. 
         FIG. 2  is a disassembled view of the mixing and delivery system. 
         FIG. 3  is a cross section of the mixing device assembly. 
         FIG. 4  is a graph showing the average number of passes/strokes used to hydrate 6.0 grams of a calcium phosphate compressed to the indicated density with 3.0 cc of saline using the mixing device of the invention. 
     
    
    
     DETAILED DESCRIPTION 
     Structure 
     Referring to  FIG. 1 , powder  101  is filled into barrel  100  and compressed to occupy a desired density (e.g., between 0.1 g/cc and 1.1 g/cc) within barrel  100  and stopper  103 . Luer connector  105  is attached to tip  104 , and porous cap  112  is attached to Luer connector  105 . This device may be packaged within a moisture barrier configuration along with desiccant as preservative (not shown). A desiccant is defined as any material with an affinity for moisture higher than that of the protected product; examples include but are not limited to clay, silica gel, or molecular sieve. 
     Referring to  FIGS. 2 and 3 , barrel  100  contains powder  101  and a movable plunger  102 . While disassembled, a second barrel  106  can be filled with liquid  110  by retracting movable plunger  107 . Rubber stoppers  103  and  108  prevent leakage of contents from the barrels. Barrels  100  and  106  have Luer fittings  104  which are connected using Luer connector  105 , which provides a leak-tight seal. In a preferred embodiment, barrels  100  and  106  are of different capacities and can accommodate various powder and liquid volumes. For example, one or both of the barrels of the mixing device into which the bone cement powder and liquid are added can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cc, preferably 15, 20, 25, 30, 35, 40, 45, or 50 cc, more preferably 60, 70, 80, 90, or 100 cc, and most preferably 150, 200, 250, 300, 350, 400, 450, or 500 or more cc in volume. The device can be manufactured so that the barrels of the device hold the same volume or different volumes, and the barrels can be filled with the same or different volumes of components (e.g., bone cement powder or liquid). In preferred embodiments, the liquid (cc):powder (g) ratio is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, and 1.5:1, preferably 2, 3, 4, 5, 6, 7, 8, 9, or 10:1, more preferably 15, 20, 25, 30, 35, 40, 45, or 50:1 or more. 
     Operation 
     Referring to  FIG. 1 , the mixing device includes barrel  100 , which is filled with calcium phosphate powder  101 , and piston/plunger  102 , which is inserted into barrel  100 . Depressing piston/plunger  102  compresses the calcium phosphate powder to a desired density to reduce air content, facilitate wetting, and allow easy mixing. Barrel  100  also includes porous cap  112 , which is attached at the distal end of barrel  100  to permit easy filling and compression. Porous cap  112  allows gas present in barrel  100  to vent when depressing piston/plunger  102  while retaining calcium phosphate powder  101  in barrel  100 . Compression of the calcium phosphate powder in the device to 0.8 g/cc or less produces a poorly and ineffectively mixed paste following hydration. The same powder, when compressed to a density of 1.0 g/cc and hydrated, is effectively and uniformly wetted and mixed. 
     With reference to  FIGS. 2 and 3 , the mixing device also includes barrel  106 , which is adapted to accept a needle, e.g., a 16 gauge needle, which is attached at the distal end of barrel  106 . Liquid  110 , e.g., USP saline, is drawn into barrel  106  through the needle by suction pressure by retracting piston/plunger  107 . The needle is removed from the distal end of barrel  106  and barrel  106  is coupled to barrel  100  using Luer fittings  104  to form Luer connector  105 . The saline is injected into calcium phosphate powder  101  by depressing piston/plunger  107 , which injects the saline into barrel  100 . After a brief delay to allow the liquid to wet the powder, air is vented by disconnecting barrel  100  from barrel  106  and slowly depressing the plungers. Barrel  100  and barrel  106  can be composed of clear polycarbonate to allow easy visualization during the venting step. Barrel  100  is reconnected to barrel  107  and mixing is performed by alternately and rapidly depressing pistons/plungers  102  and  107  several times until a uniform mixture (e.g., a paste) is formed (approximately 3-20 times). In the event not all material passes between barrel  100  and barrel  106 , a series of alternating passes of plungers  107  and  102  can be performed until all material transfers and a uniform mixture is achieved. The narrow orifice that connects barrel  100  to barrel  106  increases shear, reduces agglomerates, and improves homogeneity and injectability of the mixture. After about 1 minute of mixing, the fully mixed paste is transferred into barrel  106 , which is disconnected from barrel  100 . A delivery needle or cannula (not shown) is attached to barrel  106  at Luer tip  104  and the cement can be fully extruded through the needle. 
     In at least some embodiments, the mixed material is injectable, i.e., capable of passing through a 7- to 18-gauge needle. The paste can also be prepared for delivery through a catheter (e.g., a catheter having a 7-15 gauge needle, and more preferably through a 7, 8, 9, 10, 11, 12, 13, 14, or 15 gauge needle). 
     Manufacture 
     Barrel  100  and piston/plunger  102  combine to form the powder syringe, while barrel  106  and piston/plunger  107  combine to form the delivery syringe, both of which can be obtained from various industry suppliers. Barrel  100  and barrel  106  can be independently manufactured from glass or plastic (e.g., polypropylene, polyethylene, polycarbonate, polystyrene, and the like). Pistons/Plungers  102  and  107  include a plastic or glass arm attached to stopper  102  and  108 , respectively. Barrel  100  is filled with calcium phosphate powder  110  (e.g., any of the calcium phosphate powders described herein). Porous cap  112 , which includes a porous polymer insert and a Luer connector, can be obtained from B. Braun (e.g., SAFSITE® Capped Valve System; ULTRASITE® Capless Valve System). 
     The mixing device can also include a standard hypodermic needle, which can be obtained from various industry suppliers. 
     In an embodiment, the powder syringe is placed into a moisture barrier tray along with a silica gel desiccant canister (e.g., a thermoformed tray inside a foil pouch may be used or a moisture barrier tray formed from a poly(ester) copolymer of terephthalic acid, ethylene glycol and cyclohexane dimethanol known as “PETG” can be used; see, e.g., U.S. Pat. No. 4,284,671; incorporated herein by reference). This moisture barrier configuration preserves the product (i.e., the calcium phosphate powder) by allowing moisture transmission through the porous cap so that it can be absorbed into the desiccant; the device design is particularly effective at elevated temperatures which would normally lead to cement degradation. The cement composition within the mixing device was degraded within 2 weeks at 50° C. without desiccant, but was intact after 4 months with desiccant. 
     The invention is illustrated by the following examples, which are not intended to be limiting of the invention. 
     EXAMPLES 
     Example 1 
     In order to determine the optimum compaction for a calcium phosphate powder, fifteen 20 mL mixing devices (syringes) with porous caps were each filled with 6.0 grams of calcium phosphate. The plungers were inserted into the barrel and compressed using a uniaxial testing machine until a given powder density was achieved. Three syringes were compressed to each of the following densities; 0.75, 0.86, 1.0, 1.1, 1.2 g/cc. Syringes were then tested by hydrating with 3.0 cc of saline using a 10 mL syringe and mixed by passing the powder and saline back and forth between the syringes until a smooth paste was achieved. The number of passes, or strokes, required to achieve complete mixing was recorded and averaged for each density. The results are shown in  FIG. 4 . A powder density of 1.0 g/cc was found to be optimal for this calcium phosphate. 
     Example 2 
     To demonstrate the ability of the present device and its method of use to simplify preparation and to enhance injectability of a conventional calcium phosphate cement (CPC) the following study was performed. 
     Two CPC precursors; an amorphous calcium phosphate (ACP) (with Ca/P&lt;1.5) and dicalcium phosphate dihydrate (DCPD) seeded with apatite (10-25% w/w) were prepared using a low temperature double decomposition technique. The two powders were mixed at a 1:1 ratio and milled in a high-energy ball mill for 3 hours. The resulting powder was filled into a syringe and connected to a second syringe filled with saline by means of a luer connector. The saline was injected into the powder at a liquid to powder (L/P) ratio of 0.5:1 and the mixture was then passed back-and-forth between the syringes until a uniform paste was formed (approximately 5 passes). The same cement mixed (with the same L/P) in a bowl with a spatula and then transferred into a syringe was used as a control. The materials were tested for chemical composition (FT-IR, XRD, and Ca:P atomic ratio) and performance characteristics (injection force and yield, working time, hardening rate, compressive strength, and resistance to washout). 
     Syringe mixing reduced preparation time from two minutes to one minute, and the cement was deliverable through a 16 gauge needle with less than 3 kgf force. A 50% reduction in injection force relative to bowl mixed materials was observed. Syringe mixing also increased the percentage of CPC delivered. The delivered amount was less than 90% for bowl mixed cement but was 100% for syringe mixed cement. Syringe mixed cement could be stored for up to 6 minutes at room temperature and remixed while retaining full injectability. The mixing did not affect the hardening rate, compressive strength, or resistance to washout of the CPC, nor did it change the chemical composition. The injectable cement hardened in less than 5 minutes at 37° C., achieved a compressive strength of 30 MPa in 2 hours and could be injected directly into a water bath without loss of material. 
     Other Embodiments 
     All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. 
     While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. 
     Other embodiments are within the claims.