Abstract:
The present invention is directed to a multi-compartment medical device for segregated storage and on demand mixing of at least two components and expression of the resulting mixture from the device. The mixing device comprises a syringe having an open end and outlet and containing a first component; and a cap with a fixed outer body and an expandable chamber contained therein, wherein said cap is removably attached to the outlet of the syringe and a cross-section of the cap is larger than a syringe cross-section and the cap is shorter than the syringe.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to multi-compartment medical devices for segregated storage and on demand mixing of at least two components and for expressing the resulting mixture from the device for use in treating a patient. The invention further relates to methods of segregated storage and on demand mixing of at least two components and for expressing the resulting mixture from the device. The invention further relates to devices for and methods of reconstituting lyophilized materials. 
       BACKGROUND OF THE INVENTION 
       [0002]    Currently there are a number of biomedical applications where there is a need to rapidly and thoroughly mix two or more components in the operating room substantially immediately prior to administration to the patient. The mixing of components can typically involve extraction of one component in fluid form from a vial or other container and transfer of such component into a separate container which holds another component. In particular instances, only a portion of the contents of a vial or container is to be utilized for preparing a mixture prior to administering. Accordingly, the extraction and transfer can involve precise measuring of one or more components to be mixed. 
         [0003]    A variety of problems can occur when utilizing conventional methodology and devices for mixing and/or administering biomedical agents to an individual. For example, where multiple components are to be mixed, extraction and transfer of one component and introduction of such component into another component can potentially expose one or both of the components to a non-sterile or contaminated environment leading to contamination of the resulting mixture. Additionally, incomplete extraction or improper measurement of one or more components can result in preparation and/or administration of an improper dosage. In particular instances, once biomedical agents are mixed the mixture must again be extracted from a vial or container into a syringe prior to administering to an individual. Such additional transfer can lead to additional opportunities for contamination, incomplete extraction of contents and/or inaccurate measuring of a component or the resulting biomedical agent. 
         [0004]    In practice, there is limited availability of sterile environments for maintaining sterility during transfer and/or mixing of components, or preparation and transfer of biomedical agents. Additional errors can result from use of the wrong diluent to reconstitute the medication. Finally, preparation of biomedical agents utilizing multiple components can be tedious and time consuming due to factors such as the need to access individually packaged items such as separate vials and/or transfer devices, or to measure one or more components to be combined to form the biomedical agent. The multiple packaging and storage containers such as separate vials and/or transfer devices increase the cost of care and also create an additional waste stream which has to be dealt with in accordance with regulations governing the disposal of biomedical waste. There is a need in a simplified system for segregated storage and rapid and thorough mixing of two or more components in the operating room substantially immediately prior to administration to the patient, which can also reduce the risk of contamination during preparation. 
         [0005]    Preparation of injectable drugs or hemostatic agents often requires a thorough mixing of two or more components which are stored in separate compartments. Use of multiple vials and syringes is expensive and wasteful, complicates the preparation, increases the probability of error, and requires proper disposal of used containers. For example, in preparation of a hemostatic paste based on biopolymer, such as gelatin, in mixture with thrombin, the surgeon often performs the mixing by using two interconnected connected syringes and moving the paste back and forth to mix gelatin with saline solution containing thrombin. One syringe is then discarded. 
         [0006]    In preparation of reconstituted solution of a protein, such as reconstituted thrombin or fibrinogen from lyophilized thrombin or fibrinogen, the dry lyophilized powders need to be thoroughly mixed when reconstituted with water or saline. 
         [0007]    In some commercially available hemostatic kits, reconstitution of lyophilized thrombin is performed in a vial into which water is injected from a syringe. After swirling the mixture, the solution is aspirated back into syringe. The reconstitution of the thrombin can be slow because there is no forced mixing in the vial. Then the solution is expressed into a sterile cup and the syringe and the vial are discarded. The solution is then aspirated by another syringe and can be connected via a luer to the syringe containing the gelatin matrix. The contents are then mixed by moving between syringes back and forth, after which one syringe is discarded and the ready mixture is expressed from the last syringe. The process of using and discarding a vial, a cup, and two syringes to prepare one syringe with the hemostatic paste in multiple sequential steps requires time and high attentiveness of the healthcare professional. 
         [0008]    There are a number of known multi-chamber, single barrel as well as multi-barrel syringes which attempt to accomplish the segregated storage of two components and subsequent mixing and expression of the resulting mixture from the syringe. 
         [0009]    A number of references disclose two syringes which are interconnected and used for mixing components by moving from the mix from one syringe to another. 
         [0010]    None of the references provide, in a single syringe, for the capability of vigorous back and forth mixing between the compartments and thus for rapid effective reconstitution and/or mixing of separately stored components. The known systems utilizing valves are complex and can plug up with the mixing materials, or can leak during storage. Only uni-directional movement of the plunger (i.e. forward) is possible, resulting in insufficiently efficient mixing of the components. 
         [0011]    U.S. Published Patent Application 2014/0114276 RECONSTITUTION AND APPLICATOR SYSTEM FOR WOUND SEALANT PRODUCT discloses a system for mixing or reconstituting agents including engageable syringe barrels, one of which having a male engagement region and the other a female engagement region. Each of the male and female engagement regions is provided with a screen. The screens are closely spaced from one another when the first and second syringe barrels are engaged with one another. The screens can take the form of a mesh, a plurality of protuberances, or cantilevered wedges having tapering thicknesses. It further discloses a method for reconstituting a powdered agent comprising: providing a first syringe barrel including a main chamber defined by a cylindrical barrel wall, an open proximal end, and a male engagement region at a distal end, the male engagement region including a screen; providing a second syringe barrel including a main chamber defined by a cylindrical barrel wall, an open proximal end, and a female engagement region at a distal end, the female engagement region including a screen; depositing the powdered agent into the main chamber of one of the first syringe barrel or the second syringe barrel; inserting a plunger in the open proximal end of the first syringe barrel; inserting a plunger in the open proximal end of the second syringe barrel; drawing a diluent into the main chamber of one of the first syringe barrel or the second syringe barrel; engaging the male engagement region of the first syringe barrel with the female engagement region of the second syringe barrel; and tilting the engaged first and second syringe barrels back and forth. 
         [0012]    U.S. Pat. No. 5,566,729 entitled Drug reconstitution and administration system, discloses a drug reconstitution and administration system that includes a container for a concentrated drug or other medicament, a syringe assembly which can be pre-filled with a liquid diluent, and a mixing adapter assembly which facilitates mixing of the medicament with the liquid diluent. 
         [0013]    U.S. Patent publication No. 2003/0032935 entitled Packages facilitating convenient mixing and delivery of liquids, discloses embolic devices and methods for mixing and delivering embolic material in a sterile environment that facilitate delivery of the embolic material directly into a patient thereby preventing the embolic material from becoming contaminated. Such devices include a sealable container couplable to a syringe, a dissolvable caplet or gel-cap including a solid or liquid embolic material, a sealed vial with a breakable neck containing an embolic material, and a flexible container including internal compartments separated by breakable membranes. 
         [0014]    European Patent Publication EP1466572B1 entitled Device for packaging, mixing and applying bone cement discloses a device for packaging, mixing and applying bone cement obtainable from at least one first component and one second component, comprising: a first container, in which the first component is packaged hermetically and which is provided with an opening that is associated with first temporary closure means; a second substantially cylindrical container, which is provided with an outlet that is associated with second temporary closure means; and piston means, which are inserted so that they can slide hermetically within the second container and can be actuated from outside with a rectilinear motion; the second component is packaged between the outlet and the piston means; the opening and the outlet are temporarily mutually associable, and the piston means are suitable to push the second component from the second container to the first container for mixing with the first component and to aspirate the cement thus formed from the first container into the second container. 
         [0015]    U.S. Pat. No. 6,723,131 entitled Composite bone marrow graft material with method and kit discloses a kit containing sterilized implements useful in preparing enriched composite bone marrow graft material, kit having two loading syringes attached to a matrix column. 
         [0016]    U.S. Patent Publication No. 2011/0224648 entitled Syringe Filter Cap and Method of Using the Same for Administration of Medication Dosage discloses a syringe and filter cap that ease the administration of medication to patients. The cap fits securely over the syringe nozzle and has at least one orifice. The orifice is configured to retain medication particles within the syringe, while allowing liquid to be drawn into the syringe through the cap. 
         [0017]    U.S. Pat. No. 8,226,627 entitled Reconstitution assembly, locking device and method for a diluent container, discloses a reconstitution assembly that includes: a flexible bag containing a diluent; a drug vial containing a drug; a reconstitution device further comprising: a first sleeve connected to the first container; a second sleeve connected to the second container, the second sleeve being associated with the first sleeve and movable axially with respect thereto from an inactivated position to an activated position; a piercing member positioned in the sleeves, the piercing member providing a fluid pathway between the bag and vial when the sleeves are in the activated position. 
         [0018]    U.S. Pat. No. 6,699,229 entitled Fluid transfer device, discloses a fluid transfer and mixing device for use in the aseptic intermixing of a powder component with a fluid component. The device is of a simple, compact construction that includes a first adapter that can be easily connected to a container containing the powder component and a second adapter that can be removably interconnected with the first adapter and can also be readily connected to a container containing a fluid such as a diluent so as to permit aseptic intermixing of the diluent with the powder. In use a conventional needleless syringe can be easily connected to the first adapter so that the mixture of the powder and diluent can be aseptically aspirated from the first container for subsequent delivery to the patient. 
         [0019]    U.S. Patent Publication No. 2005/0155901 entitled surgical cement preparation system, discloses a surgical cement preparation system designed for the rapid, clean, safe, accurate and thorough handling and combining of cement ingredients, particularly useful in the preparation of surgical cements such as polymethylmethacrylate to ensure their thorough mixture and presentation in advance of the cured or hardened state. It provides a surgical cement preparation system for combining a liquid ingredient together with at least one solid powder ingredient comprising a needle and syringe assembly and a mixing vial structured to optimize their relative functions and cooperatively interact with other components. 
         [0020]    U.S. Patent Publication No. 2014/0135831 entitled BIOADHESIVE MIXING AND PREPARATION SYSTEMS AND METHODS USING TWO SYRINGES, discloses a bioadhesive mixing assembly that includes first and second syringes and an adapter. The first syringe includes first and second chambers holding a first sealant component and an activator, respectively. The second syringe includes third and fourth chambers holding a second sealant component and one of an activator or a third sealant component, respectively. The adapter is mounted to the first syringe and includes first and second channels in flow communication with the first and second chambers, a first seal member providing sealed access to the first and second channels, first and second needles connected in flow communication with the third and fourth chambers, and a second seal member enclosing the first and second needles. Connecting the adapter to the second syringe punctures the first and second seal members with the first and second syringes to create flow communication between the first and third chambers and the second and fourth chambers. 
         [0021]    U.S. Pat. No. 7,135,027 titled Devices and methods for mixing and extruding medically useful compositions discloses devices and methods for mixing and extruding compositions which are medically and non-medically useful. The devices are particularly useful for mixing substances which are relatively inert when alone but become reactive when mixed. A common feature of all of the devices is that they allow the user to mix and ultimately extrude a composition from a single device which includes a single container or multiple interconnected containers. 
         [0022]    U.S. Pat. No. 7,322,956 titled System and method for mixing at least four components, discloses a system for mixing four components including a first syringe arrangement and a second syringe arrangement each with two chambers for holding components. Each of the two respective chambers of the syringe arrangements are connected in a uniquely defined fashion due to specific means for connecting the syringe arrangements. A component held by one chamber is mixed with a component of the corresponding other chamber by transfer into the other chamber. After mixing and disconnecting the second syringe arrangement from the first syringe arrangement, the two component mixtures in the chambers of the first syringe arrangement are further mixed and discharged by means of a mixing device which is to be connected to the first syringe arrangement. The connecting means allows connecting of the mixing device to the first syringe arrangement only after removal of the second syringe arrangement and a portion of the connecting means. 
         [0023]    None of the references provide, for the capability of vigorous back and forth mixing between the compartments and thus for rapid effective reconstitution and mixing of separately stored components. The known systems utilizing valves are complex and can plug up with the mixing materials, or can leak during storage. Only unidirectional movement of the plunger (i.e. forward) is possible, resulting in insufficiently efficient mixing of the components. It would be desirable to develop alternative multi-compartment medical devices for segregated storage and on demand mixing of at least two components and for expressing the resulting mixture from the device for use in treating a patient. 
       SUMMARY OF THE INVENTION 
       [0024]    Briefly, the present invention in one aspect relates to a mixing device comprising: a syringe having an open end and outlet and containing a first component; and a cap with a fixed outer body and an expandable chamber contained therein, wherein said cap is removably attached to the outlet of the syringe and a cross-section of the cap is larger than a syringe cross-section and the cap is shorter than the syringe. 
         [0025]    In another aspect, the present invention relates to a method of making and delivering a mixture, comprising: attaching a cap having a fixed outer body and an expandable chamber therein containing a second component to a syringe containing a first component; the cap having larger cross-section than the cross-section of the syringe and the cap being shorter than the syringe; the expandable chamber can expand within the cap to accommodate all of the first and second components; expressing the first component from the syringe into the expandable chamber; retrieving the first component and the second component from the expandable chamber back into the syringe; optionally repeating steps (b) and (c) several times until the first component and the second component are thoroughly mixed; retrieving the first component and the second component from the expandable chamber back into the syringe; detaching the cap from the syringe leaving substantially all of the first component and the second component in the syringe; and expressing the mixed first component and the second component from the syringe onto a target. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0026]      FIGS. 1 a    and  1   b,  respectively, show a syringe and an embodiment of mixing cap of the present invention. 
           [0027]      FIG. 1 c    shows a schematic perspective view of syringe connected to mixing cap of the present invention. 
           [0028]      FIG. 2  shows syringe connected to mixing cap of the present invention. 
           [0029]      FIG. 3  shows syringe connected to mixing cap of the present invention in operation. 
           [0030]      FIG. 4  shows syringe connected to mixing cap of the present invention in operation. 
           [0031]      FIG. 5  shows syringe connected to mixing cap of the present invention via connector luer. 
           [0032]      FIG. 6  shows embodiments of syringe and mixing cap of the present invention. 
           [0033]      FIGS. 7 a  and 7 b    show embodiments of mixing cap of the present invention. 
           [0034]      FIG. 8  shows an embodiment of mixing cap of the present invention. 
           [0035]      FIG. 9  shows syringe connected to mixing cap of the present invention via connector luer. 
           [0036]      FIG. 10  shows syringe connected to an embodiment of mixing cap of the present invention. 
           [0037]      FIG. 11  shows an embodiment of mixing cap of the present invention. 
           [0038]      FIG. 12  shows syringe connected to mixing cap of the present invention. 
           [0039]      FIG. 13  shows syringe connected to mixing cap of the present invention in operation. 
           [0040]      FIG. 14  shows syringe connected to mixing cap of the present invention in operation. 
           [0041]      FIG. 15  shows syringe connected to two mixing caps of the present invention in series. 
           [0042]      FIG. 16  shows syringe connected to two mixing caps of the present invention in parallel. 
           [0043]      FIG. 17  shows syringe connected to two mixing caps of the present invention in series. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0044]    According to one aspect of the present invention, there is provided a mixing device useful for mixing two or more separately stored components immediately before application to tissue or wound. The mixing device comprises a syringe filled with the first component which is a fluid, suspension, or a paste, and one or more removable caps affixed to the syringe. The removable cap has within it an expandable chamber. The chamber has a moveable piston or an elastic collapsible bag or bladder to accept material from the syringe. The cross-section or the diameter (for round cross-sections) of the chamber is larger than that of the syringe which allows the cap to be substantially shorter than the length of the syringe body. The cross-sections of the chamber or the cap can be round, elliptical, rectangular polygonal, or any other suitable cross-section. 
         [0045]    The chamber can contain at least a second component intended for mixing with the first component. The chamber can contain an optional porous mixing or absorbing section. The optional porous section can contain an optional additional releasable component that is released upon contact with the liquid or semi-liquid first component. 
         [0046]    Examples of components include one or more of gelatin; saline; thrombin; fibrinogen; oxidized regenerated cellulose powder or any medically useful substance for mixing. In one aspect, first component is gelatin and second component is saline. In one aspect, at least one component is a clotting factor, such as thrombin. In one aspect at least one component is cross-linkable material, such as fibrinogen. 
         [0047]    The second component is contained within the expandable chamber in the cap. The optional third component and/or fourth component are contained within the luer connector and/or within the optional porous section and/or within the second cap. 
         [0048]    Referring to  FIG. 1A , a syringe  100  has a hollow syringe body  110 , a syringe plunger  120  disposed within syringe body  110  and slidably movable inside syringe body  110  when actuated by an elongated syringe handle  130  attached to syringe plunger  120 , syringe handle  130  extending from syringe body  110  at a syringe proximal end  101 . Syringe body  110  is terminated at a syringe distal end  102  with a syringe nozzle  150  capped by a syringe stopper  160 . Syringe  100  is at least partially filled with a first component  170 . 
         [0049]    Referring to  FIG. 1B , a cap  200  is configured to be attached onto and detached from syringe nozzle  150 . In one aspect, cap  200  comprises a hollow cap body  210 , a cap piston  220  disposed within cap body  210  and slidably movable inside cap body  210  from a proximal end  201  to a distal end  202 . Cap body  210  with cap piston  220  is enclosed in an optional cap housing  280  which encapsulates cap body  210 . At proximal end  201  of cap housing  280  there is a cap nozzle  250  capped by a cap stopper  260 . 
         [0050]    Cap body  210  is at least partially filled with a second component  270  with the second component being held within cap body  210  in the area between cap nozzle  250  and cap piston  220  which forms an expandable chamber. 
         [0051]    First and second components  170  and  270  can be liquid, semi-liquid (paste), or solid, with at least one of components being either liquid or semi-liquid. 
         [0052]    Referring to  FIGS 1 c    and  2 , syringe  100  is shown connected to cap  200  with cap nozzle  250  engaged with syringe nozzle  150  by any known interconnection mechanism, such as by snap-on joint or by a threaded screw-on joint, or similar. The connection of syringe  100  to cap  200  is performed after removal of syringe stopper  160  and cap stopper  260 . Connecting of syringe  100  to cap  200  enables mixing of first and second components  170  and  270  by moving syringe plunger  120  using syringe handle  130  back and forth between syringe proximal end  101  and syringe distal end  102 . Moving syringe plunger  120  towards syringe distal end  102  is displacing first component  170  to cap body  210  mixing first component  170  with second component  270 , with cap piston  220  moving towards cap distal end  202 . 
         [0053]    Referring to  FIG. 3 , in operation, syringe plunger  120  is moved using syringe handle  130  towards syringe distal end  102  displacing all first component  170  to cap body  210 , mixing first component  170  with second component  270 . Cap piston  220  is shown being moved towards cap distal end  202 , with cap body  210  accommodating combined volumes of first component  170  and second component  270 . 
         [0054]    Referring to  FIG. 4 , in continued operation, syringe plunger  120  is moved using syringe handle  130  towards syringe proximal end  101  pulling all first component  170  and second component  270  from cap body  210  into syringe body  110 . As first component  170  and second component  270  transfer from cap  200  to syringe  100  through syringe nozzle  150  and cap nozzle  250  first component  170  and second component  270  continue to intermix. 
         [0055]    In continued operation, syringe plunger  120  is again moved towards syringe distal end  102  displacing all first component  170  and second component  270  to cap body  210 , resulting in position depicted earlier in  FIG. 3 . As first component  170  and second component  270  transfer from syringe  100  to cap  200  through syringe nozzle  150  and cap nozzle  250  first component  170  and second component  270  continue to intermix. 
         [0056]    In operation, the steps described above are repeated several times, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times, moving syringe plunger  120  back and forth between syringe distal end  102  and syringe proximal end  101  and thus moving first component  170  and second component  270  from syringe body  110  to cap body  210  and back, whereby first component  170  thoroughly mixes with second component  270 . 
         [0057]    After moving syringe plunger  120  back and forth between syringe distal end  102  and syringe proximal end  101  and thus moving mixture of first component  170  and second component  270  from syringe body  110  to cap body  210  and back several times, first component  170  is thoroughly mixed with second component  270 . Syringe plunger  120  is then pulled towards syringe proximal end  101  thus transferring all or substantially all mixed first component  170  and second component  270  into syringe  100  as illustrated in  FIG. 4 . Cap  200  is then disconnected from syringe  100 . Syringe  100 , now containing substantially all mixture of first component  170  and second component  270  is then directed towards tissue or wound and is used to express mixed first component  170  and second component  270  onto tissue or wound, either directly through syringe nozzle  150  or through an appropriate attachment nozzle or cannula or drip tip or spray tip. 
         [0058]    Cap body  210  is configured to be able to accommodate all volume of first component  170  and second component  270  combined. Syringe body  110  is configured to be able to accommodate all volume of first component  170  and second component  270  combined. 
         [0059]    Cap body  210  has cross-section substantially larger than cross-section of syringe body  110 . Cross-section of syringe body  110  is defined as area formed by plane AA shown in  FIG. 1A  by a dashed line, with plane AA dissecting syringe body  110  perpendicularly to direction of movement of syringe plunger  120 . Cross-section of cap body  210  is defined as area formed by plane BB shown in  FIG. 1B  by a dashed line, with plane BB dissecting cap body  210  perpendicularly to direction of movement of cap piston  220 . 
         [0060]    In case of round cross-sections, cap body  210  has diameter substantially larger than the diameter of syringe body  110 . Preferably, cap body  210  cross-section or diameter is at least 1.5 times larger relative to the cross-section or diameter of syringe body  110 , such as 2 times larger, 2.5 times larger, 3 times larger, 4 times larger, 5 times larger, or similar. Cap body  210  length from proximal end  201  to distal end  202  is substantially shorter than syringe body  110  length from proximal end  101  to distal end  102 . 
         [0061]    In one aspect, cap body  210  inside diameter or inside cross-section is 2 times larger relative to the inside diameter or inside cross-section of syringe body  110 . The displacement of syringe plunger  120  within syringe body  110  of 10 cm results in displacement of cap piston  220  of about 2.5 cm. Cap housing  280  length from cap proximal end  201  to cap distal end  202  is configured to accommodate displacement of cap piston  220  of about 2.5 cm, with cap housing  280  length being in one aspect in the range from 2.7 cm to 3.5 cm, such as 3 cm. 
         [0062]    In one aspect, cap body  210  inside diameter or inside cross-section is 3 times larger relative to the inside diameter or inside cross-section of syringe body  110 . The displacement of syringe plunger  120  within syringe body  110  of 9 cm results in displacement of cap piston  220  of 1 cm. Cap housing  280  length from cap proximal end  201  to cap distal end  202  is configured to accommodate displacement of cap piston  220  of about 1 cm, with cap housing  280  length being in one aspect in the range 1.2 cm to 2 cm, such as 1.5 cm. 
         [0063]    In one aspect, cap housing  280  is opaque. 
         [0064]    Referring to  FIG. 5 , in one aspect, there is provided an optional luer connector  900  configured for interconnecting cap nozzle  250  to syringe nozzle  150 . In one aspect, there are provided optional static mixing elements or baffles or porous plug or filter within one or more of cap nozzle  250 ; syringe nozzle  150 , and/or luer  900 . In one aspect, there are static mixing elements or baffles  910  installed within luer  900  as shown in  FIG. 5 , creating a tortuous path resulting in more turbulence and/or turns in the flow of mixed first component  170  and second component  270 , thus facilitating further intermixing. In other aspects, optional static mixing elements or baffles are installed within cap nozzle  250  or syringe nozzle  150  (optional mixing elements or baffles not shown installed within cap nozzle  250  or syringe nozzle  150 ). 
         [0065]    In one aspect, there are provided optional flow restricting valves at cap nozzle  250  and/or syringe nozzle  150 , preventing inadvertent loss of first component  170  or second component  270  or their mixture when syringe  100  is disconnected from cap  200 . Referring to  FIG. 6 , optional flow restricting valves  920  comprise membranes with at least one slit or fine aperture installed at the exits of cap nozzle  250  and/or syringe nozzle  150 . Optional flow restricting valves  920  enable fluids to move into and from syringe  100  and cap  200  under pressure or vacuum generated by moving plunger  120 , but prevent drips of fluids to exit syringe  100  and cap  200  when no pressure or vacuum is applied. In one aspect, cap nozzle  250  and/or syringe nozzle  150  are optionally covered by optional foil seals or flip lids (not shown) to allow for storage and easy opening or foil breakage upon connecting or upon expression. 
         [0066]    In one aspect, cap housing  280  is sealed so that as cap piston  220  moves towards cap distal end  202 , cap housing  280  is pressurized and resistance to movement of cap piston  220  towards cap distal end  202  increases. Once exerting pressure on syringe handle  130  towards syringe distal end  102  stopped or syringe handle  130  is being moved towards syringe proximal end  101 , pressure within cap housing  280  pushes cap piston  220  towards cap proximal end  201  helping moving mixture of components  170  and  270  from cap  200  to syringe  100 . 
         [0067]    In another aspect, as shown in  FIG. 7A , an optional pressure relief aperture  290  is provided in cap housing  280 , preventing pressure or vacuum build-up within cap housing  280 . 
         [0068]    In yet another aspect, as shown in  FIG. 7B , there is provided an optional spring  295  positioned in cap housing  280  so as to exert pressure on cap piston  220 , with no pressure or fully relaxed spring in the initial or storage position of cap piston  220 . As cap piston  220  moves towards cap distal end  202  spring  295  compresses and resistance to movement of cap piston  220  towards cap distal end  202  increases. Once exerting pressure on syringe handle  130  towards syringe distal end  102  stopped or syringe handle  130  is being moved towards syringe proximal end  101 , spring  295  pushes cap piston  220  towards cap proximal end  201  helping moving mixture of components  170  and  270  from cap  200  to syringe  100 . Pressure relief aperture  290  can be employed (as shown in  FIG. 7B ) or not employed (not shown in  FIG. 7B ) when spring  295  is utilized. In some embodiments spring  295  is pre-loaded, i.e. it exerts pressure on cap piston  220 , with spring  295  somewhat compressed even in the initial or storage position of cap piston  220 . 
         [0069]    Optional spring  295  or pressure build up inside cap housing  280  in the absence of optional pressure relief aperture  290  creates a pressure on cap piston  220  pushing cap piston  220  towards cap proximal end  201 . This helps return movement of the piston and prevents gas bubbles forming in the fluid due to vacuum formation. 
         [0070]    In one aspect, there is an optional porous absorption or desorption section within the cap  200  or within the luer connector  900 . Referring to  FIG. 8 , cap porous section  930  is positioned inside cap body  210  at cap proximal end  201 . Referring to  FIG. 9 , a luer porous section  935  is inside luer  900 . Porous section, such as luer porous section  935  or cap porous section  930  is configured to absorb or remove from first component  170  stabilizing or clotting preventing factors. Luer porous section  935  or cap porous section  930  alternatively is configured to release clotting factors into first component  170 . 
         [0071]    Referring to  FIGS. 10 and 11 , cap  200   a  with elastic expandable chamber is configured to be attached onto and detached from syringe nozzle  150 . In one aspect, cap  200   a  comprises an elastic and expandable bladder  220   a  disposed within and enclosed in cap housing  280   a.  At proximal end  201  of cap housing  280   a  there is a cap nozzle  250 . Bladder  220   a  is at least partially filled with a second component  270  with bladder  220   a  forming an expandable chamber. 
         [0072]    In  FIG. 10 , syringe  100  is shown connected to cap  200   a  with cap nozzle  250  engaged with syringe nozzle  150  by any known interconnection mechanism, such as by snap-on joint or by a threaded screw-on joint, or similar. Connecting of syringe  100  to cap  200   a  enables mixing of first and second components  170  and  270  by moving syringe plunger  120  using syringe handle  130  back and forth between syringe proximal end  101  and syringe distal end  102 . Moving syringe plunger  120  towards syringe distal end  102  is displacing first component  170  to expandable bladder  220   a  mixing first component  170  with second component  270 .  FIG. 10  shows bladder  220   a  at least partially expanded accepting at least a portion of first component  170 . 
         [0073]    Referring further to  FIG. 11 , at proximal end  201  of cap housing  200   a  there is a cap nozzle  250  capped by a cap stopper  260  when cap  200   a  is in storage. Bladder  220   a  is shown in an unexpanded state and contains second component  270 . Referring to  FIG. 12 , in operation, after removing cap stopper  260 , cap is connected to syringe nozzle  150 , with bladder  220   a  in unexpanded state. Syringe plunger  120  is then moved using syringe handle  130  towards syringe distal end  102  displacing first component  170  to bladder  220   a,  mixing first component  170  with second component  270  inside expanding bladder  220   a  which is accommodating combined volumes of first component  170  and second component  270 , as shown in  FIG. 13 . 
         [0074]    Referring to  FIG. 14 , in continued operation, syringe plunger  120  is moved using syringe handle  130  towards syringe proximal end  101  pulling all first component  170  and second component  270  from cap  200   a  into syringe body  110  and fully or at least partially collapsing bladder  220   a.  As first component  170  and second component  270  transfer from cap  200   a  to syringe  100  through syringe nozzle  150  and cap nozzle  250  first component  170  and second component  270  continue to intermix. 
         [0075]    In continued operation, syringe plunger  120  is again moved towards syringe distal end  102  displacing all first component  170  and second component  270  to cap  200   a  as shown in  FIG. 13 . As first component  170  and second component  270  transfer from syringe  100  to cap  200   a  through syringe nozzle  150  and cap nozzle  250  first component  170  and second component  270  continue to intermix. 
         [0076]    In further operation, the steps described above are repeated several times, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times, moving syringe plunger  120  back and forth between syringe distal end  102  and syringe proximal end  101  and thus moving first component  170  and second component  270  from syringe body  110  to cap  200   a  and back, whereby first component  170  thoroughly mixes with second component  270 . 
         [0077]    After moving syringe plunger  120  back and forth between syringe distal end  102  and syringe proximal end  101  and thus moving mixture of first component  170  and second component  270  from syringe body  110  to cap body  210  and back a number of times appropriate for full intermixing of components, first component  170  is thoroughly mixed with second component  270 . Syringe plunger  120  is then pulled towards syringe proximal end  101  thus transferring all or substantially all mixed first component  170  and second component  270  into syringe  100  as illustrated in  FIG. 14 . Cap  200   a  is then disconnected from syringe  100 . Syringe  100 , now containing substantially all first component  170  and second component  270  is then directed towards tissue or wound and is used to express mixed first component  170  and second component  270  onto tissue or wound, either directly through syringe nozzle  150  or through an appropriate attachment nozzle or cannula or drip tip or spray tip. 
         [0078]    Bladder  220   a  is configured to be able to accommodate all volume of first component  170  and second component  270  combined. Syringe body  110  is configured to be able to accommodate all volume of first component  170  and second component  270  combined. Cap  200   a  has a cross-section substantially larger than the cross-section of syringe body  110 . In case of round cross-sections, cap  200   a  has diameter substantially larger than the diameter of syringe body  110 . Cap  200   a  is substantially shorter than syringe body  110 . 
         [0079]    Similarly to the embodiments shown above, in some aspects, there is an optional porous absorption or desorption section within the cap  200   a  or within the luer connector  900  (not shown). Cap porous section can be positioned inside cap  200   a  at cap proximal end  201 . Porous section, such as luer porous section or cap  200   a  porous section, is configured to absorb or remove from first component  170  stabilizing or clotting preventing factors. Luer porous section or cap  200   a  porous section alternatively is configured to release clotting factors into first component  170 . 
         [0080]    In some aspects of the present invention, there are two or more caps attached to syringe  100 , each cap containing a different component  270   a,    270   b  to be mixed with first component  170 . Referring to  FIG. 15 , first cap  200   a  is shown attached to nozzle  150 , while second cap  200   b  is shown attached to rear port  250   b  positioned at first cap  200   a  distal end  202 , with both first cap  200   a  and second cap  200   b  having expandable bladders  220   a  and  220   b.  In this aspect of the present invention, first cap  200   a  has cap nozzle  250   a  at proximal end  201  and rear port  250   b  at distal end  202 . Second cap  200   b  has only cap nozzle  250   b.    
         [0081]    In other aspects of the present invention, as shown in  FIG. 16 , two or more caps are attached to syringe  100  via any multi-port connector or manifold, such as shown “T” shaped connector  251 , each cap containing a different component  270   a,    270   b  to be mixed with first component  170 . First cap  200   a  is shown attached to nozzle  150 , while second cap  200   b  is shown attached to rear port  250   b  positioned at first cap  200   a  distal end  202 . 
         [0082]    In operation of embodiments shown in  FIGS. 15 and 16 , syringe plunger  120  is moved towards syringe distal end  102  and back displacing first component  170  into bladders  220   a  and  220   b  and then withdrawing first component  170 , second component  270   a,  and third component  270   b  back into syringe  100 . As first component  170 , second component  270   a,  and third component  270   b  transfer from syringe  100  to caps  200   a  and  200   b  and back through syringe nozzle  150  all components continue to intermix. 
         [0083]    After moving syringe plunger  120  back and forth between syringe distal end  102  and syringe proximal end  101  and thus moving mixture of first component  170  and components  270   a  and  270   b  from syringe body  110  to caps  200   a  and  200   b  a number of times appropriate for full intermixing of components, syringe plunger  120  is then pulled towards syringe proximal end  101  thus transferring all or substantially all mixed components  170 ,  270   a,    270   b  into syringe  100 . Caps  200   a,    200   b  are then disconnected from syringe  100 , and T shaped connector  251  of the embodiment shown in  FIG. 16  also disconnected from syringe  100 . Syringe  100 , now containing substantially all mixed components  170 ,  270   a,  and  270   b  is then directed towards tissue or wound and is used to express mixed components onto tissue or wound, either directly through syringe nozzle  150  or through an appropriate attachment nozzle or cannula or drip tip or spray tip. 
         [0084]    In an alternative aspect of the present invention, there are two or more caps attached to syringe  100 , each cap containing a different component  270   a,    270   b  to be mixed with first component  170 , with first cap  200   a  having bladder  220   a  and second cap  200   c  having cap piston  220 . In one embodiment (not shown), both caps  200   a  and  200   c  are connectable to nozzle  150  via a manifold, similarly to the arrangements shown in  FIG. 16 . In another embodiment, similar to the embodiment of  FIG. 15  and shown in  FIG. 17 , first cap  200   a  with bladder  220   a  is attached to nozzle  150 , while second cap  200   c  with cap piston  220  is shown attached to rear port  250   b  positioned at first cap  200   a  distal end  202 . In this aspect of the present invention, first cap  200   a  has cap nozzle  250   a  at proximal end  201  and rear port  250   b  at distal end  202 . 
         [0085]    While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.