U.S. patent application number 09/976556 was filed with the patent office on 2003-09-25 for system for reconstituting pastes and methods of using same.
Invention is credited to Bernhardt, Andy, Kao, Penelope, Wironen, John F..
Application Number | 20030180262 09/976556 |
Document ID | / |
Family ID | 27413270 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030180262 |
Kind Code |
A1 |
Wironen, John F. ; et
al. |
September 25, 2003 |
System for reconstituting pastes and methods of using same
Abstract
Disclosed herein is an efficient and cost-effective system for
reconstituting bone pastes comprising a first syringe containing a
reconstitution fluid and second syringe containing paste
components, wherein said first and second syringes are
communicatingly interconnectable. Also disclosed are novel methods
for producing and storing bone pastes. Alternatively, a mixing
syringe is disclosed, which is useful for reconstituting a paste,
inter alia, comprising a flexible midportion, whereby repeated
compression of the flexible midportion results in mixing the
contents of the syringe.
Inventors: |
Wironen, John F.; (Alachua,
FL) ; Kao, Penelope; (Alachua, FL) ;
Bernhardt, Andy; (Alachua, FL) |
Correspondence
Address: |
Donald J Pochopien
McAndrews Held & Malloy LTD
Citicorp Center 34th Floor
500 West Madison Street
Chicago
IL
60661
US
|
Family ID: |
27413270 |
Appl. No.: |
09/976556 |
Filed: |
October 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09976556 |
Oct 11, 2001 |
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09792894 |
Feb 26, 2001 |
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09792894 |
Feb 26, 2001 |
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09751929 |
Dec 29, 2000 |
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09792894 |
Feb 26, 2001 |
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09474276 |
Dec 29, 1999 |
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Current U.S.
Class: |
424/93.7 ;
424/484; 424/486; 424/488 |
Current CPC
Class: |
A61F 2/4601 20130101;
B01F 2101/20 20220101; A61B 17/8816 20130101; B01F 33/50112
20220101; A61B 17/8825 20130101; B01F 33/5011 20220101; A61F
2002/30677 20130101; A61F 2/4644 20130101; A61J 1/201 20150501;
B01F 35/7163 20220101; A61J 1/2058 20150501; B01F 35/71 20220101;
A61J 1/2096 20130101; A61J 1/2041 20150501; B01F 35/3202 20220101;
A61J 1/2062 20150501; A61B 2017/8838 20130101; A61F 2002/2835
20130101; A61F 2002/4685 20130101; B01F 31/441 20220101; A61J
1/2089 20130101; A61F 2002/2817 20130101 |
Class at
Publication: |
424/93.7 ;
424/484; 424/486; 424/488 |
International
Class: |
A61K 045/00; A61K
009/14 |
Claims
What is claimed is:
1. A dried paste composition comprising freeze-dried DBM particles
and a carrier, wherein said carrier is gelatin, hyaluronic acid,
polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol,
collagen or dextran, or combinations thereof.
2. The dried paste composition of claim 1, wherein said carrier is
also dried.
3. The dried paste composition of claim 1, wherein said
freeze-dried DBM particles are about 125 microns to about 850
microns in size.
4. The dried paste composition of claim 3, wherein said
freeze-dried DBM particles are about 250 microns to about 500
microns in size.
5. The dried paste composition of claim 1, wherein said carrier is
gelatin.
6. The dried paste composition of claim 5, wherein said gelatin is
in the form of granules having a size of about 125 microns to about
710 microns.
7. The dried paste composition of claim 6, wherein said gelatin is
in the form of granules having a size of about 500 microns to about
710 microns.
8. The paste composition of claim 1, further comprising
antibiotics; or sucrose, dextrose or other biologically compatible
anti-caking agents; or combinations thereof.
9. The paste composition of claim 1, further comprising barium,
iodine, or other radioopaque substances, or combinations
thereof.
10. The paste composition of claim 1, further comprising an
exothermic substance.
11. The paste composition of claim 10, wherein said exothermic salt
comprises Magnesium chloride, Sodium sulfate, or Magnesium sulfate
or other exothermic salts, or combinations thereof.
12. A reconstituted paste composition comprising an admixture of a
dried paste composition comprising freeze-dried DBM particles and a
carrier, wherein said carrier is gelatin, hyaluronic acid,
polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol,
collagen or dextran, or combinations thereof; and reconstitution
fluid, wherein said reconstitution fluid is selected from the group
consisting of water, water-based salines, blood or fractions
thereof, protein solutions, gelatin solutions, growth factor
solutions, antibiotic solutions, analgesic solutions, platelet rich
plasma, crude platelet extract, and combinations thereof.
13. A reconstituted paste composition comprising an admixture of a
dried paste composition comprising freeze-dried DBM particles and
gelatin; and reconstitution fluid, wherein said reconstitution
fluid comprises water.
14. An article of manufacture comprising a container having the
dried paste composition of claim 1 disposed therein.
15. The article of manufacture of claim 14, wherein said container
is a syringe.
16. A dried paste composition comprising freeze-dried DBM particles
and gelatin, wherein the DBM particles are about 250 microns to
about 500 microns in size.
17. A method of treating a bone defect or injury comprising
reconstituting the dried paste composition of claim 1 with a
reconstitution fluid to form a paste composition, wherein said
reconstitution fluid is selected from the group consisting of
water, water-based salines, blood or fractions thereof, protein
solutions, gelatin solutions, growth factor solutions, antibiotic
solutions, analgesic solutions, platelet rich plasma, crude
platelet extract, and combinations thereof; and administering the
paste composition to a site of need.
18. The dried paste composition of claim 1, wherein said dried bone
paste is stored at room temperature for more than about 24 hours,
and which is reconstituted to form a reconstituted paste
composition prior to administration, whereby upon reconstitution
said reconstituted paste composition is osteogenic, chondrogenic,
or chondroprotective, or a combination thereof.
19. A dried paste composition comprising freeze-dried DBM particles
and a carrier, wherein said carrier is gelatin, hyaluronic acid,
chondroitin sulfate, polyethylene oxide, polyvinylpyrrolidone,
polyvinyl alcohol, collagen or dextran, or combinations thereof,
wherein said dried paste composition is stored at room temperature
for more than about 24 hours, and wherein said dried paste
composition is osteogenic, chondrogenic, or chondroprotective or a
combination thereof upon reconstitution.
20. A dried paste composition capable of being stored at room
temperature and upon reconstititution, possesses osteogenic,
chondrogenic, or chondroprotective properties, or a combination
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. Nos. 09/792,894, filed Feb. 26, 2001, which is a
continuation in part of 09/751,929 filed Dec. 29, 2000, which is a
continuation in part of 09/474,276 filed Dec. 29, 1999, and claims
the benefit of such applications under 35 USC .sctn. 120.
BACKGROUND OF THE INVENTION
[0002] The ability to preserve biomedical substances has a great
impact on the usefulness and applicability of such substances. This
is especially true for important liquid or semi-solid substances
whose vital components are prone to degradation and/or spoiling
when left in liquid form for extended periods of time. One method
routinely utilized for preserving liquid or semi-solid substances
involves the removal of the aqueous component of such substances
(e.g. freeze-drying) to produce a dry powder. While converting
liquid substances into powder form may address the problems of
degradation and spoiling, problems still arise as to how to
reconstitute such powders back into usable liquid form in a
convenient and practical fashion.
[0003] An example of an increasingly important biomedical substance
is osteogenic Bone Paste (WO 98/40113). Osteogenic Bone Paste has
provided surgeons with a revolutionary means for repairing serious
bone defects, as well as other bone-related injuries and problems.
While current methods of utilizing bone paste have shown promise,
there is a constant need for devising new, cost-effective
techniques of storing and preserving bone paste and other
biomedical substances, which, in turn, will increase their
usefulness and adaptability to medical applications.
SUMMARY OF THE INVENTION
[0004] The subject invention concerns a system that allows for a
more expeditious and facile use and preparation of pastes.
Specifically exemplified is a novel system for reconstituting bone
paste, and/or other biomedical pastes or powders, that results in
decreasing the time involved in processing such pastes, as well as
diminishing the costs and inefficiencies associated with their
storage. One aspect of the subject invention pertains to a system
that comprises a first syringe containing reconstitution liquid and
a second syringe containing paste components, wherein said first
and second syringes are communicatingly interconnectable.
[0005] Another aspect of the subject invention pertains to a method
of reconstituting a paste that comprises obtaining a first syringe
that contains reconstitution liquid; obtaining a second syringe
that contains paste components; and contacting (e.g. mixing) the
contents of the first syringe with the contents of the second
syringe.
[0006] A further aspect of the subject invention pertains to an
article of manufacture comprising a syringe containing paste
components under a vacuum.
[0007] Yet another aspect of the subject invention pertains to a
kit comprising a first syringe containing reconstitution liquid, a
second syringe containing paste components, and packaging
materials.
[0008] Further still, another aspect of the subject invention
pertains to a storing method for bone pastes that provides
long-shelf life and simple implementation of the stored bone
paste.
[0009] Further still, another aspect to the subject invention
pertains to a mixing syringe that comprises a barrel having a first
and second ends and a midsection that comprises a flexible portion.
When contents are put in the mixing syringe, they can be easily
mixed by squeezing the flexible portion by hand or by appropriate
mechanical devices known in the art.
[0010] The subject invention provides an easy means for preparing
pastes for utilization in medical and/or dental procedures. In
addition, the subject invention cuts down on the costs of
preserving bone and/or other biomedical pastes, and extends their
shelf life. With respect to graft pastes, current methods require
that they are stored at extremely cold temperatures (-80.degree.
C.). Such freezing presents a number of problems. Refrigeration at
these temperatures is very costly, and the handling of the pastes
at this temperature can be very time consuming. Also, extremely
careful attention is required to ensure that the integrity of the
paste is maintained. In contrast, the subject invention allows the
graft paste to be processed down to its critical components, for
example, by freeze-drying, and provides a simple means to
reconstitute the paste components back into a workable paste,
immediately before surgery. Processing the graft paste into its
critical components allows for the storage of the paste at ambient
(room) temperature for extended periods of time.
[0011] The subject invention also pertains to freeze-dried
compositions that possess osteogenic, chondrogenic or
chondroprotective, or other beneficial properties. The subject
dried paste compositions are capable of being stored at room
temperature and retaining their osteogenic, chondrogenic, or
chondroprotective properties upon reconstitution.
[0012] The ability to store freeze-dried bone pastes at room
temperature and then reconstitute the paste prior to surgery is one
of the primary advantages of the subject invention. These and other
advantageous aspects of the subject invention are described in
further detail below.
DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows a side view of a disassembled apparatus for
reconstituting pastes according to the principles of the subject
invention, including a first syringe having a male connector end
(FIG. 1A) and a second syringe having a female connector end (FIG.
1B).
[0014] FIG. 2 shows a longitudinal cross-section of the assembled
apparatus as shown in FIG. 1.
[0015] FIG. 3 shows an embodiment of the invention illustrating an
assembled syringe comprising a septum cap engaged thereon for
accepting a needle.
[0016] FIG. 4 shows an embodiment of the invention illustrating the
assembled syringe of FIG. 3 accepting a needle for the transfer of
reconstitution fluid.
[0017] FIG. 5 shows a side view of an embodiment of the invention
illustrating a syringe with a depression interlock disposed thereon
for securing the syringe.
[0018] FIG. 6 shows a side view of an embodiment of the invention
illustrating a syringe with a guard rack designed for aiding the
loading of paste components into the syringe.
[0019] FIG. 7 shows a side view of an embodiment of the invention
tailored for reconstituting larger quantities of paste components
that comprises a three-way valve coupler.
[0020] FIG. 8 shows a side view of an embodiment of the invention
comprising interconnectable syringes having larger bores and
fasteners.
[0021] FIG. 9 shows a perspective view of the embodiment shown in
FIG. 8.
[0022] FIG. 10 shows a side view 10A and a perspective view 10B of
an embodiment of the invention pertaining to a plunger comprising
an aperture and channel to facilitate expulsion of air from the
contents of a syringe.
[0023] FIG. 11 shows a side view of a mixing syringe, disassembled
(FIG. 11A) and assembled (FIG. 11B), having a flexible midsection
to facilitate mixing of its contents.
[0024] FIG. 12 shows a side view of another version of the mixing
syringe, diassembled (FIG. 12A) and assembled (FIG. 12B), wherein
the plunger of the syringe has a larger end for stabilizing a
portion of the flexible midsection.
[0025] FIG. 13 shows a longitudinal cross-section of a first
configuration (FIG. 13A) of the first end of the barrel shown in
FIGS. 11 and 12; a second configuration (FIG. 13B) representing a
transverse cross-section along line AA; and a third configuration
(FIG. 13C) which is shorter in length.
[0026] FIG. 14 shows the configuration as shown in FIG. 13C rigidly
attached to the first end of the barrel of the mixing syringe shown
in FIGS. 11 and 12.
DETAILED DISCLOSURE OF THE INVENTION
[0027] Definitions
[0028] The term "communicatingly interconnectable" as used herein
refers to the ability of two or more syringes to be connected in
such as way as to allow the contents of a given syringe to be
transferred to another syringe.
[0029] The term "paste" as used herein refers to a malleable
composition useful in medical procedures. Pastes for use with the
principles of the invention include, but are not limited to
allograft pastes (e.g., osteogenic pastes or chondrogenic pastes),
carrier associated Growth Factors, carrier associated mineralized
particles, morsellized skin or other tissue, Fibrin powder,
Fibrin/plasminogen glue, biomedical plastics, Demineralized Bone
Matrix (DBM)/glycerol, cortico cancellous chips (CCC),
DBM/pleuronic F127, and DBM/CCC/F127, human tissue/polyesters or
polyhydroxy compounds, or polyvinyl compounds or polyamino
compounds or polycarbonate compounds or any other suitable viscous
carrier; or alpha-BSM.RTM. or polyethylene oxide,
polyvinvylpyrrolidone, polyvinyl alcohol, collagen and dextran.
Preferably, pastes used in accordance with the principles of the
subject invention are graft pastes having osteogenic or
chondrogenic properties. Furthermore, the paste components can
include other materials such as, but not limited to, antibiotics,
sucrose, dextrose or other biologically compatible anti-caking
agents, and optionally, barium, iodine, or other high atomic weight
elements for purposes of radioopacity.
[0030] In a most preferred embodiment, the paste for use as taught
herein contains a carrier, an osteoconductive component, and an
osteoinductive component. Carriers can include, but are not limited
to, gelatin, collagen, glycerol, hyaluronic acid, chondroitin
sulfate, polyethylene oxide, polyvinylypyrrolidone, polyvinyl
alcohol, dextran and/or mixtures thereof. Osteoconductive materials
suitable for use with the subject invention include, but are not
limited to, hydroxapatite (HA), tricalcium phosphate (TCP), CCC,
bioactive glass, bioactive ceramics, and/or mixtures thereof.
Osteoinductive materials suitable for use with the subject
invention include, but are not limited to, DBM, and growth factors
such as bone morphogenic protein (BMP), TGF-beta, PDGF, and/or
mixtures thereof.
[0031] The term "paste components" as used herein refers to those
components of a paste that are produced by removing liquid from a
paste, and are capable of reconstitution into a workable paste upon
contact with a reconstitution liquid. One skilled in the art will
readily appreciate processing methods suitable in accord with the
principles of the subject invention. Preferably, paste components
are those components produced by removing water from a paste of
interest, such as, but not limited to, by freeze-drying of a
paste.
[0032] The term "reconstitution liquid" as used herein refers to a
liquid capable of reconstituting paste components into a workable
paste upon mixing with the paste components. Reconstitution liquids
useful in accordance with the principles of the subject invention
include, but are not limited to, water and water-based salines, or
any other non-toxic fluid such as blood, Growth Factor solutions,
antibiotic solutions, protein solutions, gelatin solutions,
analgesic solutions, synovial fluid and platelet rich plasma. In a
preferred embodiment, the reconstitution fluid is blood, or
fractions thereof (e.g., serum or plasma). More preferably, paste
components are reconstituted with a patient's blood to form a paste
that is implanted back into the patient.
[0033] The term "syringe" as used herein refers to an apparatus
that comprises a barrel and plunger, which is capable of containing
a substance, and ejecting that substance at a desired site. In a
preferred embodiment, two or more syringes are connectable with
each other, and are capable of sending and receiving their contents
to and from each other. The mode of actuating the transfer of a
syringe's contents can be by hand, but can include other mechanical
means, for example, by a motor. In an even more preferred
embodiment, the syringe is capable of holding its contents under a
vacuum, preferably, up to 5 years or more. Further, as discussed
above, the syringes are preferably communicatingly
interconnectable. One means of connection includes, but is not
limited to, the presence of a male Luer-type connector on a first
syringe and a female Luer-type connector on a second syringe. The
presence of this reciprocal male and female connection not only
provides for a simple and efficient interconnection, but decreases
undesirable "dead" space between the two syringes. Other means of
connection will be readily appreciated by those skilled in the art,
such as, for example, a stop-cock for receiving two male connectors
or a two-sided female adapter for receiving two male
connectors.
[0034] Turning now to the drawings, a reconstitution system is
shown generally in FIGS. 1-3. The system comprises a first syringe
10 and a second syringe 12 communicatingly interconnectable with
each other. Syringes 10 and 12 comprise substantially cylindrical
body portions 11, suitable for receiving a plunger rod 20. Plunger
rod 20 has disposed on one end a crown 21, made of a material for
forming a seal between its surface and the surface of the inner
walls of the syringe body 11. Materials contemplated for the crown
21 include, but are not limited to, rubber and plastic. Second
syringe 12 preferably has a female end 16 for receiving a male end
14 of first syringe 10. As shown in FIG. 2, the first syringe 10
comprises paste components 26 and the second syringe 12 comprises
reconstitution fluid 28. The reciprocating male and female ends
provide for a tightly sealed connection that minimizes "dead" space
between the two syringes, thereby alleviating unwanted air bubbles.
Alternatively, albeit less preferred, a first syringe and a second
syringe may be connected by an adapter having two male ends, two
female ends or a male end and female end, depending on the ends of
the first and second syringes. Further, the first syringe and
second syringe may be connected through friction by snapping into
each other, or snapping into an adapter.
[0035] In yet another embodiment, the introduction of air is
minimized in the system through the use of a stopcock valve. In
this embodiment, a first syringe and a second syringe are evacuated
and then communicatingly interconnected via a stopcock valve. Upon
rotation of the stopcock valve, the contents of one syringe are
allowed to flow into the other syringe. In light of the teachings
herein, those skilled in the art will appreciate the types of
valves suitable for this purpose. The important aspect of the valve
is the ability to interconnect to at least two syringes.
[0036] Operation of the system to reconstitute a paste can comprise
applying pressure to a first plunger rod 20 of syringe 12 which
thereby pushes the reconstitution fluid 28 into syringe 10. Upon
transfer of the reconstitution fluid 28, it is brought into contact
with the paste components 26. Preferably, the plunger rod 20 in
syringe 10 is gradually pulled in coordination with the pushing of
rod 20 in syringe 12 to create negative pressure and more space in
syringe 10 to aid in and accommodate the transfer of the
reconstitution fluid 28. In a preferred embodiment, the paste
components are inserted into syringe 10, and syringe 10 is
evacuated such that the paste components are held under a vacuum.
Once an adequate amount of reconstitution fluid is transferred from
syringe 12 to syringe 10, the contents of syringe 10 can be
transferred back to syringe 12 whereby the paste components and
reconstitution fluid are mixed resulting in a useable paste.
Preferably, the contents of each syringe are transferred several
times until the desired consistency of the paste is achieved.
[0037] As shown in FIG. 3, another embodiment of the invention is
directed to a system for reconstituting pastes comprising a first
syringe 10 containing paste components 26 held under a vacuum and a
removable cap 30. The removable cap 30 comprises a rigid portion 33
that is engaged to the end of the syringe 10 and a septum portion
34. The rigid portion preferably includes an end 33 configured to
be removably engageable to the end of a syringe. More preferably,
the end 33 is a male or female connecting end. The septum portion
is preferably made of a material that is capable of accepting an
injection means (for example, a needle; see U.S. Pat. No. 5,951,160
for other examples of injection means) while still maintaining the
seal of the syringe 10, such as, but not limited to, rubber,
silicone, plastic and other elastic materials.
[0038] A further embodiment shown in FIG. 4 pertains to a system
for reconstituting pastes. Operation of this embodiment involves
drawing reconstitution fluid into a syringe 50 equipped with a
needle 52 on its end. The needle 52 is inserted into syringe 10
through the septum portion 34 of the cap 30 and the reconstitution
fluid 28 is transferred into the syringe 10. Preferably, the
reconstitution fluid 28 is transferred while the transfer of any
air is avoided. Once the reconstitution fluid 28 is transferred
into syringe 10, the cap 30 is removed, at which time a second
syringe is interconnected with syringe 10. The paste components and
reconstitution fluid present in syringe 10 are mixed by transfer
back and forth from syringe 10 to the second syringe until a paste
of a desired consistency is formed. In a preferred embodiment, the
paste components comprise a gelatin material which is melted by
heating prior to mixing. Preferably, heating may occur in a water
bath for 3 to 5 minutes. After the paste is formed, the syringe 10
and the second syringe are dissociated, and the paste is ejected as
needed.
[0039] In another embodiment, as shown in FIG. 5, the subject
invention is directed to an article of manufacture that comprises a
syringe 10 that contains paste components 26 being held under a
vacuum. To aid in preventing the inadvertent release of the vacuum,
a depression interlock 62 is provided that protects the plunger rod
18 from sliding. Alternatively, the syringe comprises a cap 30
engaged at one end. The cap 30 preferably comprises a rigid portion
33 and a septum portion 34. Those skilled in the art will readily
appreciate, in light of the teachings herein, other devices
suitable for preventing the inadvertent depression of the plunger
rod.
[0040] A further embodiment of the subject invention is directed to
kit comprising a first syringe containing paste components, a
second syringe, and a container for housing the syringes.
Preferably, the second syringe contains reconstitution fluid. In a
more preferred embodiment, the kit comprises a cap that has a rigid
portion for engaging a syringe and a septum for accepting a needle.
In an even more preferred embodiment, the kit comprises a needle
having an end for engaging a syringe. Alternatively,
[0041] FIG. 6 shows an embodiment of the invention that is directed
to a process for packing paste components into a syringe. Paste or
paste components 26 are placed within a syringe 10 having disposed
thereon a guard rack 60 having a bottom 61, two or more sides 63,
and two or more top portions 65 extending perpendicularly from the
ends of the sides 63 that are opposite the bottom 61. The top
portions 65 preferably extend toward each other such that a space
is formed between the two extended top portions 65 that is of a
suitable size to accommodate a plunger rod 20 and support the
bottom end 17 of the syringe 10. To produce an evacuated syringe, a
cap 30 is placed loosely onto the top end 14 of the syringe 10, and
the syringe 10 disposed on the guard rack 60 is placed in a
lyophilizer. Upon lyophilization of the contents in the syringe 10,
the syringe 10 and guard rack 60 is raised such that the cap 30
comes into contact with a roof surface of the lyophilizer. The cap
30 is contacted with a force sufficient to firmly engage the cap 30
onto the syringe 10, to thereby form and maintain a vacuum.
Alternatively, a valve is removably engaged to said syringe. The
configuration of the guard rack 60 and the syringe 10 prevents the
depression of the plunger rod during loading of the syringe 10.
Those skilled in the art will readily appreciate, in view of the
teachings herein, other devices suitable for preventing depression
of the plunger rod such as the depression interlock discussed
above.
[0042] FIG. 7 shows a further embodiment 700 of the invention that
is especially tailored to reconstitute larger quantities of paste
components. Embodiment 700 comprises a three-way valve coupler 710
that has three Luer-lok adapter ends: a first female end 712, a
second female end 714, and a male end 716 that are interconnectable
with corresponding Luer-lok ends on a first syringe 720 having a
male end 725, a second syringe 730 having a male end 735, and a
third syringe 740 having a female end 745, respectively. Those
skilled in the art will recognize that the Luer-lok adapter ends of
the three-way valve coupler 710 are readily interchangeable with
either male or female Luer-lok ends. The three-way valve coupler
710 is equipped with a rotatable valve 750 (preferably a
conventional Qosina valve) that is capable of directing
communication between two of three adapter ends. In a preferred
embodiment, first syringe 720 and third syringe 740 are 5 cc
syringes and second syringe 730 is a 20 cc syringe.
[0043] The preferred operation of embodiment 700 is as follows:
Syringes 720, 730, and 740 are connected to the three-way valve
coupler 710. Syringe 720 contains reconstitution fluid, syringe 740
contain paste components, and syringe 730 is empty. Rotatable valve
750 is turned to 9 o'clock (as shown) to close flow to syringe 720
and opening flow between syringes 730 and 740. The plunger 755 of
syringe 730 is pulled to draw air out of paste components contained
in syringe 740. After removing air, syringe 730 can be removed and
rotatable valve 750 is turned to open flow between syringes 720 and
740. The plunger 760 of syringe 720 is pushed and the plunger 765
of syringe 740 is pulled to draw reconstitution fluid into syringe
740. The contents of syringe 740 is then transferred back to
syringe 720 and back to syringe 740, and repeated if necessary, to
mix the reconstitution fluid with the paste components, until
desired mixture is achieved.
[0044] Alternatively, or preferably, when reconstituting larger
quantities of paste components, syringes equipped with larger bores
over standard Luer-lok ends are used to accommodate and facilitate
flow of the materials to and from the syringes. FIGS. 8 and 9
represent a side view and perspective view, respectively, of
syringes equipped with larger bores: female 810 and male 820. Those
skilled in the art will appreciate that the ends of the syringes
and three-way valve coupler shown in FIG. 7 and described above for
embodiment 700, as well as the other connecting ends of devices
described herein, can be substituted with ends having extra-large
bores. Preferably, the extra-large bores range from about 0.4
inches to about 0.6 inches in diameter for 5-10 cc syringes.
[0045] Typically, it is desirous to remove air from the paste
components before, during or after reconstitution is conducted. In
a specific embodiment, the removal of air is facilitated by
providing an aperture in the plunger of the syringes used in accord
with the teachings herein. For example, FIG. 10 shows a plunger
1000 having an aperture 1010 at its end 1020 in contact with paste
components, wherein the aperture communicates with the other end of
the plunger 1030 through a channel 1040 defined within the plunger
1000. Preferably, to prevent escape of paste components or
reconstitution fluid, the aperture is covered with an air-permeable
membrane or filled with an air-permeable plug. Materials for the
plug, membrane or other similar structures are commercially
available and include, for example, TF Membrane Filters, Gelman
(VWR Scientific) or Porex Hydrophobic vents (Porex Corp.).
According to the principles of this embodiment, as the plunger is
pushed against the contents of the syringe, the pressure caused
thereby acts to push the air contained in the contents through the
aperture and expelled out of the syringe.
[0046] Turning to FIG. 1 IA and B, an embodiment of a mixing
syringe 1100 according to the teachings of the subject invention is
shown, which allows for the ready mixing of its contents. The
mixing syringe 1100 comprises a barrel 1110 and a plunger 1105,
wherein the plunger 1105 is inserted into a second end 1115 of the
barrel 1110 (see FIG. 11B). The barrel 1110 comprises a first end
1120 having an opening 1125 for extruding the mixed contents of the
mixing syringe 1100 to the site of need. As shown, the first end
1120 is configured as a luer-lok connector, which would allow
engagement to another luer-lok connector. In a preferred
embodiment, the mixing syringe 1100 is provided with one or more
paste components and a reconstitution fluid is provided into the
mixing syringe 1100 through the first end 1120, by, for example,
connection of a syringe or other device containing said
reconstitution fluid. However, those skilled in the art will
appreciate that the first end 1120 can have a number of different
connecting means securely attached, or integral thereto, such as a
threaded neck and cap, valve or a septum, which may or may not be
removable. Between the first end 1120 and second end 1115 of the
barrel 1110 is a midsection 1130 comprising a rigid portion 1135
and a flexible portion 1140. Preferably, as shown, the rigid
portion 1135 is proximate to said second end 1115, meaning closer
to the second end 1115 than the first end 1120. When two or more
substances are disposed within the mixing syringe 1100, and with
the plunger 1105 situated within the barrel 1110, the two or more
substances are mixed by squeezing the flexible portion 1140,
preferably repeated squeezing. The rigid portion 1135, which is
part of or proximate to the second end 1105, helps maintain the
structural integrity of the barrel during mixing. The mixing
syringe 1100 is also provided with a flange 1160 to help manipulate
the mixing syringe 1100 during extrusion of the mixed contents. The
flange is preferably made of a rigid material. To aid in minimizing
the dead space within the barrel 1110 of the mixing syringe 1100,
the insertion end 1145 of the plunger 1105 has a tapered tip 1150.
Naturally, those skilled in the art will appreciated that the
insertion end of the plunger may take a number of different shapes,
such as a flat end, rounded end, conical, etc.
[0047] The flexible portion 1140 should be adequately flexible to
be compressible by hand. Those skilled in the art will readily
appreciate materials suitable for producing the flexible portion.
Examples of appropriate materials include, but are not limited to,
low density polymers such as low density polyethylene, silicone,
laminate plastics, polyurethane, Krayton, rubber latex and other
suitable flexible elastic materials. If it is desired to use a
mechanical device for squeezing the flexible portion 1140, the
flexibility of the flexible portion 1140 may be increased or
decreased depending on the desired mode of squeezing, with the
proviso that some level of flexibility should be maintained. The
rigid portion 1135 is made from a more rigid material, such as, for
example polypropylene. Other conventional materials suitable for
making the rigid portion will be readily appreciated by those
skilled in the art. The mixing syringe can be made according to
several conventional manufacturing techniques, e.g., injection
molded, dipping molded, rotational molded, or blow molded.
[0048] Upon mixing the contents of the mixing syringe 1100, the
contents are extruded out of the opening 1125 at the first end 1120
to the site of need by applying force to the plunger 1105. As
mentioned above the first end 1120 may have a number of different
connectors securely attached, or integral to the first end 1120,
such as, Luer-lok connector (friction-fit or screw-type), threaded
neck with attachable cap, smooth neck with slip-fit cap, septum,
one-valve, multiple-way valve. It is preferred that the dimensions
of the opening are smaller than the dimensions of the inner surface
of the barrel 1110, thereby providing a smaller end that governs
the flow of contents out of the syringe. However, depending on the
ultimate end-use, the first end 1120 can be cut or pre-scarred such
that the tip of the first end 1120 is removed, thereby forming a
straight-walled open-ended barrel. Naturally, the straight-walled
open ending is preferred for applications requiring a high flow
rate of delivery, or where a larger sized mass of mixed contents is
desired, or where larger bone particles or chips are mixed in the
mixing syringe. Furthermore, the need to vent air in the mixing
syringe is less of an issue because mixing occurs in a single
syringe and is not being transferred back and forth between
syringes. Indeed, preferably, the volume of contents in the syringe
is such that there is head space between the level of contents and
the first end to provide room for receiving fluid. More preferred,
the head space should be about 0-1 inches.
[0049] Another embodiment of a mixing syringe 1200 is shown in
FIGS. 12 A and B. The mixing syringe 1200 comprises a barrel 1210
and a plunger 1205. The barrel 1210 comprises a first end 1220 and
a second end 1215. The midsection 1230 is flexible and the plunger
1205 comprises a large end 1225, which upon insertion into the
barrel 1210 (see FIG. 12B) acts to stabilize the flexible
midsection 1230, and whereby contents within the syringe can be
mixed by compression of the midsection 1230 above the position of
the plunger 1205.
[0050] FIG. 13A shows a longitudinal cross-section of an optional
connector 1300 which is securely but removably attached to, or
integral to, the first end of the mixing syringes shown in FIGS. 11
and 12. The connector 1300 is essentially a one-way valve that
comprises a body 1305, which is generally cylindrical. The body
1305 comprises a channel 1325 formed within. The inner surface of
the body defining the channel has a tapered portion 1323 which
results in a narrowing of the channel 1325. A stopper 1310 is
positioned in the channel 1325 such that it abuts the inner surface
of the tapered portion 1323. The stopper 1310 is held in place by
two flexible bands 1315 that extend across the stopper and which
are attached to the body 1320. FIG. 13B represents a transverse
cross-section of a connector 1300 along line AA. FIG. 13C is a
connector 1350 similar to 1300 except that the body 1307 is shorter
in length. FIG. 14 shows the configuration of FIG. 13C engaged to
the first end 1353 of a barrel 1355 of a syringe as disclosed in
FIG. 11. Upon engagement of a fluid delivery device to the
connector 1300 or 1350, fluid injected into the mixing syringe
pushes the stopper 1310 down which creates space between the
stopper 1310 and the tapered portion 1323, thereby allowing the
fluid to pass by and into the barrel 1355. As mixing occurs,
contents within the mixing syringe cannot escape, as any pressure
created causes the stopper 1310 to be pushed up into the tapered
portion 1323. Optionally, after mixing, the connector 1350 is
removed from the barrel 1355, leaving an opening out of which mixed
contents can be extruded.
EXAMPLE 1
[0051] Syringe A is a male Luer-lock. Syringe B is a female
Luer-lock having a septum cap disposed thereon and paste components
contained therein.
[0052] (1) Attach a 22-30 gauge needle to Syringe A.
[0053] (2) Draw up an appropriate amount of reconstitution fluid
into syringe A, preferably blood or plasma.
[0054] (3) Plunge needle through the septum cap on syringe B and
inject the reconstitution into syringe B.
[0055] (4) Warm Syringe B for 2-6 minutes in 49 degree Celsius
water bath.
[0056] (5) Remove the septum cap from Syringe B. Remove the needle
from syringe A.
[0057] (6) Attach Syringe A to Syringe B.
[0058] (7) Transfer the contents from Syringe A to Syringe B.
[0059] (8) Transfer the contents from Syringe B to Syringe A.
[0060] (9) Repeat steps (7) and (8) until reconstitution fluid and
paste components are mixed to form a paste of a desired
consistency.
[0061] (10) Use or rewarm the paste.
EXAMPLE 2
[0062] The inventors have discovered that certain mix of gelatin
and DBM sizes which exhibit improved osteogenicity. In a preferred
embodiment, the subject invention is directed to a mixture of
freeze dried DBM and gelatin, where the DBM comprises certain size
ranges. In this example, the paste composition comprises
freeze-dried DBM particles having a size of about 125 microns to
about 850 microns. Preferably still, the DBM particles are about
250 microns to about 500 microns in size, which has exhibited
enhanced osteogenicity. Furthermore, the gelatin in the paste of
this example is about 125 microns to about 710 microns. Preferably
still, the gelatin is about 500 to about 710 microns in size. In
determining the appropriate size ranges, consideration must be
given to dissolution and percolation balance: smaller particles
dissolve better and larger particles provide a more balanced
percolation.
[0063] In an even more preferred embodiment, the paste composition
further comprises and exothermic salt, such as but not limited to,
Magnesium sulfate, Magnesium chloride, Sodium sulfate, and the
like. The addition of the exothermic substance causes the mixture
to heat upon contact with the reconstitution fluid which aids in
the dissolution of the gelatin and other components in the paste
mixture.
[0064] The paste composition can be stored indefinitely at room
temperature and is osteogenic upon reconstitution.
[0065] The teachings of all patents and publications cited
throughout this specification are incorporated by reference in
their entirety to the extent not inconsistent with the teachings
herein.
[0066] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and the scope of the
appended claims.
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