U.S. patent application number 09/352615 was filed with the patent office on 2001-07-19 for microparticulate surgical adhesive.
This patent application is currently assigned to POINT BIOMEDICAL CORPORATION. Invention is credited to SHORT, ROBERT E., YAMAMOTO, RONALD K..
Application Number | 20010008636 09/352615 |
Document ID | / |
Family ID | 24563490 |
Filed Date | 2001-07-19 |
United States Patent
Application |
20010008636 |
Kind Code |
A1 |
YAMAMOTO, RONALD K. ; et
al. |
July 19, 2001 |
MICROPARTICULATE SURGICAL ADHESIVE
Abstract
Flowable polymeric microparticulate surgical adhesive
formulations are provided which can be activated at the site of the
repair to produce cohesive material with tissue bonding properties
to adjacent tissues. The formulation may be activated at the site
of repair by mechanical shear forces, heat, ultrasound, UV, or
other site.
Inventors: |
YAMAMOTO, RONALD K.; (SAN
FRANCISCO, CA) ; SHORT, ROBERT E.; (LOS GATOS,
CA) |
Correspondence
Address: |
REGINALD J SUYAT
FISH & RICHARDSON
2200 SAND HILL ROAD
SUITE 100
MENLO PARK
CA
94025
|
Assignee: |
POINT BIOMEDICAL
CORPORATION
|
Family ID: |
24563490 |
Appl. No.: |
09/352615 |
Filed: |
July 13, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09352615 |
Jul 13, 1999 |
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08639285 |
Apr 25, 1996 |
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5948427 |
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Current U.S.
Class: |
424/426 |
Current CPC
Class: |
C08L 89/00 20130101;
A61L 24/043 20130101; A61L 24/0015 20130101; A61L 24/001 20130101;
C08L 89/06 20130101; A61L 24/0015 20130101; A61L 24/106 20130101;
A61L 24/106 20130101; A61L 24/043 20130101 |
Class at
Publication: |
424/426 |
International
Class: |
A61F 002/00 |
Claims
What is claimed is:
1. A microparticulate surgical adhesive composition comprising
biodegradable polymeric microparticles; which are activatable
in-situ to form a high strength, cohesive material which is
physiologically stable.
2. An adhesive composition according to claim 1 which is
activatable in-situ by rupturing of an impermeable outer shell or
coating of said microparticles to initiate a chemical reaction to
form said cohesive material.
3. An adhesive composition according to claim 1 which is
activatable in-situ by fusion of said microparticles to form said
cohesive material.
4. An adhesive composition according to claim 1 which is
activatable in-situ to form said cohesive material which comprise
channels or pores for tissue integration.
5. An adhesive composition according to claim 1 comprising a
flowable slurry with a physiologically compatible solvent.
6. An adhesive composition according to claim 1 which is
activatable by heat.
7. An adhesive composition according to claim 1 which is
activatable by ultrasound energy.
8. An adhesive composition according to claim 1 which is
activatable by radio frequency or microwave energy.
9. An adhesive composition according to claim 1 which is
activatable by light.
10. An adhesive composition according to claim 1 which is
activatable by mechanical shear.
11. An adhesive composition according to claim 1 which further
comprises a particle bridging component.
12. An adhesive composition according to claim 1 which further
comprises a coating or chemical graft on the surfaces of said
microparticles.
13. An adhesive composition according to claim 1 which further
comprises modified chemical surfaces of the microparticles.
14. An adhesive composition according to claim 1 which further
comprises growth factors or chemotactic factors.
15. An adhesive composition according to claim 1 which further
comprises wound healing agents, anti-infective agents or
anti-inflammatory agents.
16. An adhesive composition according to claim 1 which further
comprises hollow microparticles.
17. An adhesive composition according to claim 1 which further
comprises coated components which are ruptured to initiate
formation of adhesive.
18. An adhesive composition according to claim 1 which further
comprises collagen or gelatin microparticles.
19. An adhesive composition according to claim 1 which further
comprises fibrinogen and factor XIII.
20. An adhesive composition according to claim 1 which further
comprises a biodegradable thermoplastic polymer.
21. A flowable adhesive composition according to claim 1 having a
solids content greater than 20 weight percent.
22. A method for the securement and sealing of tissue by the site
activation of a biodegradable microparticle composition comprising
biodegradable polymeric microparticles, which are activatable
in-situ to form a high strength, cohesive material which is
physiologically stable.
23. A method for the securement and sealing of tissue by the
introduction of a microparticle composition comprising
biodegradable polymeric microparticles, which are activatable
in-situ to form a high strength, cohesive material which is
physiologically stable through an apparatus which activates said
composition as it is delivered to the target tissues.
24. A method for the embolization of biological vessels by the
introduction of a microparticle composition comprising
biodegradable polymeric microparticles, which are activatable
in-situ to form a high strength, cohesive material which is
physiologically stable through a catheter which activates said
composition as it is delivered to the target tissues.
25. A method for fabricating hollow microcapsules by the
introduction of limited crosslinking agent to surfaces of
microspheres, quenching the crosslinking reaction, and extracting
the centers of the microspheres with a solvent which swells the
crosslinked shell and allows extraction of the uncrosslinked
centers.
Description
BACKGROUND OF THE INVENTION
[0001] The invention relates to surgical adhesives, and in
particular to adhesives which are formed by combination or reaction
of their components (hereinafter, "activated") at the wound
site.
[0002] Surgical adhesives have long been of interest for
reconstructing tissues due to the ease of applicability and
combined mechanical securement and sealing function. Early use of a
fibrin based adhesive, while totally biodegradable, was compromised
by poor adhesive strength especially over time as enzyme
degradation rapidly depolymerized the fibrin. Modern forms of
fibrin adhesives incorporate enzyme inhibitors not only for
practical workability, but to retard in-vivo degradation and loss
of strength as described in U.S. Pat. No. 4,298,598. Still, these
fibrin adhesives require the mixing of two components with long
reconstitution times and demonstrate limited and variable working
time before setting. In addition, the use of human pooled blood in
these products has raised concern regarding potential viral
contamination and transmission.
[0003] Synthetic adhesive systems, such as the cyanoacrylates and
cyanobutylates have high adhesive strength, but have poor
degradation properties, with toxic byproducts such as formaldehyde
being formed. Further, these materials are mechanically stiff and
have poor integration properties with healing tissues. The
cyanoacrylate type adhesive systems incorporate almost pure monomer
which is initiated by water to form a high strength polymer. The
rapidly setting adhesive is difficult to apply in some cases,
especially in endoscopic use where the adhesive can set within the
catheter lumen. Synthetic prepolymer approaches such as described
in U.S. Pat. No. 4,804,691 may utilize biodegradable polymer
components, but often rely on toxic components such as isocyanates
and metal catalysts. Small amounts of toxicity may have adverse
effect on the critical tissue to adhesive interface of a surgical
adhesive.
[0004] Collagen and gelatin based adhesive solutions have been
investigated. Early clinical work with the
gelatin-resorcinol-formaldehyd- e adhesive showed problems with
tissue compatibility to the chemical agents and the cumbersome
preparation of the adhesive. The use of a more toxicologically
compatible collagen solution as described in EPA 0466383A1 requires
heating of a collagen solution to partially transform it to
gelatin. When applied heated onto the tissues, the material cools
to form a bond. In this case the adhesive is only held together by
chain entanglement of the collagen/gelatin chains, providing
limited mechanical strength which is easily disrupted during
subsequent hydration and enzymatic action. Stability of the
adhesive material at higher solids content was a performance
limitation.
[0005] A method described in U.S. Pat. No. 5,156,613 describes the
use of a solid collagen filler material which is applied to tissues
while an energy source heats both the tissues and the filler
material as a tissue welding aid. The denaturation of the tissues
and filler, upon cooling provides a mechanical bond. While the
approach utilizes high solids content adhesive, essentially a
solid, the resultant adhesive material is held together by chain
entanglement of the collagen/gelatin chains, limiting mechanical
strength and biodegradation resistance. In addition, the inherent
damage to underlying tissues of tissue welding approaches in
general may prevent use on or near sensitive tissues such as
fragile vasculature, nervous tissue, ocular tissue, and areas of
cosmetic concern such as the face and neck. A similar approach is
described in U.S. Pat. No. 5,209,776 where peptides such as
collagen and albumin are mixed with either a polysaccharide or
polyalcohol to form a viscous solution which can be used as a
sealant or coating. As the coating has no material integrity, it is
a weak flowable gel as described, with the primary utility as a
adjuvant to tissue welding techniques.
SUMMARY OF THE INVENTION
[0006] The present invention describes novel tissue adhesives
comprising a flowable polymeric microparticulate formulation which
can be site activated to produce a cohesive material with tissue
bonding properties to adjacent tissues. When activated, the
material can be used to join tissues, seal tissue junctions, act as
an injectable embolization agent, augment tissues and reinforce
organ walls. The use of microparticulates allows facile
applicability as a powder or paste to tissues, with the
microparticles able to flow into the tissue crevices and set into
the appropriate conformation.
[0007] It is an object of the invention to provide a high solids
content surgical adhesive which provides total biodegradability,
high mechanical integrity, and activation at the delivery site or
wound, which alleviates the problem of delay of application after
mixing reactive components.
[0008] Further objects are to provide a formulation for flowable
systems, to prevent damage to contacting tissues during application
of the adhesive and biodegradation, to control the degradation rate
of the adhesive, and to provide tissue ingrowth features in an
adhesive to provide a gradual load transfer to the healing
tissues.
BRIEF DESCRIPTION OF THE DRAWING
[0009] FIG. 1 shows the activation of the surface of microparticles
to form a solid material by polymer bridging.
[0010] FIG. 2 shows the activation of a polymerization mechanism by
the mixing of encapsulated reagents A and B to form a product
C.
[0011] FIG. 3 shows the formation of a material with channels
formed by activation of a particulate polymer composition.
[0012] FIG. 4 shows activation of a flowable microparticulate
formulation at the tip of a catheter with heat generating elements,
D, to deliver a molten polymer adhesive.
[0013] FIG. 5 shows activation of a flowable microcapsule
formulation at the tip of a catheter with a rotating outer shaft,
E, to spin a rotor, F, in the flow path to mechanically disrupt the
microcapsules and deliver an initiated adhesive.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] The microparticulate adhesive comprises biodegradable
components to allow for natural degradation and progressive
incorporation with newly formed tissue. This is particularly
important for the clinical success of a surgical adhesive as rapid
mechanical failure of the adhesive may lead to clinical problems.
Preferred components are biodegradable polymers including
biopolymers such as collagen, gelatin, elastin, hyaluronic acid,
and fibrin; synthetic degradable polymers such as poly
lactic/glycolic acid polymers and copolymers, polyhydroxybuterate,
and polycaprolactone; and biological polymerization components such
as fibrinogen and factor XIII.
[0015] Biopolymers such as collagen and gelatin in particular
provide a progressive degradation and load transfer to the healing
tissues which would be preferred for clinical efficacy. The tissue
integration of the surgical adhesive with the healing tissues may
be further promoted by the formation of a porous structure by the
microspheres in-situ, thereby allowing tissue ingrowth and
mechanical interlocking. Other components, such as growth factors
and chemotactic agents, may also be incorporated into the adhesive
to further increase tissue incorporation and the performance of the
tissue repair.
[0016] The use of insoluble microparticles in a solvent mixture
greatly reduces viscosity and allows the use of a very high solids
content formulation that is flowable. For example, a typical
collagen or gelatin composition can achieve solids contents up to
approximately 10 to 20 weight % before the viscosity of the polymer
increases to form a non-flowable solid. By constraining the polymer
into discreet, insoluble microparticles and preventing full polymer
mobility, flowable solids contents of approximately 50 weight % can
be achieved. Since the solvent vehicle in a polymeric adhesive,
such as water, does not participate in forming a structural
adhesive, it is important to maximize the amount of structural
polymer that is delivered as an adhesive. Small amounts of reactive
adhesive components or flow enhancers, may be incorporated into the
solvent vehicle for the microparticles, especially if they are of
lower molecular weight to prevent viscosity limitations.
[0017] The use of microparticles or microspheres not only allows
high solids content, flowable formulations, but also allows
activatable components to be packaged within hollow or surface
coated constructs similar to industrial one part adhesives. While
the typical encapsulation of a catalyst in an industrial one-part
adhesive utilizes rigid, fracturable materials such as glass,
silica, and rigid thermoplastics to enhance rupture efficiency,
these types of materials are not toxicologically acceptable for
implantation in tissues. The present invention utilizes
microcapsules fabricated entirely from biodegradable polymers that
can are rupturable by careful control of capsule thickness, and,
optionally, by use of chemical surface stabilization. In one
embodiment, hollow microspheres or microcapsules are fabricated
from biodegradable materials and packed with reactive components
such as synthetic or biological polymerization systems. The
reactive components may be isolated in discreet capsules, which
polymerize to form an adhesive when the capsules are broken by
mechanical shear and mixed, such as at the end of a delivery
catheter. An illustration of this method is shown in FIG. 5. An
example is the packaging of fibrinogen in microcapsules with
separate microcapsules of thrombin. Upon mechanical rupture, the
components react to form a fibrin adhesive. Similarly, reactive
adhesive components may be packaged within water insoluble capsules
and delivered in an non-aqueous solvent to be activated in situ by
hydration. Thus, by activation of the adhesive at a catheter tip at
the tissue site, working time and pot life considerations are
minimized and adhesive kinetics and ultimate properties can be
optimized.
[0018] Activation methods other than mechanical shear can be
utilized with the microcapsules or microparticles. Heat can be used
to flow and/or rupture the particles by tailoring the thermal
transition properties of the particulate materials. An illustration
of that method is shown in FIG. 4. Both biopolymers and
biodegradable synthetic polymers have thermal transitions such as
the glass transition temperature, which can be tailored for use as
adhesive microparticles. Physical methods such as ultrasound can be
used in a combined mechanical/thermal activation method. Radio
frequency and microwave excitation, while having some patient
shielding concerns, may also be utilized to thermally activate or
rupture the microparticles to initiate the adhesive.
[0019] It is important that the activation of the microparticles
trigger reactions which form physiologically stable linkages within
the resultant material. Typical linkages used include covalent
crosslinks either formed chemically or enzymatically, strong ionic
interactions such as chelation, strong hydrophobic interactions, or
inter-chain entanglement of polymers. For high physical strength,
covalent crosslinking and/or chain entanglement are preferred. In
the case of chain entanglement alone, such as the application of a
heat activatable thermoplastic polymer component, it is important
that the glass transition of the polymer be above physiological
temperature to form a stable material. Otherwise, the resultant
material would lack material integrity within the body, as occurs
with non-crosslinked gelatin, for example, with a transition
temperature of about 37.degree. centigrade.
[0020] Besides rupturing the microparticles to release adhesive
components, the particles themselves may physically participate in
the adhesive material. The microparticles or microcapsules are
fabricated from high strength degradable polymers with affinity for
the adhesive components. In a system where microcapsules are
ruptured to mix and initiate a chemical adhesive, the wall
components will be incorporated into the final adhesive material,
acting as particulate reinforcements, similar to glass filled
polymers. The same structural properties which allow the
microcapsule to resist premature rupture during use can be further
tailored to provide structural reinforcement of the adhesive
material, especially controllable by crosslinking the capsule
material for the proper biodegradation rate.
[0021] In some cases, it may not be necessary or desired to rupture
the microparticles. By combining the microparticles with a flowable
component which can be set into a solid, or by activating the
surface of the microparticles, polymer bridges between particles
may be formed to provide structural material from the joined
particles, similar to a sintered polymer. Suitable activation
methods may be used, such as heat to activate a thermoplastic
polymer component or coating of the microparticles. Other particle
bridging components include collagen and gelatin, which will flow
upon controlled heating and can be further enhanced by a
thermoplastic coating or chemical surface graft such as
polylactic/glycolic acid polymers. As a bridging component,
non-encapsulated polymer or reactive components such as
difunctional epoxides reagents may be used to facilitate adhesive
setting. Other particle bridging methods include optically
activatable groups such as acrylate functional materials which may
be incorporated onto the microparticles or formulated as a
non-encapsulated component.
[0022] When significant portions of microparticles remain at least
partially intact, the formation of channels of microparticles occur
in the material. Degradable microparticles may be used which to
rapidly degrade and form a porous network during biodegradation
allowing tissue ingrowth and progressive load transfer to the
healing tissues, which is ideal for preventing failure of the
surgical adhesive repair.
[0023] The degradable microparticles may be fabricated by many
available methods. Dry materials can be pulverized and sieved to
produce irregular solid particles of selected size range. Irregular
particles, while simple to fabricate, tend to pack and clog during
flow at high solids contents. Microspheres, with a smooth outer
surface have less tendency to interlock with other particles,
allowing for increased solids content of a flowable formulation.
Microspheres can be fabricated by a variety of method including
spray drying, coacervation/emulsion methods, and droplet
coagulation. In a preferred method for making hollow microspheres,
a limited amount of cross-linking agent can be applied to solid
microspheres, then the cross-linking reaction is quenched. The
uncrosslinked centers may be extracted with a suitable solvent
which swells the cross-linked shell and dissolves the uncrosslinked
centers.
[0024] Polymers in particular lend themselves to microsphere
fabrication. Polymeric microspheres may be further tailored after
fabrication by chemical crosslinking to control solubility and
biodegradation properties, and also chemically grafted or coated
for chemical activation. Microspheres with hollow cavities may be
used to isolate reactive adhesive components. Such microcapsules
may be formed with single or multiple cavities by methods such as
interfacial deposition, spray drying over a removable core, and the
like. To package the reactive components, they may be formed into
particles and coated during fabrication into microspheres.
Alternatively, some reactive components of low molecular weight may
be incorporated by swelling the prefabricated microcapsules with a
solution of the component and allowing for diffusion into the
microcapsule interior.
[0025] It is preferred that the biodegradable microparticles have
an activatable mechanism to allow in-situ formation of a cohesive
material. Heat can be used to fuse the microparticulate surfaces
together with the degree controlled by the microparticle surface
composition and thermal transition properties. In one method,
gelatin particles are fused together to form a cohesive mass upon
heating at the end of a catheter tip. The gelatin thermal
transition may be altered by the selection of the gelatin molecular
weight, degree of deamidation, the type and extent of side chain
modifications, and the degree of chemical crosslinking with
difunctional chemical agents such as dialdehydes and diisocyanates
or peptide crosslinking agents such as carbodiimides. Less
crosslinked materials show lower temperatures needed for flowing of
the particulates into a cohesive mass. The use of a thermoplastic
synthetic polymer such as polylactides/glycolides co-formulated in
the adhesive increases strength and provides a multiphased
structure to the heat activated adhesive. The physical properties
of such polymers may be selected or tailored by molecular weight,
copolymer content, and plasticizer content. In one embodiment,
thermoplastic degradable polymers such as polylactides,
polyglycolides and glycolide/lactide copolymers, and lactone
polymers may be coated or covalently grafted to the surface of a
protein microsphere, with the resulting microspheres having thermal
bonding properties. Additional material stability can be achieved
by the use of a heat activatable crosslinking component, such as a
difunctional epoxide. Suitable chemical forms include diepoxide
functional polyethylene glycols and polypropylene glycols, with
activation occurring at temperatures ranging from room temperature
to approximately 100 degrees C while demonstrating suitable
toxicology.
[0026] Another method of activation is the use of light initiated
polymerization of co-formulated monomers or activatable
crosslinkers. In one embodiment, the activatable crosslinkers are
chemically grafted to the surface of the biodegradable
microparticles to promote high material integrity. Acrylate
chemical functionality may be grafted onto gelatin microspheres for
light activated polymerization of a particle bridging component
such as acrylate and vinyl terminated polymers. An illustration of
surface bridged particles is shown in FIG. 1.
[0027] Another method of activation is the mechanical disruption of
hollow microspheres to allow mixing of reactive components. An
illustration of such a method is shown in FIG. 2. For a biological
adhesive, for example, fibrinogen and factor XIII formulations form
a useful surgical adhesive system, although with intensive
preparation required and short working time. However, the
encapsulation of the fibrinogen in a biodegradable polymer shell
and formulation with a factor XIII containing solution provides a
formulation readily applied with a catheter incorporating a
mechanical disruption/mixing tip. Upon dispensing, there is
initiation of the fibrin adhesive to form a cohesive material.
Materials having more rapid setting kinetics may be used since
working time is short. Typically, a fibrin based adhesive
incorporates at least 80 units of factor XIII activity per gram of
fibrinogen and small amounts of plasminogen activator inhibitor to
aid shelf life and extend working time, and protease inhibitor to
increase in-situ residence time. With the encapsulation of either
the factor XIII or the fibrinogen monomer, or both, a one component
activatable biological adhesive is produced.
[0028] Similarly, a combination of a synthetic polymerization
initiator and monomer may be sequestered into microencapsulated
materials for activation upon mechanical disruption and mixing.
Examples include polyethylene glycol, polyethylene glycol/lactide
or glycolide copolymers, reacted with polyethylene glycol
diisocyanate, or other reactive difunctional agents. Cyanoacrylate
monomer may be microencapsulated to prevent the initiation of
polymerization by water until delivered at the catheter tip,
thereby preventing setting and blockage in the catheter lumen.
[0029] Furthermore, rapidly degradable microparticles may be
incorporated into the adhesive. Upon degradation of such
microparticles channels or pores will be formed which are
beneficial for tissue in-growth. An illustration of an adhesive
with such channels is shown in FIG. 3.
[0030] The activation of the microparticulate adhesive can be
performed at the surgical repair site by first dispensing the
adhesive and then activating it with either light, heat, radio
frequency, or other form of energy. For endoscopic use, a catheter
with an activation mechanism at the tip is preferred. A concentric
heating element around the catheter tip provides activation that
can be coordinated with the feeding of the microparticles to
dispense an activated adhesive. Similarly, for reactive adhesive
systems where microcapsules are ruptured and mixed, small gear
mechanisms, rotating blades, or narrow orifices provide suitable
mechanical shear for activation. Small ultrasonic transducers may
be incorporated into a catheter, providing both mechanical and
thermal energy to both rupture microcapsules and thermally activate
the material. Similarly, for optical systems, a fiber optic
incorporated into the catheter tip may provide suitable adhesive
activation at the dispensing tip.
EXAMPLE 1
[0031] Gelatin/Hyaluronic Acid Microcapsules Activated by Heat
[0032] Biopolymer microcapsules were prepared containing dyed
mineral oil by means of complex coacervation using the sodium salt
of hyaluronic acid as the anionic polymer. The ratio of ingredients
were as follows:
1 gelatin, type A, 200 bloom 6 parts by wt hyaluronic acid, sodium
salt 1 part water 100 parts mineral oil, dyed 25 parts
[0033] Aqueous dispersions of the polymers were prepared, mixed
together and adjusted to pH of 6.75 while heating to 36 degrees C.
After emulsification of the mineral oil into the dispersion, the pH
was slowly adjusted to 4.80 to stabilize the microcapsules. The
resulting oil-containing microcapsules were retrieved by filtration
and converted to a free flowing powder by solvent exchange with
isopropyl alcohol with subsequent lyophilization.
[0034] The dyed mineral oil contained within the microspheres thus
serving as an active agent analog, the pre-reactant component
consisted of an aqueous slurry prepared at approximately 20% by
weight and adjusted to a basic pH. Microscopic examination of the
slurry revealed discrete multicore microcapsules uniformly
dispersed in a water medium. The slurry was fed to the delivery
site by a syringe pump and activated at the tip of the assembly
through a heated nozzle. The nozzle consisted of a brass tube
spirally wrapped with heater wire, all under a layer of fiberglass
insulation. The nozzle temperature was adjusted by a Variac power
controller applied to the heater coil. The slurry was pumped at
approximately 20 ml/min, and heated to approximately 85 degrees C.
Microscopic examination of the resulting material revealed that the
microcapsules had ruptured and dissolved, releasing the oil
contents from the protective gelatin shell.
EXAMPLE 2
[0035] Gelatin/Hyaluronic Acid Microcapsules Activated by
Ultrasound
[0036] Gelatin microcapsules containing dyed mineral oil as
previously described were prepared in accordance with the first
example. A 20% aqueous slurry was prepared and adjusted to a basic
pH. Using a Heat Systems model 2020XL ultrasonic generator with
standard probe and microtip horn, the slurry was sonicated at a
setting of 5 for approximately 40 seconds. Microscopic examination
of the resulting mixture revealed that the encapsulated oil had
been released from the ruptured polymer capsules.
EXAMPLE 3
[0037] Thrombin Based Adhesive Utilizing Encapsulated Fibrinogen
Activated Mechanically
[0038] Fibrinogen microspheres are prepared by coacervation of an
aqueous dispersion emulsified into mineral oil. Slow dehydration
with the addition of cold isopropyl alcohol yields a fibrinogen
microsphere preparation of approximately 50 micron diameter. The
resulting particles are isolated by centrifugation and washed in
isopropyl alcohol and dried under vacuum. The free flowing
particles are then encapsulated with a light coating of polylactic
acid by spray drying. The particles are suspended in a methylene
chloride dispersion of polylactic acid, in the range of 0.05 to 50
weight percent. The lower concentrations are preferred to form a
thin encapsulating shell. The resulting coated microspheres are
then formulated into a 30 weight percent slurry with phosphate
buffer with thrombin or Factor XIII activity in the ratio of
approximately 100 to 1000 units of Factor XIII activity per gram of
encapsulated fibrinogen. Upon passage of the flowable slurry
through a catheter with a mechanical shearing tip, the fibrinogen
is released and forms a cohesive gel-like material upon reaction
with the thrombin.
EXAMPLE 4
[0039] Gelatin Particulate Based Adhesive Formulation Activated by
Heat
[0040] A flowable gelatin slurry was prepared by first mixing
polyethylene glycol 400, glycerol, and water in the following
proportions:
2 polyethylene glycol 400 0.75 grams glycerol 2.25 grams water 1.00
grams
[0041] To this solution was added 3 grams of gelatin powder having
a grain size no greater than approximately 500 microns to form a 40
weight percent solids slurry. The slurry was fed to the delivery
site using the nozzle system described in the first example. The
slurry was pumped at approximately 3 ml/min and heated to
approximately 100 degrees C. Exiting the nozzle was a highly
viscous, molten gelatin. Upon cooling the material hardened into a
cohesive rubbery mass.
EXAMPLE 5
[0042] Gelatin Microsphere Based Adhesive Formulation with In-Situ
Crosslinking
[0043] A gelatin adhesive formulation was prepared with the
following components:
3 gelatin microspheres, .about.25 to 50 micron diameter 250 mg
polyethylene glycol, dialdehyde, 3400 MW 50 mg deionized water 2
grams
[0044] The mixture was quickly mixed and allowed to set at room
temperature. After one half hour, the material has become a firm
gel. Incubation at 45 degrees C showed a stable gel, unlike the
non-crosslinked control sample which dissolved. Microscopic
examination showed a cohesive mass of microspheres, bridged
together to form the material.
EXAMPLE 6
[0045] Gelatin Particulate Based Adhesive Formulation with Heat
Activated Crosslinking
[0046] A gelatin adhesive formulation was prepared with the
following components:
4 gelatin powder, grain size < 500 microns 9 grams polyethylene
glycol 400 2.25 grams glycerol 7.5 grams polyethylene glycol,
diepoxide, MW3400 200 mg
[0047] The components were stirred together to form a particulate
slurry of approximately 47 weight % solids. With a syringe, the
mixture was extruded through a heating element with a 0.5 cm bore,
heated to approximately 140 degrees C. The extrudate was a uniform
transparent amber color, indicating fusion of the gelatin material.
Once cooled, the material exhibited a cohesive, rubbery properties.
The material was stable when placed in water heated to 40 degrees C
for 17 hours, indicating crosslinking into a stable adhesive
material.
EXAMPLE 7
[0048] Hollow Gelatin Microsphere with Thermoplastic Polymer Graft
Based Adhesive Formulation. Activated by Heat
[0049] Hollow gelatin microspheres were prepared by fabricating
.about.50 micron diameter gelatin microspheres by emulsion of a 200
bloom gelatin dispersion into mineral oil. The microspheres were
recovered after precipitation with cold isopropanol and surface
crosslinked in a mixture of 1,3
dimethylaminopropyl-3-ethylcarbodiimide hydrochloride at 0.67 mg/ml
in 1:14 volume ratio of water:acetone for 12 minutes at room
temperature. The microsphere crosslinking was quenched with a
chilled, acidified water:acetone solution, and washed two time by
centrifugation in acetone. The microspheres were resuspended in
deionized water and heated to 80 degrees C for 4 hours, after which
the microspheres were isolated by centrifugation. Approximately 21%
of the original gelatin weight was remaining, indicating an
extraction of the uncrosslinked center. The resulting microspheres
demonstrated a hollow morphology with very thin walls when examined
microscopically. The gelatin microspheres were then washed in THF
and grafted with caprolactone to form a thermoplastic
polycaprolactone coating, covalently attached to the microsphere
surface. Approximately 50 mg of the dried microspheres were placed
in a reaction mixture containing the following components:
5 0.2 ml triethyl aluminum, 50% in toluene 2.0 grams caprolactone
monomer 8.0 grams tetrahydrofurane
[0050] The reaction was heated for approximately 5 hours at 40
degrees C. The microspheres were isolated from the reaction mixture
by centrifugation at 2400 rpm for 15 minutes. The microspheres were
washed 3 times in fresh THF solvent and recovered as dry, free
flowing particles. When heated on a glass slide at approximately 90
degrees C, the particles fused into a mass of aggregated
microspheres. Under microscopy, the fused mass of material showed a
reticulated morphology.
EXAMPLE 8
[0051] Gelatin Particulate Based Adhesive with Thermoplastic
Binding Agent
[0052] A polymer dispersion of polycaprolactone (Solvay CAPA 650),
7.2 g in 30 ml of methylene chloride was prepared. A separate
dispersion of gelatin, 4.8 g of gelatin was dissolved with light
heating into 11.2 ml of deionized water containing 1.6 g each of
glycerol and PEG 400. A finely divided emulsion was formed by
mixing the two immiscible solutions together with vigorous mixing.
The viscous mixture was then poured on a glass plate, heated to 80
degrees C on a glass plate and allowed to dry at room temperature
overnight. The material was then heated to 80 degrees C to form a
melt, and molded into cylindrical shapes approximately 8.5 cm long
and 0.65 cm in diameter. The resulting flexible rod was then melted
and extruded through a heating tube of 0.2 cm diameter and heated
to approximately 140 degrees centigrade. A molten polymer was
dispensed which cooled into a very cohesive, flexible material with
an appearance similar to the starting material. A 0.134 g specimen
of the dispensed adhesive was placed in deionized water at 40
degrees C for approximately 64 hours to simulate extraction of the
gelatin particle component in-vivo. The specimen was then removed
and allowed to dry. The weight of the specimen was 0.064 g, a
reduction of approximately one half of the weight, which roughly
corresponds to the gelatin and glycerol/PEG components. The
specimen had become white, the color of the caprolactone polymer.
Microscopic inspection of the sample showed that the gelatin had
been dissolved to form a surface porosity, with both interconnected
and non-interconnected pores through the material
cross-section.
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