U.S. patent application number 17/340055 was filed with the patent office on 2021-10-28 for tympanoplastic patch applicator.
The applicant listed for this patent is TYMCURE LTD.. Invention is credited to Eyal AVIRAM, Mazal DAHAN, Nir LILACH, Ariel MARGULIS, Erez ZELNIK.
Application Number | 20210330453 17/340055 |
Document ID | / |
Family ID | 1000005705153 |
Filed Date | 2021-10-28 |
United States Patent
Application |
20210330453 |
Kind Code |
A1 |
MARGULIS; Ariel ; et
al. |
October 28, 2021 |
TYMPANOPLASTIC PATCH APPLICATOR
Abstract
A tympanoplatic patch applicator comprising: a handle disposed
with a deployment control; a deployment stem comprising multiple
nested sleeves connected to the handle; a patch configured to be
affixed to the distal end of the deployment stem via an actuation
filament embedded in the deployment stem; and a filament-based
deployment system controllable by the deployment control, wherein
the deployment stem is configured to position the patch at the
internal side of a perforated tympanic membrane in the middle ear
by introducing the patch into the ear canal and penetrating the
perforated tympanic membrane with the distal end of the deployment
stem, and wherein the filament-based deployment system is
configured to release the patch from the distal end of the
deployment stem, thereby deploying the patch on the internal side
of the perforated tympanic membrane.
Inventors: |
MARGULIS; Ariel; (Ramat
Hasharon, IL) ; DAHAN; Mazal; (Mazkeret Batya,
IL) ; LILACH; Nir; (Kfar Yehoshua, IL) ;
AVIRAM; Eyal; (Herzeliya, IL) ; ZELNIK; Erez;
(Caesarea, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TYMCURE LTD. |
CAESAREA |
|
IL |
|
|
Family ID: |
1000005705153 |
Appl. No.: |
17/340055 |
Filed: |
June 6, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15761103 |
Mar 18, 2018 |
11033383 |
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PCT/IB2016/055575 |
Sep 19, 2016 |
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17340055 |
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62220122 |
Sep 17, 2015 |
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62220283 |
Sep 18, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2002/183 20130101;
A61F 2/18 20130101; A61F 11/002 20130101; A61F 11/004 20130101 |
International
Class: |
A61F 2/18 20060101
A61F002/18 |
Claims
1. A method for deploying a patch at the internal side of a
perforated tympanic membrane with a patch applicator, comprising:
introducing a patch, affixed to the distal end of a distally
disposed stem of said applicator, into an ear canal; penetrating a
perforation of a tympanic membrane with the patch; using a
deployment control provided with a proximally disposed handle of
the applicator to maneuver a deployment system that releases the
patch from the distal end of the stem at the internal side of the
tympanic membrane; and deploying the patch on the internal side of
the perforated tympanic membrane.
2. The method of claim 1, further comprising, while the patch is
positioned at the internal side of the tympanic membrane, aligning
the orientation of the patch with the orientation of the perforated
tympanic membrane by rotating the posture adjustor to rotate a
middle sleeve of the applicator, wherein the patch is secured to a
beveled distal end of the middle sleeve.
3. The method of claim 1, further comprising activating a debriding
actuator disposed with the proximally disposed handle of the
applicator to advance at least one blade to the distal end of the
stem, and rotate the at least one blade about the circumference of
the perforation.
4. The method of claim 3, further comprising collecting the removed
tissue in a niche of the applicator and preventing the removed
tissue from reaching the middle ear.
5. The method of claim 1, wherein deploying comprises pulling the
patch proximally to come into contact with the internal side of the
tympanic membrane by pulling the applicator proximally and securing
the patch to the tympanic membrane using the fresh blood as a
glue.
6. The method of claim 5, wherein using the deployment control to
maneuver the filament-based deployment system comprises decoupling
a cord of the patch from a filament of the applicator in a second
detachment stage.
7. The method of claim 1 wherein said deployment system comprises a
filament-based deployment system controllable by said deployment
control.
8. The method of claim 1, wherein said deployment system comprises
multiple nested sleeves
9. The method of claim 3, wherein said applicator further comprises
a penetration depth controlling mechanism that limits the
penetration depth of the at one blade.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a continuation of U.S. 15/761,103 filed
Mar. 18, 2018, which is a National Phase Application of PCT Patent
Application No. PCT/IB2016/055575 having International filing date
of Sep. 19, 2016, which claims the benefit of priority of U.S.
Provisional Patent Application No. 62/220,283, filed Sep. 18, 2015
and entitled "Tympanoplastic Patch Applicator", and U.S.
Provisional Patent Application No. 62/220,122; filed Sep. 17, 2015
and entitled "Tympanic Membrane Patch." The contents of the above
applications are all incorporated by reference as if fully set
forth herein in their entirety.
TECHNICAL FIELD
[0002] The invention relates to the field of tympanoplasty.
BACKGROUND
[0003] Tympanoplasty is a surgical treatment for repairing a
perforation in the tympanic membrane (also known as the "eardrum")
and defects in one or more of the ossicular bones. Perforation in
the eardrum may be the result of a birth defect, or may be
attributed to ear/nose/throat infections, physical ear injury,
exposure to high noise levels, aging, etc.
[0004] A hole in the eardrum (tympanic membrane perforation) is a
common consequence of an ear injury or an ear infection. These
perforations are often surgically repaired for the sake of
preventing further complications and improve hearing. Young kids as
well as adults and also elderly people can suffer from tympanic
membrane perforation. The exact number of surgical tympanic
membrane perforation (TMP) performed each year is unknown.
[0005] One of the major causes for perforation in the eardrum is
recurrent ear infections. The eardrum (tympanic membrane) becomes
"scarred" with less blood supply than normal tissue. As such, it is
less resistant to infection and eventually, a point may come that
the eardrum, when faced with the stress of an abscess, dissolves
away, leaving a hole in the eardrum.
[0006] Moreover, the eardrum may also become perforated by trauma
caused by foreign objects. Although many traumatic perforations
heal spontaneously, many require repair. Perforations may also
occur following extrusion of pressure equalization tubes placed to
prevent recurrent middle ear infections.
[0007] Chronic Eustachian tube problems cause negative middle ear
pressures that can retract and thin the eardrum so much that it
stops working as a sound collector and threatens to form
cholesteatoma. In these cases, the collapsed sections of eardrum
are removed surgically and repaired.
[0008] A hole in the eardrum leads to hearing loss because the
eardrum no longer has the surface area to collect all of the sound
coming into the ear. The magnitude of hearing loss is directly
related to the size of the perforation.
[0009] An ear with a hole in the eardrum is highly susceptible to
develop infections because as the endogenous barrier against
moisture is perforated. Moisture evaporating from the exposed
linings of the middle ear also tends to humidify the ear canal and
creates a good environment for bacteria and fungi to grow.
[0010] Excessive humidity in the ear canal with recurrent infection
is a common problem for hearing aid users. The hearing aid acts as
a plug that keeps the ear from drying out, and promotes an
environment for infection.
[0011] A small hole in the eardrum can sometimes be repaired by a
procedure called myringoplasty. This is performed by irritating the
margins of the perforation and then giving it some sort of template
to grow across. Often, a small piece of tissue such as a piece of
fat can be placed through the very small perforation and result in
a successful closure.
[0012] Tympanoplasty: If a hole in the eardrum fails myringoplasty
or is too large to repair with myringoplasty, then tympanoplasty is
required. It is often performed by trimming the margins of the
perforation and creating a patch out of the covering of the
temporalis muscle above the ear.
[0013] In tympanoplasty, the graft material has to be held against
the edges of the perforation until healing occurs. This generally
takes a minimum of several weeks. Because the surgical area is too
small to sew the graft into place, the graft and eardrum are
sandwiched together between a mass of gelatin packing placed in the
middle ear beneath the graft and in the ear canal over the
graft.
SUMMARY
[0014] The following embodiments and aspects thereof are described
and illustrated in conjunction with systems, tools and methods
which are meant to be exemplary and illustrative, not limiting in
scope.
[0015] There is provided, in accordance with an embodiment, a
tympanoplatic patch applicator comprising: a handle disposed with a
deployment control; a deployment stem comprising multiple nested
sleeves connected to the handle; a patch configured to be affixed
to the distal end of the deployment stem via an actuation filament
embedded in the deployment stem; and a filament-based deployment
system controllable by the deployment control, wherein the
deployment stem is configured to position the patch at the internal
side of a perforated tympanic membrane in the middle ear by
introducing the patch into the ear canal and penetrating the
perforated tympanic membrane with the distal end of the deployment
stem, and wherein the filament-based deployment system is
configured to release the patch from the distal end of the
deployment stem, thereby deploying the patch on the internal side
of the perforated tympanic membrane.
[0016] In some embodiments, the multiple nested sleeves include an
inner sleeve, wherein the actuation filament is embedded within the
inner sleeve.
[0017] In some embodiments, the multiple nested sleeves include a
middle sleeve encasing the inner sleeve, wherein the patch is
configured to be affixed at the distal end of the middle sleeve,
thereby being affixed at the distal end of the deployment stem.
[0018] In some embodiments, the distal end of the middle sleeve is
serrated to secure the position of the patch and prevent its
rotation with respect to the middle sleeve, wherein a first
activation of the deployment control causes the serrated distal end
of the middle sleeve to withdraw proximally from the patch, thereby
releasing the patch from the distal end of the middle sleeve.
[0019] In some embodiments, the distal end of the middle sleeve is
beveled such that the patch is affixed at an angle that is
non-perpendicular to the longitudinal axis of the middle sleeve,
thereby allowing the orientation of the patch to align with the
orientation of the perforated tympanic membrane.
[0020] In some embodiments, the tympanoplatic patch application
further comprises a posture adjustor configured with the handle,
wherein the posture adjustor is configured to align the orientation
of the patch with the orientation of the perforated tympanic
membrane.
[0021] In some embodiments, the deployment stem is bent, and
further comprises a first spring configured to transfer an
adjustment of the posture adjustor to a corresponding adjustment of
the orientation of the patch over the bend.
[0022] In some embodiments, the filament-based deployment system
comprises an exposable distal end of the inner sleeve, wherein the
patch is disposed with a proximally positioned cord configured to
extend from the distal end of the middle sleeve and engage with the
actuation filament at the exposable distal end of the inner sleeve,
thereby affixing the patch at the distal end of the middle sleeve
when the exposable distal end of the inner sleeve is encased within
the middle sleeve, and wherein a second activation of the
deployment control causes the middle sleeve to withdraw proximally
with respect to the inner sleeve and expose the exposable distal
end, allowing the cord to disengage from the actuation filament to
release the patch from the tympanoplatic patch applicator.
[0023] In some embodiments, the proximal end of the cord comprises
a first bulge, and the distal end of the actuation filament
comprises a second bulge, wherein positioning the first bulge
proximal to the second bulge at the exposable distal end of the
inner sleeve engages the cord with the actuation filament, and
wherein exposing the exposable distal end of the inner sleeve
allows the first bulge to slide distally over the second bulge,
thereby disengaging the cord from the actuation filament.
[0024] In some embodiments, the deployment control is provided with
a safety mechanism configured to prevent an accidental second
activation of the deployment control.
[0025] In some embodiments, the tympanoplatic patch applicator
further comprises a debridement mechanism, comprising: a
debridement actuator configured with the handle, an outer sleeve of
the multiple nested sleeves encasing the middle sleeve, and at
least one protruding blade disposed at a distal end of the outer
sleeve, where the actuator is configured to advance the outer
sleeve relative to the middle sleeve until the blade reaches the
distal end of the deployment stem, rotate the outer sleeve relative
to the middle sleeve, thereby rotating the protruding blade and
causing a debridement of the circumference of the perforation, and
retract the outer sleeve relative to the middle sleeve.
[0026] In some embodiments, the debridement mechanism further
comprises a niche configured to collect debrided tissue.
[0027] In some embodiments, a curvature of the at least one
protruding blade controls a penetration depth of the blade into the
perforation.
[0028] In some embodiments, the debridement mechanism further
comprises a penetration depth controlling mechanism that limits the
penetration depth of the at one protruding blade by limiting the
advancement of the outer sleeve relative to the middle sleeve.
[0029] In some embodiments, the deployment stem is bent, and
wherein the debridement actuator is configured to advance and
retract the outer sleeve relative to the middle sleeve over the
bend.
[0030] In some embodiments, the deployment stem further comprising
a second spring configured to transfer a motion of the debridement
actuator to the outer sleeve over the bent deployment stem, thereby
enabling the advancement and retraction of the outer sleeve
relative to the middle sleeve over the bend.
[0031] In some embodiments, the patch is constructed from a
resilient material that flexes to fit through the perforation, and
restores its original shape when emerging in the middle ear at the
internal side of the tympanic membrane.
[0032] There is provided, in accordance with an embodiment, a
method for deploying a patch at the internal side of a perforated
tympanic membrane, comprising: introducing a patch, affixed to the
distal end of a distally disposed stem of an applicator, into an
ear canal; penetrating a perforation of a tympanic membrane with
the patch; using a deployment control provided with a proximally
disposed handle of the applicator to maneuver a filament-based
deployment system that releases the patch from the distal end of
the stem at the internal side of the tympanic membrane; and
deploying the patch on the internal side of the perforated tympanic
membrane.
[0033] In some embodiments, while the patch is positioned at the
internal side of the tympanic membrane, aligning the orientation of
the patch with the orientation of the perforated tympanic membrane
using a posture adjustor provided with the proximally disposed
handle of applicator.
[0034] In some embodiments, using the posture adjustor comprises
rotating the posture adjustor to rotate a middle sleeve of the
applicator, wherein the patch is secured to a beveled distal end of
the middle sleeve.
[0035] In some embodiments, the method further comprises activating
a debridement mechanism to debride dead tissue from the
circumference of the perforation, and wetting the circumference of
the debrided perforation with fresh blood released by the
debriding.
[0036] In some embodiments, activating the debridement mechanism
comprises using a debriding actuator disposed with the proximally
disposed handle of the applicator to advance at least one
debridement blade to the distal end of the stem, and rotate the at
least one blade about the circumference of the perforation.
[0037] In some embodiments, the method further comprises collecting
the removed tissue in a niche of the applicator, and preventing the
removed tissue from reaching the middle ear.
[0038] In some embodiments, the method further comprises removing
the at least one blade from the perforation by using the
debridement actuator to retract the at least one blade from the
distal end of the applicator.
[0039] In some embodiments, using the deployment control to
maneuver the filament-based deployment system comprises detaching
the patch from a serrated distal tip of the stem in a first
detachment stage.
[0040] In some embodiments, deploying comprises pulling the patch
proximally to come into contact with the internal side of the
tympanic membrane by pulling the applicator proximally, and
securing the patch to the tympanic membrane using the fresh blood
as a glue.
[0041] In some embodiments, using the deployment control to
maneuver the filament-based deployment system comprises decoupling
a cord of the patch from a filament of the applicator in a second
detachment stage.
[0042] There is provided, in accordance with an embodiment, a
biodegradable patch construct having a first thickness and a second
thickness.
[0043] In some embodiments, the second thickness is from 1.2 to 10
times thicker than said first thickness.
[0044] In some embodiments, the biodegradable patch further
comprising an upper portion and a bottom portion.
[0045] In some embodiments, 0.5% to 20% of the surface area of the
upper portion, the surface area bottom portion, or both comprises a
projection.
[0046] In some embodiments, said bottom portion is a uniform
surface.
[0047] In some embodiments, said upper portion comprises a
projection.
[0048] In some embodiments, the surface area of the upper portion,
the surface area of the bottom portion, or both comprises a cell
adhesion molecule.
[0049] In some embodiments, the surface area of the upper portion,
the surface area bottom portion, or both comprises an
anti-inflammatory agent, an antibacterial agent, an antiseptic
agent, a healing enhancing agent or any combination thereof.
[0050] In some embodiments, said patch is freeze-dried.
[0051] In some embodiments, the surface area of the upper portion,
the surface area of the bottom portion, or both comprises a
chondrocyte, a fibroblast, a chondrocyte precursor, a fibroblast
precursor, or any combination thereof.
[0052] In some embodiments, the biodegradable patch comprises a
hydrogel.
[0053] In some embodiments, said hydrogel is selected from the
group consisting of polysaccharides, proteins, polyphosphazenes,
poly(oxyethylene)-poly(oxypropylene) block polymers,
poly(oxyethylene)-poly(oxypropylene) block polymers of ethylene
diamine, poly(acrylic acids), poly(methacrylic acids), copolymers
of acrylic acid and methacrylic acid, poly(vinyl acetate), and
sulfonated polymers.
[0054] In some embodiments, said hydrogel is selected from the
group consisting of alginate, chitosan, pluronic, collagen,
cellulose, agarose and any modification thereof.
[0055] There is provided, in accordance with an embodiment, a kit
comprising a biodegradable patch as disclosed above, suspended in a
sterile wetting solution, and instructions for use in repairing a
perforation in a tympanic membrane in a mammal.
[0056] There is provided, in accordance with an embodiment, a
method of repairing a perforation in a tympanic membrane in a
mammal, the method comprising: providing biodegradable patch of
claim 28 and implanting the biodegradable patch of claim 28 in the
tympanic membrane in the mammal.
[0057] In some embodiments, said biodegradable patch of claim 28 is
the biodegradable patch of any one of claims 29 to 40.
[0058] There is provided, in accordance with an embodiment, a
tympanoplatic patch applicator comprising: a distally disposed
handle configured with a deployment control mechanism; a proximally
disposed deployment stem comprising multiple nested sleeves
connected to the handle; two patches, comprising a distally
disposed patch superimposed with a proximally disposed patch,
wherein the distally disposed patch is configured to be affixed to
the distal end of the deployment stem via a distal filament
embedded in the deployment stem, and wherein the proximally
disposed patch is configured to be affixed to the distal end of the
deployment stem via a proximal filament embedded in the deployment
stem; and a filament-based deployment system controllable by the
deployment control mechanism, wherein the deployment stem is
configured to introduce the two patches into the ear canal and
penetrate the perforated tympanic membrane with at least the
distally disposed patch, and wherein the filament-based deployment
system is configured to: deploy the distally disposed patch at the
internal side of the perforated tympanic membrane in the middle
ear, and deploy the proximally disposed patch at the external side
of the perforated tympanic membrane in the outer ear, thereby
sandwiching the tympanic membrane between the distally disposed
patch and the proximally disposed patch.
[0059] In some embodiments, the multiple nested sleeves include an
inner sleeve and a middle sleeve encasing the inner sleeve, wherein
the distal actuation filament is embedded within the inner sleeve
thereby affixing the distal patch to the distal end of the inner
sleeve, and wherein the proximal actuation filament is embedded
within the middle sleeve, thereby affixing the proximal patch to
the distal end of the middle sleeve.
[0060] In some embodiments, the deployment control mechanism
comprises a first deployment actuator disposed on the handle,
wherein the first deployment actuator is configured to retract and
advance the middle sleeve relative to the inner sleeve.
[0061] In some embodiments, the deployment stem is further
configured penetrate the perforated tympanic membrane with the
proximally disposed patch, retract the proximal patch from the
middle ear through the perforation of the tympanic membrane by
retracting the middle sleeve relative to the inner sleeve using the
first deployment actuator, and position the proximal patch at the
external side of the perforated tympanic membrane in the outer ear,
by advancing the middle sleeve relative to the inner sleeve using
the first deployment actuator, thereby positioning the proximal
patch against the external side of the perforated tympanic
membrane.
[0062] In some embodiments, the deployment control mechanism
comprises a second deployment actuator configured to release the
distal patch and the proximal patch from the deployment stem.
[0063] In some embodiments, the distal patch is disposed with a
distal patch cord configured to engage with the distal filament by
looping the proximal end of the distal patch cord over the distal
end of the distal filament in the inner sleeve, and [0064] wherein
the proximal patch is disposed with a proximal patch cord
configured to engage with the proximal filament by looping the
proximal end of the proximal patch cord over the distal end of the
proximal filament in the middle sleeve, wherein the filament-based
deployment system comprises: a first filament locking boss
configured to anchor the proximal end of the distal filament to the
handle, and a second filament locking boss configured to anchor the
proximal end of the proximal filament to the handle, wherein the
second deployment actuator is connected to the first and second
filament locking bosses, wherein activating the second deployment
actuator retracts the distal and proximal filaments, causing the
distal patch cord to disengage from the distal filament and the
proximal patch cord to disengage from the proximal filament.
[0065] In some embodiments, the deployment control mechanism
comprises a debridement actuator configured to control a
debridement system, comprising: an outer sleeve of the multiple
nested sleeves encasing and connected to the middle sleeve, and at
least one protruding blade disposed at a distal end of the outer
sleeve, wherein the debridement actuator is configured to rotate
the outer sleeve, thereby rotating the protruding blade and causing
a debridement of the circumference of the perforation, wherein the
first deployment actuator is configured to retract and advance the
outer sleeve with the middle sleeve.
[0066] In some embodiments, the debridement mechanism further
comprises a niche configured to collect debrided tissue.
[0067] In some embodiments, a curvature of the at least one
protruding blade controls a penetration depth of the blade into the
perforation.
[0068] In some embodiments, the debridement mechanism further
comprises a penetration depth controlling mechanism that limits the
penetration depth of the at one protruding blade by limiting the
advancement of the outer sleeve relative to the middle sleeve.
[0069] In some embodiments, the penetration depth controlling
mechanism comprises the first deployment actuator.
[0070] In some embodiments, the debridement mechanism further
comprises a power supply, a motor, and a gear wheel mechanically
connecting the motor to the outer sleeve, wherein the debridement
control is configured to control the power supply to activate the
motor and turn the gear wheel, wherein turning the gear wheel
causes the outer sleeve to rotate with the debridement blade.
[0071] In some embodiments, the deployment stem is bent, and
wherein the first deployment actuator is configured to advance and
retract the outer sleeve relative to the middle sleeve over the
bend.
[0072] In some embodiments, the two patches are constructed from a
resilient material that flexes to fit through the perforation, and
restores its original shape when emerging from the perforation.
[0073] There is provided, in accordance with an embodiment, a
tympanoplatic patch applicator comprising: a distally disposed
handle configured with a deployment actuator; a proximally disposed
deployment stem connected to the handle; two patches, comprising a
distally disposed patch superimposed with a proximally disposed
patch, wherein the distally disposed patch is configured to be
affixed to the distal end of the deployment stem, and wherein the
proximally disposed patch is configured to be affixed to the distal
end of the deployment stem; and a deployment mechanism controllable
by the deployment actuator, wherein the deployment stem is
configured to introduce the two patches into the ear canal and
penetrate the perforated tympanic membrane with at least the
distally disposed patch, and wherein the deployment mechanism is
configured to: deploy the distally disposed patch at the internal
side of the perforated tympanic membrane in the middle ear, and
deploy the proximally disposed patch at the external side of the
perforated tympanic membrane in the outer ear, thereby sandwiching
the tympanic membrane between the distally disposed patch and the
proximally disposed patch.
[0074] There is provided, in accordance with an embodiment, a
method for repairing a tympanic membrane, comprising: introduce two
patches, comprising a distally disposed patch superimposed with a
proximally disposed patch, into an ear canal via a deployment stem,
wherein the distally disposed patch is affixed to the distal end of
the deployment stem via a distal filament embedded in the
deployment stem, and wherein the proximally disposed patch is
affixed to the distal end of the deployment stem via a proximal
filament embedded in the deployment stem; penetrating the
perforated tympanic membrane with at least the distally disposed
patch; deploying the distally disposed patch at the internal side
of the perforated tympanic membrane in the middle ear; and deploy
the proximally disposed patch at the external side of the
perforated tympanic membrane in the outer ear, thereby sandwiching
the tympanic membrane between the distally disposed patch and the
proximally disposed patch.
[0075] In some embodiments, the deployment stem comprises an inner
sleeve wherein the distal actuation filament is embedded within the
inner sleeve thereby affixing the distally disposed patch to the
distal end of the inner sleeve, wherein penetrating the perforated
tympanic membrane with at least the distally disposed patch
comprises penetrating the perforated tympanic membrane with at
least the inner sleeve.
[0076] In some embodiments, the deployment stem further comprises a
middle sleeve encasing the inner sleeve, wherein the proximal
actuation filament is embedded within the middle sleeve, thereby
affixing the proximal patch to the distal end of the middle sleeve,
the method further comprising: penetrating the perforated tympanic
membrane with both the distally disposed patch together with the
proximally disposed patch by inserting the middle sleeve encasing
the inner sleeve through the perforation, retracting the proximal
patch from the middle ear through the perforation of the tympanic
membrane by retracting the middle sleeve relative to the inner
sleeve, and positioning the proximal patch at the external side of
the perforated tympanic membrane in the outer ear.
[0077] In some embodiments, the method further comprises retracting
the deployment stem until the distally disposed patch is flush with
the internal side of the perforated tympanic membrane, thereby
deploying the distally disposed patch.
[0078] In some embodiments, the method further comprises advancing
the middle sleeve relative to the inner sleeve until the proximally
disposed patch is flush against the external side of the perforated
tympanic membrane, thereby deploying the proximally disposed
patch.
[0079] In some embodiments, the distally disposed patch is disposed
with a distal patch cord configured to engage with the distal
filament by looping the proximal end of the distal patch cord over
the distal end of the distal filament in the inner sleeve, and
wherein the proximally disposed patch is disposed with a proximal
patch cord configured to engage with the proximal filament by
looping the proximal end of the proximal patch cord over the distal
end of the proximal filament in the middle sleeve, the method
further comprising exerting a tension on the distal and proximal
filaments to disengage the distal patch cord from the distal
filament and the proximal patch cord from the proximal filament,
and release the distally disposed patch and the proximally disposed
patch from the deployment stem.
[0080] In some embodiments, the method further comprises, prior to
deploying the distally disposed patch and the proximally disposed
patch, performing a debridement of a circumference of the
perforation of the tympanic membrane, wherein deploying the
distally disposed patch and the proximally disposed patch further
comprises gluing the distally disposed patch and the proximally
disposed patch to the perforated tympanic membrane using blood
released from the debridement.
[0081] In some embodiments, the method further comprises collecting
debrided tissue resulting from the debridement.
[0082] In some embodiments, performing the debridement comprises:
penetrating the perforated tympanic membrane with an outer sleeve
encasing the middle sleeve and the inner sleeve, wherein the outer
sleeve is disposed with a debridement blade, rotating the outer
sleeve, thereby rotating the debridement blade about the
circumference of the perforation, and evacuating the outer and
middle sleeves from the middle ear by retracting the outer sleeve
together with the middle sleeve through the perforation.
[0083] In some embodiments, the method further comprises
controlling a penetration depth of the at one protruding blade by
limiting the advancement of the outer sleeve relative to the inner
sleeve.
[0084] In addition to the exemplary aspects and embodiments
described above, further aspects and embodiments will become
apparent by reference to the figures and by study of the following
detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0085] Exemplary embodiments are illustrated in referenced figures.
Dimensions of components and features shown in the figures are
generally chosen for convenience and clarity of presentation and
are not necessarily shown to scale. The figures are listed
below.
[0086] FIGS. 1A-1I, show various views of a tympanoplatic patch
applicator, in accordance with an embodiment;
[0087] FIGS. 2A-2F show various views of the tympanoplatic patch
applicator of FIGS. 1A-1I in an initial deployment stage, in
accordance with an embodiment;
[0088] FIGS. 3A-3F show various views of the tympanoplatic patch
applicator of FIGS. 1A-1I in a follow-up deployment stage, in
accordance with an embodiment;
[0089] FIGS. 4A-4F show various views of the tympanoplatic patch
applicator of FIGS. 1A-1I in another follow-up deployment stage, in
accordance with an embodiment;
[0090] FIGS. 5A-5C show various views of a deployed tympanoplatic
patch, in accordance with an embodiment; and
[0091] FIGS. 6A-6C show various views of a tympanoplatic patch, in
accordance with an embodiment;
[0092] FIGS. 7A-7F show multiple exemplary embodiments of a
tympanic patch;
[0093] FIGS. 8A-8F show multiple views of a tympanoplatic patch
applicator, in accordance with another embodiment; and
[0094] FIGS. 9A-9H illustrate a method for deploying two patches
using the applicator of FIGS. 8A-8E.
DETAILED DESCRIPTION
[0095] Disclosed herein is a tympanoplatic patch applicator
configured for transcanal approach, and a method for operating the
same.
[0096] The applicator may introduce at least one biocompatible, and
optionally biodegradable patch through a perforation in the
tympanic membrane, and deploy the patch over the perforation from
the inner side of the tympanic membrane--inside the middle ear.
Optionally, the applicator includes a debridement mechanism that
removes dead tissue from the circumference of the perforation, wets
the circumference with fresh blood, and collects the removed tissue
to prevent it from reaching the middle ear.
[0097] Reference is now made to FIGS. 1A-1I, which show various
views of a tympanoplatic patch applicator 100, in accordance with
an embodiment. FIG. 1A shows a side view of applicator 100 and
FIGS. 1B-1C show two top views of applicator 100. FIG. 1D shows a
side view similar to FIG. 1A, and FIG. 1E shows a detail of section
A of FIG. 1D.
[0098] Applicator 100 generally includes a proximally disposed
handle 102 configured with a deployment control, such as a button
134 moveable within a niche 132. Handle 102 may be connected to a
distally disposed deployment stem 104 which extends from handle
102, and may be operated so as to deploy a biocompatible optionally
biodegradable patch 108 over a perforation in the tympanic
membrane. Optionally, patch 108 may be affixed to the distal end of
deployment stem 104 via an actuation filament 126 embedded in the
deployment stem 104, and will be described in greater detail below.
An actuator 114 and actuator 116 may be provided at the proximal
end of stem 104 connecting to the distal end of handle 102 for
controlling the deployment of patch 108.
[0099] Stem 104 may position patch 108 at the internal side of a
perforated tympanic membrane 142 in the middle ear by introducing
patch 108 into the ear canal and penetrating the perforated
tympanic membrane with the distal end of the deployment stem 104,
such as illustrated in FIG. 1F. A deployment mechanism provided
with applicator 100, such as may be filament-based, may release
patch 108 from the distal end of deployment stem 104 while it's
positioned at the internal side of the tympanic membrane, to deploy
the patch 108 on the internal side of the perforated tympanic
membrane.
[0100] The deployment control, provided with proximally disposed
handle 102 of applicator 100, may be used by a surgeon to maneuver
the filament-based deployment system to release patch 108 from the
distal end of applicator 100 at the internal side of the tympanic
membrane. Thus, patch 108 may be deployed on the internal side of
the perforated tympanic membrane using the proximally disposed
deployment control provided on handle 102.
[0101] Button 134 may have three positions within niche 132: A
distal position at the beginning of the deployment, shown in FIGS.
1A-1C and 2A-2C, a middle position that implements a first stage
for releasing patch 108 from stem 104, shown in FIGS. 3A-3C, and a
proximal position that implements a second stage for releasing
patch 108 from stem 104, shown in FIGS. 4A-4C.
[0102] Referring to FIG. 1G, stem 104 may be include multiple
nested sleeves and substantially concentric cylindrical sleeve,
such as an inner sleeve 118, encased within a middle sleeve 120,
which is encased within an outer sleeve 122. The multiple sleeves
may be telescoping, and may slide longitudinally with respect to
each other, allowing each sleeve to advance and retract
accordingly.
[0103] Optionally, patch 108 is affixed, or supported, at the
distal end of middle sleeve 120 encasing inner sleeve 118, thereby
being affixed to, or supported at, the distal end of the deployment
stem 104. Referring to FIG. 1F, a detailed view of the distal end
of middle sleeve 120 is shown. Optionally, the distal end 122b of
middle sleeve 120 is serrated to secure the position and/or
orientation of patch 108 at distal end 122b, and prevent or reduce
its rotation with respect to the middle sleeve 120.
[0104] Optionally, the distal end 120b of middle sleeve 120 is
beveled, or cut at an angle, such that patch 108 is affixed at an
angle that is non-perpendicular to the longitudinal axis of middle
sleeve 120. This may allow aligning the orientation of the patch
108 with the posture, or orientation, of the perforated tympanic
membrane.
[0105] Optionally, inner sleeve 118 extends along the full length
of stem 104, serving as its rigid core. Inner sleeve 118 may be
bent, resulting in a corresponding bend in stem 104 at an area
denoted 106, shown in FIG. 1A, allowing the distal end of stem 104
to be at a different height than the proximal end of handle 102.
Bend 106 may improve a surgeon's control during the deployment of
patch 108 by preventing or reducing an obstruction of the line of
vision to the distal end of stem 104 due to the surgeon's hand
holding the applicator 100 by handle 102. Thus, when the surgeon
grasps handle 102 and inserts stem 104 into a patient's ear canal,
the handle 102 and the surgeon's hand do not block his or her view
of the canal's internals.
[0106] Referring to FIG. 11, a posture adjustor, such as a second
actuator 114, may be configured with handle 102 and used to align
the orientation of patch 108 with the orientation of the perforated
tympanic membrane. A middle sleeve actuator 120a, comprising a tube
disposed between second actuator 114 at handle 102 and a proximal
side of bend 106, may convey a rotational motion of actuator 114 to
middle sleeve 120 over bend 106. In one implementation, stem 104 is
provided with an inner spring 130 that mechanically connects middle
sleeve actuator 120a to middle sleeve 120, to allow transferring an
adjustment of the posture adjustor, such as a rotation of actuator
114, to a corresponding adjustment of the orientation of patch 108
over the bend 106. It may be appreciated that other suitable
mechanical elements structured to convey a rotational motion over a
bend may be used.
[0107] A first activation of the deployment control 134, such as
moving button 134 from a distal position to a middle position
within niche 132, may cause a slight retraction of middle sleeve
120 relative to inner sleeve 118, such as may range from 3 to 7
millimeters (mm). This may cause the serrated distal end 120b of
the middle sleeve 120 to withdraw proximally from patch 108,
releasing the tension that the serrated end 120b of middle sleeve
120 applies to patch 108, thereby releasing patch 108 from the
distal end of the middle sleeve 120. This release may allow the
surgeon to position patch 108 in place, while evacuating the tip of
middle sleeve 120 from the perforation, serving to enhance the
visibility of the perforation by the surgeon.
[0108] Referring to FIG. 1H, a detailed cross-sectional view of the
base of handle 102 is shown, illustrating a portion of the
filament-based deployment system controllable by deployment control
134. Optionally, the actuation filament 126 is embedded within
inner sleeve 118 of stem 104. Inner sleeve 118 may extend through
to handle 102. Filament 126 may be anchored or secured to handle
102 at its proximal area, for example using glue 140 disposed
around the proximal tip of filament 126, or using any other
mechanical means. Filament 126 may be a biocompatible fiber-based
thread, such as nylon thread, metallic wire, or other suitable
material that allows attaching patch 108 to device and exert a
tension to pull patch 108 proximally.
[0109] The filament-based deployment system may include an
exposable distal end of the inner sleeve 118, such as a window of a
side cutout in its wall, along a length denoted 118a. Responsive to
a rotation or sliding motion of middle sleeve 120 causing inner
sleeve 118 to no longer be encased by middle sleeve 120, the inside
of inner sleeve 118 may be exposed at exposable distal end
118a.
[0110] Patch 108, also shown in FIGS. 6A-6C from various angles, is
optionally composed of a disc 136 and a securing mechanism 138. In
the embodiment shown in the figures, securing mechanism 138 is a
proximally positioned cord 138b threaded through a hole, optionally
central, in disc 136; the cord may have a wider distal end 138a
that secures it from a distal side of the disc, and a bulgy
proximal end 138c. Disc 136 may have a diameter of 3 to 10
millimeters, and a thickness of 0.1 to 1 millimeters, as one
example. Cord 138b may be between 5 to 50 millimeters long, as one
example. Optionally, patch 108 is constructed from a resilient
material that flexes to fit through the perforation, and restores
its original shape when emerging in the middle ear at the internal
side of the tympanic membrane.
[0111] Reference is now made to FIG. 1F which shows a cross section
of the distal tip of stem 104. Patch 108 may be secured at a distal
end of stem 104 as follows: Cord 138b may extend from the distal
end of the middle sleeve 120 to the exposable distal end 118a of
the inner sleeve 118 where it engages with actuation filament 126.
Actuation filament 126 may have a bulgy distal end 126a. The
engagement may be implemented by positioning bulge 138c of cord
138b proximal to bulge 126a of filament 126. When middle sleeve 120
covers exposable distal end 118a, bulgy distal end 138c of cord
138b is prevented from sliding over bulge 126a of actuation
filament 126, securing bulgy distal end 138c at sleeve section
118a. Thus, when middle sleeve 120 encases the exposable distal end
118a of inner sleeve 118, patch 108 is affixed at the distal end of
the middle sleeve 120.
[0112] A second activation of the deployment control 134, such as
moving button 134 from a middle position to a proximal position
within niche 132, may cause middle sleeve 120 to withdraw
proximally with respect to the inner sleeve 118 and expose the
exposable distal end 118a, allowing bulge 138c to slide distally
over bulge 126a and exit the inner sleeve through its distal end.
This disengages cord 138b from actuation filament 126 and release
patch 108 from the tympanoplatic patch applicator 100.
[0113] Optionally, the deployment control is provided with a safety
mechanism configured to prevent an accidental second activation of
the deployment control. The safety mechanism may be implemented as
a stopper, such as a small protrusion or step within niche 132 that
requires moving button 134 sideways before moving from the middle
to the proximal positions.
[0114] Reference is now made to FIGS. 2D-2F which illustrate a
debridement mechanism of applicator 100, in accordance with an
embodiment. FIG. 2D shows a side view of applicator 100; FIG. 2E
shows a detailed view of section B of FIG. 2D; and FIG. 2E shows a
detailed cross-sectional view of blades 110a-b penetrating
perforation 142a of the tympanic membrane 142. The debridement
mechanism may include outer sleeve 122, outer sleeve actuator 116
disposed with handle 102, and at least one protruding blade 110
disposed at a distal end of the outer surface of outer sleeve 122.
Optionally, the at least one protruding blade 110 is implemented by
two protruding, curved blades 110a-b. The curvature of blades
110a-b may control a penetration depth of the blades 110a-b into
the perforation.
[0115] Outer sleeve actuator 116 may be a tube disposed between
handle 102 and a proximal side of bend 106, and may control the
advancement and retraction of outer sleeve 122 to and from the
distal end of stem 104, thereby controlling the debridement
mechanism. Optionally, actuator 116 may convey motion to the outer
sleeve 122 over bend 106, such as via an outer spring 128, as shown
in FIG. 1G, or other suitable mechanical element structured to
convey motion over a bend. Outer spring 128 may be disposed on stem
104 and may mechanically connect actuator 116 to outer sleeve 122
via a connecting ring 124. Spring 128 may transfer a motion, such
as an advancement, retraction, or rotation of the debridement
actuator 116 to outer sleeve 122 over the bend 106 of deployment
stem 104, thereby enabling the advancement and retraction of the
outer sleeve 122 relative to the middle sleeve 120 over the bend
106. This allows actuator 116 to control the debridement mechanism
over bend 106.
[0116] Referring to FIG. 2D, advancing actuator 116 distally away
from actuator 114 at the proximal base of stem 104 may advance
outer sleeve relative 122 to the middle sleeve 120 until blade(s)
110a-b reach the distal end of the deployment stem 104, as shown in
FIG. 2E, until blades 110a-b and come into contact with the
circumference of the perforation, as illustrated in FIG. 2F.
Rotating actuator 116 may rotate outer sleeve 122 relative to the
middle sleeve 120, thereby rotating the protruding blade(s) 110a-b
and causing a debridement of the circumference of the perforation.
Retracting actuator 116 may retract outer sleeve 122 relative to
the middle sleeve 120, retracting blades 110a-b once the
debridement has been completed.
[0117] Optionally, the debridement mechanism further comprises a
niche for collecting debrided tissue. For example, the area
delimited between the curvature of at least one of blades 110a-b
and the outer surface of outer sleeve 122 may form the niche where
debrided tissue may collect during the debridement, preventing this
tissue from falling into the middle ear.
[0118] Optionally, the debridement mechanism includes a penetration
depth controlling mechanism that limits the penetration depth of
blades 110a-b by limiting the advancement of outer sleeve 122
relative to the middle sleeve 120. For example, the penetration
depth controlling mechanism may be implemented by ring 150, shown
in FIG. 1G. Ring 150 may block the distal extension of outer sleeve
122 by engaging with the inner surface of actuator 116 as actuator
116 is pushed distally, preventing blades 110a-b from penetrating
too deeply into the perforation and thereby preventing any further
damage to the tympanic membrane by blades 110a-b. For example, ring
150 may prevent outer sleeve 122 from extending distally beyond
middle sleeve 120.
[0119] The following steps describe a method for deploying a
tympanoplatic patch at the internal side of a perforated tympanic
membrane using applicator 100:
[0120] Step 1: Referring to FIGS. 1A-1F, when actuator 116 is
positioned flush with actuator 114 at the distal end of handle 102,
outer sleeve 122 is retracted, exposing middle sleeve 120 with
patch 108 affixed to serrated distal end 120b, and comprising the
distal end of distally disposed stem 104 of applicator 100. Thus
exposed, patch 108 may be introduced into a patient's ear canal by
inserting the distal end of stem 104 into the ear canal.
[0121] Step 2: The distal end of stem 104 may be progressed therein
until patch 108 penetrates through the perforation 142a in the
tympanic membrane 142. Patch 108, constructed from a resilient
material, flexes to fit through the perforation and restores its
original disc shape when emerging in the middle ear, at the distal
side of the tympanic membrane.
[0122] The deployment control, provided with proximally disposed
handle 102 of applicator 100, may be used to maneuver the
filament-based deployment system that releases patch 108 from the
distal end of stem 104 at the internal side of the tympanic
membrane, and the patch may be deployed on the internal side of the
perforated tympanic membrane, as follows:
[0123] Step 3: If needed, while patch 108 is positioned at the
internal side of the tympanic membrane, the posture of patch 108
may be adjusted to align the orientation of patch 108 with the
orientation of the perforated tympanic membrane 142 by using a
posture adjustor, implemented by second actuator 114 provided with
proximally disposed handle 102. Rotating the posture adjustor 114
rotates middle sleeve 120 of applicator 100 through a rotation of
inner spring 130. Since patch 108 is secured to beveled and
serrated distal end 120b of the middle sleeve 120, rotating sleeve
120 adjusts the posture of patch 108, accordingly.
[0124] Reference is not made to FIGS. 2A-2F, which show various
views of the tympanoplatic patch applicator of FIGS. 1A-1I in an
initial deployment stage, in accordance with an embodiment. FIGS.
2A-2F show a debridement mechanism that may be activated to debride
dead tissue from the circumference of perforation 142a. As a
result, the circumference of the debrided perforation may be wetted
with fresh blood released by the debriding. The debridement may be
activated, as follows:
[0125] Step 4: To activate the debridement mechanism, debriding
actuator 116, disposed with the proximally disposed handle 102 of
applicator 100, may be used to advance at least one debridement
blade, such as blades 110a-b, to the distal end of stem 104, as
follows: outer sleeve 122 may be advanced distally by grasping and
pushing actuator 116, positioned at the proximal base of stem 104,
distally. As shown in FIGS. 1G and 1I, actuator 116 is attached to
outer spring 128 which is, in turn, attached to outer sleeve 122
via a ring 124. Thus, pushing first actuator 116 distally away from
actuator 114 causes outer spring 128 to be pushed distally, which
causes outer sleeve 122 disposed with blades 110a-b to be extended
distally, and encase the distal end of middle sleeve 122. This
positions blades 110a-b flush with the distal end of stem 104 for
debridement of the tympanic membrane.
[0126] Step 5: Positioned thus, rotating first actuator 116 rotates
outer sleeve 122 which rotates blades 110a-b about the
circumference of the perforation 142a, causing a debridement of the
perforated tympanic membrane 142.
[0127] Step 6: The removed tissue may be collected in a niche of
applicator 100, formed between curved blades 110a-b and sleeve 122,
preventing the removed tissue from reaching the middle ear.
[0128] Reference is now made to FIGS. 3A-3F which show various
views of the tympanoplatic patch applicator of FIGS. 1A-1I in a
follow-up deployment stage, in accordance with an embodiment.
[0129] Step 7: Referring to FIGS. 3A-3C, the at least one blade
110a-b may be removed from the perforation by using the debridement
actuator 116 to retract the at least one blade from the distal end
of the applicator 100, as follows: outer sleeve 122 may be
retracted by pulling actuator 116 proximally towards actuator 114
causing outer sleeve 122 to retract, removing blades 110a-b from
perforation 142a. This is illustrated in the contrast between FIG.
2A, which shows actuator 116 positioned distally from actuator 114
with a gap therebetween, and resulting in the advancement of outer
sleeve 122, versus FIG. 3A, which shown actuator 116 flush with
actuator 114 at the proximal base of stem 104, and resulting in the
retraction of outer sleeve 122.
[0130] Additionally, the deployment control, comprising button 134
and niche 132, may be used to maneuver the filament-based
deployment system and detach patch 108 from serrated distal tip
120b of stem 104 in a first detachment stage, as follows:
[0131] Step 8: Referring to FIGS. 3A-3F, button 134 may be moved
from the distal position in niche 132, as shown in FIGS. 1A-1C, to
the middle position in niche 132, as shown in FIGS. 3A-3C, causing
serrated tip 120b of middle sleeve 120 to detach from patch 108 and
release the applied tension, thus leaving patch 108 attached to
applicator 100 only by the engagement of cord 138b with filament
126. FIG. 3E, which is a detailed view of section D of FIG. 3D,
shows patch 108 in the first stage of detachment from applicator
100.
[0132] Step 9: Referring to FIG. 3F, the deployment of patch 108
may continue by pulling the entire applicator 100 proximally,
causing inner sleeve 118 to be retracted proximally. This proximal
motion causes patch 108 to be pulled proximally until it comes into
contact with the internal side of the tympanic membrane 142. Patch
108 may then be secured to the tympanic membrane using the fresh
blood, released by the debridement, as a glue. inner sleeve 118 may
then be retracted by pulling applicator 100 proximally.
[0133] Reference is now made to FIGS. 4A-4F which show various
views of the tympanoplatic patch applicator of FIGS. 1A-1I in a
follow-up deployment stage, in accordance with an embodiment. The
deployment control may be used to maneuver the filament-based
deployment system to decouple cord 138b of patch 108 from filament
126 of applicator 100, in a second detachment stage:
[0134] Step 10: Referring to FIGS. 4A-4F, button 134 may be moved
from the middle position in niche 132, as shown in FIGS. 3A-3C, to
the proximal position in niche 132, as shown in FIGS. 4A-4C,
causing middle sleeve 120 to withdraw proximally with respect to
the inner sleeve 118 and expose the exposable distal end 118a,
allowing bulge 138c to slide distally over bulge 126a and exit the
inner sleeve through its distal end. This disengages cord 138b from
actuation filament 126 and releases patch 108 from the
tympanoplatic patch applicator 100, comprising the second
detachment stage. As can be seen in FIG. 1I, inner spring 130,
mechanically connects middle sleeve actuator 120a to middle sleeve
120, and button 134 is mechanically connected to middle sleeve
actuator 120a within handle 102, thus a proximal motion by button
134 may cause a corresponding proximal motion of middle sleeve
actuator 120a, retracting middle sleeve 120 with respect to inner
sleeve 118, accordingly. This exposes distal end 118a, allowing
cord 138b to disengage from filament 126. Reference is now made to
FIGS. 5A-5C which, taken together, show patch 108 after it has been
released from applicator 100. Fresh blood (not shown) released as a
result of the debridement of the perforation may serve to secure
patch 108 in place, attached to the inner side of the tympanic
membrane and covering the perforation. Optionally, the surgeon may
wait several minutes prior to releasing patch 108 from applicator
100, to enable the blood to at least partially coagulate and
essentially glue the patch to the inner side of the tympanic
membrane. Alternatively, biological glue may be injected to the
interface between patch 108 and the inner side of the tympanic
membrane before contact between the two is made. This may be
performed using an injection channel in stem 104 (not shown).
[0135] Following the above procedure, and over a typical period of
several weeks, new cells may grow at the circumference of the
perforation, slowly closing the perforation. The proximal side of
patch 108 may serve as a bedding for this cellular growth. Patch
108 may eventually degrade leaving a fully, repaired tympanic
membrane without any external remnants.
[0136] Reference is now made to FIGS. 7A-7F, which show multiple
exemplary embodiments of a tympanic patch, such as any of patches
108, and 808P and 808D described below.
[0137] The present invention discloses, in one embodiment, a
biodegradable patch construct having a first thickness and a second
thickness. Optionally, disclosed herein a unitary biodegradable
patch construct having a first thickness and a second thickness.
Optionally, a biodegradable patch comprises hydrogel. Optionally, a
biodegradable patch consists a hydrogel or a combination of
hydrogels.
[0138] "hydrogel", in some embodiments, is a substance formed when
an organic polymer (natural or synthetic) is set or solidified to
create a three-dimensional open-lattice structure that entraps
molecules of water or other solution to form a gel. The
solidification can occur, e.g., by aggregation, coagulation,
hydrophobic interactions, temperature change, pH change or
cross-linking. The hydrogels employed in this invention rapidly
solidify to keep the cells evenly suspended within a mold until the
gel solidifies. The hydrogels are also biocompatible, e.g., not
toxic, to cells, e.g., cells suspended in the hydrogel, or in the
surrounding membrane.
[0139] Any hydrogel composition known to one skilled in the art is
encompassed within the invention, e.g., any of the hydrogel
compositions disclosed in the following reviews: Graham, 1998, Med.
Device Technol. 9(1): 18-22; Peppas et al, 2000, Eur. J. Pharm.
Biopharm. 50(1): 27-46; Nguyen et al, 2002, Biomaterials, 23(22):
4307-14; Henincl et al, 2002, Adv. DrugDeliv. Rev 54(1): 13-36;
Skelhorne et al, 2002, Med. Device. Technol. 13(9): 19-23;
Schmedlen et al, 2002, Biomaterials 23: 4325-32; all of which are
incorporated herein by reference in their entirety.
[0140] Optionally, the patch comprises biodegradable and
biocompatible polymers. Optionally, a biodegradable polymer and/or
biocompatible polymer is a hydrogel. Optionally, the biodegradable
and biocompatible polymers based patch comprises: polysaccharides,
proteins, polyphosphazenes, poly(oxyethylene)-poly(oxypropylene)
block polymers, poly(oxyethylene)-poly(oxypropylene) block polymers
of ethylene diamine, poly(acrylic acids), poly(methacrylic acids),
copolymers of acrylic acid and methacrylic acid, poly(vinyl
acetate), sulfonated polymers, or any combination thereof.
Optionally, the biodegradable biocompatible patch comprises:
alginate, chitosan, pluronic, collagen, agarose, gelatin, cellulose
or any combination thereof. Optionally, the biodegradable
biocompatible patch comprises of chemical and physical
modifications of these polymers.
[0141] A "hydrogel-cell composition" is a suspension of a hydrogel
comprising cells. These cells can be isolated directly from a
tissue source or can be obtained from a cell culture. A "tissue" is
a collection or aggregation of particular cells embedded within its
natural matrix, wherein the natural matrix is produced by the
particular living cells.
[0142] Optionally, a suitable polymer hydrogel according to the
invention is one that is biologically compatible and non-cytotoxic.
Optionally, a suitable polymer hydrogel according to the invention
is one that is formed through controllable crosslinking (gelation).
Optionally, a suitable polymer hydrogel according to the invention
is one that is compatible with viability of cells suspended in a
solution.
[0143] Optionally, provided herein a biodegradable patch construct
("patch" or "construct") having a first thickness and a second
thickness. Optionally, provided herein a biodegradable patch
comprising an upper portion and a bottom portion. In some
embodiment, a portion as used herein is synonymous with "surface".
Optionally, the second thickness is from 1.2 to 100 times thicker
than said first thickness. Optionally, the second thickness is from
1.2 to 50 times thicker than said first thickness. Optionally, the
second thickness is from 5 to 60 times thicker than said first
thickness. Optionally, the second thickness is from 3 to 25 times
thicker than said first thickness.
[0144] Optionally, the second thickness is a result of a projection
from the upper portion. Optionally, the second thickness is a
result of a projection from the bottom portion. Optionally, the
second thickness is a result of projections from both the upper and
bottom portions (see the crossed lines in the patch of FIG. 7E).
Optionally, the second thickness results from thickening of a
segment of the upper portion, the bottom portion, or both.
Optionally, the second thickness provides structural support for
the patch. Optionally, the second thickness enables the patch be
present in a folded position and in an open position (as further
described herein). Optionally, the second thickness renders the
patch fully open by default. Optionally, a patch as described
herein is in an open configuration unless it is attached or
contained within a patch-tympanic membrane insertion device.
Optionally, a patch as described herein is in an open configuration
unless it is associated with a patch-tympanic membrane insertion
device. Optionally, the bottom portion is portion which is adapted
or configured to face the tympanic membrane. Optionally, the bottom
portion is the tympanic membrane portion of the patch.
[0145] Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 3
in FIG. 7C. Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 4
in FIG. 7C. Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 3
in FIG. 7C and at least one projection such as element 4 in FIG.
7C. Optionally, a patch of the invention comprises a first
thickness such as element 1 in FIG. 7C.
[0146] Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 3
in FIG. 7F. Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 4
in FIG. 7F. Optionally, a patch of the invention comprises a second
thickness in the form of at least one projection such as element 3
in FIG. 7F and at least one projection such as element 4 in FIG.
7F. Optionally, a patch of the invention comprises a first
thickness such as element 1 in FIG. 7F. Optionally, a first
thickness is the base thickness of the patch (element 1 of FIGS. 7C
and 7F). Optionally, a second thickness provides physical support
to the patch. Optionally, a second thickness provides attachments
means to the tympanic membrane such as element 3 in FIG. 7C.
[0147] Optionally, 0.1% to 20% of the surface area of the upper
portion, the surface area bottom portion, or both comprises a
projection. Optionally, 0.05% to 10% of the surface area of the
upper portion, the surface area bottom portion, or both comprises a
projection. Optionally, 0.5% to 20% of the surface area of the
upper portion, the surface area bottom portion, or both comprises a
projection. Optionally, 0.1% to 5% of the surface area of the upper
portion, the surface area bottom portion, or both comprises a
projection. Optionally, 1% to 10% of the surface area of the upper
portion, the surface area bottom portion, or both comprises a
projection. Optionally, 0.05% to 4% of the surface area of the
upper portion, the surface area bottom portion, or both comprises a
projection.
[0148] Optionally, the bottom surface is free of projections as
described herein. Optionally, the bottom surface comprises pores.
Optionally, the bottom portion has a uniform surface.
[0149] Optionally, the surface area of the upper portion, the
surface area of the bottom portion, or both comprises a cell
adhesion molecule. Optionally, the surface area of the upper
portion, the surface area of the bottom portion, or both comprises:
an anti-inflammatory agent, an antibacterial agent, an antiseptic
agent, a healing enhancing agent, factor XIII, Thrombin, an
adherence enhancer agent or any combination thereof. Optionally,
the surface area of the upper portion, the surface area of the
bottom portion, or both comprises a chondrocyte, a fibroblast, a
chondrocyte precursor, a fibroblast precursor, a mesenchymal cell,
or any combination thereof.
[0150] Optionally, the patch is dried. Optionally, the patch is
hydrated. Optionally, the patch is dried.
[0151] Optionally, provided herein a kit comprising the
biodegradable patch, suspended in a sterile wetting solution, and
instructions for use in repairing a perforation in a tympanic
membrane in a mammal. Optionally, provided herein the sterile
wetting solution can consist of saline, calcium chloride, an
anti-inflammatory agent, an antibacterial agent, an antiseptic
agent, a healing enhancing agent, factor XIII, Thrombin, an
adherence enhancer agent or any combination thereof
[0152] Optionally, provided herein method of repairing a
perforation in a tympanic membrane in a mammal, the method
comprising: providing biodegradable patch and implanting the
biodegradable patch in a mammal's tympanic membrane.
[0153] In another specific embodiment, the patch is of a single
layer with predefined thickness. In another specific embodiment,
the patch is of a single layer with at least two predefined
thicknesses. In another specific embodiment, the patch is a
laminate of two or more layers.
[0154] In another specific embodiment, the patch is hydrated prior
to contacting with the tympanic membrane. Optionally, the patch is
between about 20 micrometers and about 200 micrometers in thickness
in the dry state. Optionally, the patch is between about 10
micrometers and about 140 micrometers in thickness in the dry
state. Optionally, the patch is between about 10 micrometers and
about 100 micrometers in thickness in the dry state. Optionally,
the patch is between about 80 micrometers and about 400 micrometers
in thickness in the dry state.
[0155] Optionally, a patch is at least 20 microns in thickness.
Optionally, the first thickness is 20 to 80 microns thick.
Optionally, the first thickness is 30 to 60 microns thick.
Optionally, the measures of thickness and density are provided for
the dry state or the substantially dried state of the patch.
Optionally, the measures of thickness and density are provided for
the hydrated state of the patch.
[0156] Optionally, a hydrated patch has a thickness between about
0.05 and 0.8 mm. Optionally, a hydrated patch has a thickness
between about 0.1 and 0.8 mm. Optionally, a hydrated patch has a
thickness between about 0.1 and 0.5 mm. Optionally, a first
thickness of the hydrated patch has a thickness between about 0.05
to 0.4 mm. Optionally, a first thickness of the hydrated patch has
a thickness between about 0.1 to 0.3 mm.
[0157] Optionally, a dry or a substantially dry patch (such as but
not limited to a collagen of all types, either non cross-linked or
cross-linked) has a density of 0.05 g/cm.sup.2 to about 1
g/cm.sup.2. Optionally, a dry or a substantially dry patch has a
density of 0.05 g/cm.sup.2 to about 0.8 g/cm.sup.2. Optionally, a
dry or a substantially dry patch has a density of 0.1 g/cm.sup.2 to
about 0.8 g/cm.sup.2. Optionally, a dry or a substantially dry
patch has a density of 0.1 g/cm.sup.2 to about 0.5 g/cm.sup.2.
[0158] Optionally, a patch is a scaffold. Optionally, a patch as
described herein is adapted to be inserted via the middle ear and
onto the inner side of the tympanic membrane. Optionally, a patch
as described herein is adapted to withstand pressure changes in the
ear cavity, as well as shear forces. Optionally, a patch as
described herein is adapted to adhere to the edges of the tympanic
membrane tissue, in order to allow for hermetic closure.
Optionally, a patch as described herein is adapted to promote cell
proliferation, cell migration and cell differentiation. Optionally,
a patch as described herein is adapted to promote cell
migration.
[0159] Optionally, the upper portion, the lower portion or both
sides of the patch comprise rough and/or ragged surface which
promotes adherence to the tympanic membrane and/or adherence of
cells attached to the patch. Optionally, the upper portion, the
lower portion or both sides of the patch comprise sub-micron and/or
micron sized pores which promote adherence to the tympanic membrane
and/or adherence of cells attached to the patch.
[0160] Optionally, the upper portion, the lower portion or both
sides of the patch comprise 0.1 micrometer to 1 micrometer
(diameter of the pore) pores which promote adherence to the
tympanic membrane and/or adherence of cells attached to the patch.
Optionally, the upper portion, the lower portion or both sides of
the patch further comprise a graft layer laminated to a surface of
the patch. Optionally, a graft layer is a layer which promotes cell
survival, cell proliferation, cell maturation, cell migration or
any combination thereof. Optionally, a graft layer is composed of a
hydrogel. Optionally, a graft layer further comprises cell adhesion
molecules, growth factors, proteins, carbohydrates, cytokines,
chemokines or any combination thereof.
[0161] Optionally a patch as described herein is in a folded
position (for insertion) or in an open position (placement
position). Optionally a patch as described herein is pre packed
(folded) and contained within an ear/tympanic membrane insertion
device which spreads flat the patch in proximity to the tympanic
membrane. Optionally, a patch as described herein has structural
memory of its flat appearance as well as strength and flexibility
withstanding the folding through shelf life storage. Optionally, a
patch as described herein comprises a string or an anchor for
attaching it to the insertion device (see FIG. 7A).
[0162] Optionally a patch as described herein comprises a
concentric cord, string, filament, or wire for attaching it to the
insertion device. Optionally, a patch as described herein comprises
an absorbable spring (FIG. 7B) serving as a tissue anchor which is
screwed into the tympanic membrane thus connecting the patch to the
tympanic membrane. Optionally, an absorbable sponge is attached to
a surface of the bottom portion (facing the tympanic membrane) of
the patch to fixate the patch onto the tympanic membrane (see FIG.
7C).
[0163] Optionally, a patch as described herein is rounded.
Optionally, a patch as described herein has a shape of a circle.
Optionally, a patch as described herein has a shape of a
rectangular. Optionally, a patch as described herein has a shape of
an ellipse.
[0164] Optionally, a patch as described herein comprises suture on
its upper portion, on its lower portion or both (see FIG. 7D).
Optionally, a patch comprising a suture is made by electrospinning
of the hydrogel polymer. Optionally, a suture is connected to a
first thickness. Optionally, a suture is further connected to a
first thickness via the threads (element 2 in FIG. 7F). Optionally,
the threads (element 2 in FIG. 7F) ensure that the inserted folded
patch is fully open upon approach to the tympanic membrane.
Optionally, the threads (element 2 in FIG. 7F) ensure that the
inserted folded patch is fully opened upon attachment to the
tympanic membrane. Optionally, the threads are stretchers,
stretching-opening the patch upon or prior to contacting the patch
with the tympanic membrane.
[0165] Optionally, the height of the suture is at least 5 times the
thickness of the thickest portion of the upper portion of the
patch, lower portion of the patch, or both. Optionally, the height
of the suture is at least 50 times the thickness of the thickest
portion of the upper portion of the patch, lower portion of the
patch, or both. Optionally, the height of the suture is 10 to 50
times the thickness of the thickest portion of the upper portion of
the patch, lower portion of the patch, or both. Optionally, the
height of the suture is 20 to 2000 times the thickness of the
thickest portion of the upper portion of the patch, lower portion
of the patch, or both. Optionally, the height of the suture is 20
to 500 times the thickness of the thickest portion of the upper
portion of the patch, lower portion of the patch, or both.
Optionally, the height of the suture is 100 to 800 times the
thickness of the thickest portion of the upper portion of the
patch, lower portion of the patch, or both.
[0166] Optionally, the height of the suture is 500 to 4000 times
the thickness of the thickest portion of the upper portion of the
patch, lower portion of the patch, or both. Optionally, the height
of the suture is 500 to 1500 times the thickness of the thickest
portion of the upper portion of the patch, lower portion of the
patch, or both. Optionally, the height of the suture is 200 to 1200
times the thickness of the thickest portion of the upper portion of
the patch, lower portion of the patch, or both. Optionally, the
height of the suture is 400 to 1000 times the thickness of the
thickest portion of the upper portion of the patch, lower portion
of the patch, or both.
[0167] Optionally, the polymer hydrogel or "hydrogel" is an
alginate or a salt thereof. Optionally, a suitable polymer hydrogel
according to the invention comprises a polysaccharide. Optionally,
a suitable polymer hydrogel according to the invention comprises a
polyphosphazene. Optionally, a suitable polymer hydrogel according
to the invention comprises a polyacrylate. Optionally, a suitable
polymer hydrogel according to the invention comprises a
poly(oxyethylene)-poly(oxypropylene) Optionally, a suitable polymer
hydrogel according to the invention comprises a
poly(oxyethylene)-poly(oxypropylene). Optionally, a suitable
polymer hydrogel according to the invention comprises any
combination of: chitosan, polyesters, poly urethans, polyimides,
poly carbonate, PLLA, PLA, PLGA.
[0168] Optionally, a suitable polymer hydrogel according to the
invention comprises a poly(phosphazene). Optionally, a suitable
polymer hydrogel according to the invention comprises a
poly(acrylic acid). Optionally, a suitable polymer hydrogel
according to the invention comprises a poly(methacrylic acid).
Optionally, a suitable polymer hydrogel according to the invention
comprises a poly(vinyl amine). Optionally, a suitable polymer
hydrogel according to the invention comprises a poly(vinyl
pyridine). Optionally, a suitable polymer hydrogel according to the
invention comprises a poly(vinyl imidazole). Optionally, a suitable
polymer hydrogel according to the invention comprises a
polyphosphazene. Optionally, a suitable polymer hydrogel according
to the invention comprises a collagen. Optionally, a suitable
polymer hydrogel according to the invention comprises ethylene
diamine, poly(acrylic acids), poly(methacrylic acids), copolymers
of acrylic acid and methacrylic acid, poly(vinyl acetate),
sulfonated polymers, or any combination thereof. Optionally, the
hydrogel is alginate, chitosan, pluronic, collagen, agarose, or any
combination thereof.
[0169] Optionally, a suitable polymer hydrogel according to the
invention comprises collagen. Optionally, a suitable polymer
hydrogel according to the invention comprises non-protease-treated
collagen. Optionally, the collagen is not cross-linked, e.g., the
collagen is not fixed. Optionally, the collagen is partially
cross-linked. Optionally, the collagen is cross-linked. Optionally,
the collagen is substantially dry prior to use within a patient.
Optionally, the collagen comprises 25% or less water by weight.
Optionally, the collagen comprises 20% or less water by weight.
Optionally, the collagen comprises 15% or less water by weight.
Optionally, the collagen comprises 2% to 20% water by weight.
[0170] Optionally, collagen is placenta-derived amniotic derived or
chorion derived. Optionally, collagen is derived from a transgenic
plant. Optionally, one of skill in the art can readily choose a
collagen from various sources.
[0171] Optionally, collagen is a mixture of collagen types I, III
and IV. Optionally, a hydrogel or a collagen further comprises
fibrin, fibronectin, elastin, glycosaminoglycans, proteoglycans, or
any combinations thereof.
[0172] Optionally, a patch as described herein comprises a cell
growth factors such as but not limited to PDGF, VEGF, FGF, TGF (3,
an interleukin, a cytokine or any combination thereof. Optionally,
a patch as described herein induces the migration of fibroblasts
and macrophages, and thus the promotion of wound healing.
[0173] Optionally, a patch as described herein is impregnated or
coated with a bioactive compound, such as but not limited to: small
organic molecules (e.g., drugs), antibiotics (such as Clindamycin,
Minocycline, Doxycycline, Gentamycin), hormones, growth factors,
anti-tumor agents, anti-fungal agents, anti-viral agents, pain
medications, anti-histamines, anti-inflammatory agents,
anti-infectives including but not limited to metals, metal-oxides
and/or silver (such as silver salts, including but not limited to
silver nitrate and silver sulfadiazine), elemental silver,
antibiotics, bactericidal enzymes (such as lysozyme), wound healing
agents (such as cytokines including but not limited to PDGF, TGF;
thymosin), hyaluronic acid as a wound healing agent, wound sealants
(such as fibrin with or without thrombin), cellular attractant and
scaffolding reagents (such as added fibronectin) and the like.
[0174] Optionally, a patch as described herein is impregnated or
coated with small organic molecules such as specific inhibitors of
particular biochemical processes e.g., membrane receptor
inhibitors, kinase inhibitors, growth inhibitors, anticancer drugs,
antibiotics, etc.
[0175] Optionally, a patch as described herein is impregnated or
coated with a macrolide (e.g., tobramycin (Tobi.RTM.)), a
cephalosporin (e.g., cephalexin (Keflex.RTM.)), cephradine
(Velosef.RTM.)), cefuroxime (Ceftin.RTM., cefprozil (Cefzil.RTM.),
cefaclor (Ceclor.RTM.), cefixime (Suprax.RTM. or cefadroxil
(Duricef.RTM.), a clarithromycin (e.g., clarithromycin (Biaxin)),
an erythromycin (e.g., erythromycin (EMycin.RTM.)), a penicillin
(e.g., penicillin V (V-CillinK.RTM. or Pen VeeK.RTM.)) or a
quinolone (e.g., ofloxacin (Floxin.RTM.), ciprofloxacin
(Cipro.RTM.) ornorfloxacin (Noroxin.RTM.)), aminoglycoside
antibiotics (e.g., apramycin, arbekacin, bambermycins, butirosin,
dibekacin, neomycin, neomycin, undecylenate, netilmicin,
paromomycin, ribostamycin, sisomicin, and spectinomycin),
amphenicol antibiotics (e.g., azidamfenicol, chloramphenicol,
florfenicol, and thiamphenicol), ansamycin antibiotics (e.g.,
rifamide and rifampin), carbacephems (e.g., loracarbef),
carbapenems (e.g., biapenem and imipenem), cephalosporins (e.g.,
cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone,
cefozopran, cefpimizole, cefpiramide, and cefpirome), cephamycins
(e.g., cefbuperazone, cefinetazole, and cefminox), monobactams
(e.g., aztreonam, carumonam, and tigemonam), oxacephems (e.g.,
flomoxef, and moxalactam), penicillins (e.g., amdinocillin,
amdinocillin pivoxil, amoxicillin, bacampicillin,
benzylpenicillinic acid, benzylpenicillin sodium, epicillin,
fenbenicillin, floxacillin, penamccillin, penethamate hydriodide,
penicillin o-benethamine, penicillin 0, penicillin V, penicillin V
benzathine, penicillin V hydrabamine, penimepicycline, and
phencihicillin potassium), lincosamides (e.g., clindamycin, and
lincomycin), macrolides (e.g., azithromycin, carbomycin,
clarithomycin, dirithromycin, erythromycin, and erythromycin
acistrate), amphomycin, bacitracin, capreomycin, colistin,
enduracidin, enviomycin, tetracyclines (e.g., apicycline,
chlortetracycline, clomocycline, and demeclocycline),
2,4-diaminopyrimidines (e.g., brodimoprim), nitrofurans (e.g.,
furaltadone, and furazolium chloride), quinolones and analogs
thereof (e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine,
and grepagloxacin), sulfonamides (e.g., acetyl
sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide,
phthalylsulfacetamide, sulfachrysoidine, and sulfacytine), sulfones
(e.g., diathymosulfone, glucosulfone sodium, and solasulfone),
cycloserine, mupirocin and tuberin.
[0176] Optionally, a patch as described herein is impregnated or
coated with an antifungal agent. Suitable antifungal agents include
but are not limited to amphotericin B3 itraconazole, ketoconazole,
fluconazole, intrathecal, flucytosine, miconazole, butoconazole,
clotrimazole, nystatin, terconazole, tioconazole, ciclopirox,
econazole, haloprogrin, naftifine, terbinafine, undecylenate, and
griseofuldin.
[0177] Optionally, a patch as described herein is impregnated or
coated with an anti-inflammatory agent. Useful antiinflammatory
agents include, but are not limited to, non-steroidal
anti-inflammatory drugs such as salicylic acid, acetylsalicylic
acid, methyl salicylate, diflunisal, salsalate, olsalazine,
sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen,
ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome,
phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone
and nimesulide; leukotriene antagonists including, but not limited
to, zileuton, aurothioglucose, gold sodium thiomalate and auranofm;
and other anti-inflammatory agents including, but not limited to,
methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone
and benzbromarone.
[0178] Optionally, a patch as described herein is impregnated or
coated with an antiviral agent. Useful antiviral agents include,
but are not limited to, nucleoside analogs, such as zidovudine,
acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, and
ribavirin, as well as foscarnet, amantadine, rimantadine,
saquinavir, indinavir, ritonavir, and the alpha-interferons.
[0179] Optionally, a patch as described herein is impregnated or
coated with a cytokine receptor modulator. Examples of cytokine
receptor modulators include, but are not limited to, soluble
cytokine receptors (e.g., the extracellular domain of a TNF-.alpha.
receptor or a fragment thereof, the extracellular domain of an
IL-10 receptor or a fragment thereof, and the extracellular domain
of an IL-6 receptor or a fragment thereof), cytokines or fragments
thereof (e.g., interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-7,
IL-8JL-9, IL-10, IL-I1, IL-12, IL-15, TNF-.alpha., TNF-.beta.,
interferon (IFN)-.alpha., IFN-.beta., IFN-.gamma., and GM-CSF),
anti-cytokine receptor antibodies (e.g., anti-IFN receptor
antibodies, anti-IL-2 receptor antibodies (e.g., Zenapax (Protein
Design Labs)), anti-IL-4 receptor antibodies, anti-IL-6 receptor
antibodies, anti-IL-10 receptor antibodies, and anti-IL-12 receptor
antibodies), anti-cytokine antibodies (e. g., anti-IFN antibodies,
anti-TNF-.alpha.antibodies, anti-IL-10 antibodies, anti-IL-6
antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)), and
anti-IL-12 antibodies). In a specific embodiment, a cytokine
receptor modulator is IL-4, IL-IO, or a fragment thereof.
Optionally, a cytokine receptor modulator is an anti-IL-1 antibody,
anti-IL-6 antibody, anti-IL-12 receptor antibody, or
anti-TNF-.alpha. antibody. Optionally, a cytokine receptor
modulator is the extracellular domain of a TNF-.alpha. receptor or
a fragment thereof. In certain embodiments, a cytokine receptor
modulator is not a TNF-.alpha. antagonist. Optionally, a patch as
described herein is impregnated or coated with proteins,
polypeptides or peptides (including antibodies) that are utilized
as immunomodulatory agents are derived from the same species as the
recipient of the proteins, polypeptides or peptides so as to reduce
the likelihood of an immune response to those proteins,
polypeptides or peptides.
[0180] Optionally, a patch as described herein is impregnated or
coated with a cytokine. Examples of cytokines include, but are not
limited to, colony stimulating factor 1 (CSF-I), interleukin-2
(IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5
(IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9
(IL-9), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin
15 (IL-15), interleukin 18 (IL-18), insulin-like growth factor 1
(IGF-I), platelet derived growth factor (PDGF), erythropoietin
(Epo), epidermal growth factor (EGF), fibroblast growth factor
(FGF) (basic or acidic), granulocyte macrophage stimulating factor
(GM-CSF), granulocyte colony stimulating factor (G-CSF), heparin
binding epidermal growth factor (HEGF), macrophage colony
stimulating factor (M-CSF), prolactin, and interferon (IFN), e.g.,
IFN-alpha, and IFN-gamma), transforming growth factor alpha
(TGF-.alpha.), TGF.beta.1, TGF.beta.2, tumor necrosis factor alpha
(TNF-.alpha.), vascular endothelial growth factor (VEGF),
hepatocyte growth factor (HGF), etc.
[0181] Optionally, a patch as described herein is impregnated or
coated with a hormone. Examples of hormones include, but are not
limited to, luteinizing hormone releasing hormone (LHRH), growth
hormone (GH), growth hormone releasing hormone, ACTH, somatostatin,
somatotropin, somatomedin, parathyroid hormone, hypothalamic
releasing factors, insulin, glucagon, enkephalins, vasopressin,
calcitonin, heparin, low molecular weight heparins, heparinoids,
synthetic and natural opioids, insulin thyroid stimulating
hormones, and endorphins. Examples of .beta.-interferons include,
but are not limited to, interferon .beta.1-a and interferon
.beta.1-b.
[0182] Optionally, a patch as described herein is impregnated or
coated with an alkylating agent. Examples of alkylating agents
include, but are not limited to nitrogen mustards, ethylenimines,
methylmelamines, alkyl sulfonates, nitrosoureas, triazenes,
mechlorethamine, cyclophosphamide, ifosfamide, melphalan,
chlorambucil, hexamethylmelaine, thiotepa, busulfan, carmustine,
streptozocin, dacarbazine and temozolomide.
[0183] Optionally, a patch as described herein is impregnated or
coated with an immunomodulatory agent, including but not limited to
methothrexate, leflunomide, cyclophosphamide, cyclosporine A,
macrolide antibiotics (e.g., FK506 (tacrolimus)),
methylprednisolone (MP), corticosteroids, steroids, mycophenolate
mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin,
brequinar, malononitriloamindes (e.g., leflunamide), T cell
receptor modulators, and cytokine receptor modulators, peptide
mimetics, and antibodies (e.g., human, humanized, chimeric,
monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or
epitope binding fragments), nucleic acid molecules (e.g., antisense
nucleic acid molecules and triple helices), small molecules,
organic compounds, and inorganic compounds. In particular,
immunomodulatory agents include, but are not limited to,
methothrexate, leflunomide, cyclophosphamide, Cytoxan, Imrnuran,
cyclosporine A, minocycline, azathioprine, antibiotics(e.g-., FK506
(tacrolimus)), methylprednisolone (MP), corticosteroids, steroids,
mycophenolate mofetil, rapamycin (sirolimus), mizoribine,
deoxyspergualin, brequinar, malononitriloamindes (e.g.,
leflunamide), T cell receptor modulators, and cytokine receptor
modulators. Examples of T cell receptor modulators include, but are
not limited to, anti-T cell receptor antibodies (e.g., anti-CD4
antibodies (e.g., cM-T412 (Boeringer), IDEC-CE9. S (IDEC and SKB),
mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3
antibodies (e.g., Nuvion (Product Design Labs), OKT3 (Johnson &
Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (e.g., an
anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (e.g.,
CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand
monoclonal antibodies (e.g., IDEC-131(IDEC)), anti-CD52 antibodies
(e.g., CAMPATH IH (Ilex)), anti-CD2 antibodies, anti-CD1 Ia
antibodies (e.g., Xanelim (Genentech)), and anti-B7 antibodies
(e.g., IDEC-114) (IDEC))) and CTLA4-immunoglobulm. Optionally, a
patch as described herein is impregnated or coated with an
immunomodulatory compound known as IMiD. Optionally, impregnation
is accomplished by immersing the patch in a solution of the
bioactive compound of the desired concentration for a time
sufficient to allow the patch to absorb and to equilibrate with the
solution.
[0184] Making The Patch
[0185] Optionally, the patch of the invention for repairing a
perforation in a tympanic membrane is made by providing a mold
having a defined, e.g., predetermined, negative shape of the patch.
Optionally, the methods include introducing a liquid hydrogel
composition into the mold; inducing gel formation to solidify the
liquid hydrogel composition to form a hydrogel patch; and removing
the hydrogel patch from the mold after gel formation, wherein the
construct has a shape suitable for repairing a perforation in a
tympanic membrane.
[0186] Optionally, the hydrogel polymer patch is produced by
electrospinning of a polymer.
[0187] Optionally, the methods further include suspending cells,
cell adhesion molecule, a cell growth factor, an antibiotic, an
antibacterial agent, an anti-inflammatory agent, an anti-septic
agent or any combination thereof in the liquid hydrogel to form a
composition or a patch as described herein. Optionally, gel
formation is induced by contacting the liquid hydrogel with a
suitable concentration of a divalent cation.
[0188] Repairing a Tympanic Membrane
[0189] The present invention provides a method for the repair of a
tympanic membrane using a patch as described herein. In one
embodiment, the tympanic membrane to be repaired has a deformity.
Optionally, the deformity is an acute perforation. Optionally, the
deformity is a chronic perforation. Optionally, the deformity
relates to cholesteatoma. Optionally, the deformity is caused by a
tumor in the middle ear. Optionally, the deformity is a disease of
the tympanic membrane such as dimeric drum, a retraction, a
retraction pocket (i.e., pocket formed in the eardrum resulting
from retraction of the tympanic membrane into the middle ear cavity
due to loss of pressure in the middle ear cavity), or
tympanosclerosis, and the like.
[0190] Optionally, repair of a tympanic membrane deformity or
perforation encompass contacting the tympanic membrane with a patch
for a time sufficient to heal the tympanic membrane deformity, for
a time sufficient to measurably improve one or more aspects of the
tympanic membrane deformity or perforation, or for a time
sufficient to lessen the worsening of one or more aspects of the
tympanic membrane deformity, as compared to a tympanic membrane not
contacted with a patch. Optionally, the terms "deformity" and
"perforation" are used interchangeably.
[0191] Optionally, aspects of a tympanic membrane deformity include
objectively measurable criteria, such as ability of the tympanic
membrane to transmit sound, hearing loss in decibels, appearance of
the tympanic membrane or surrounding tissue, ingrowth of epithelial
tissue into or around a perforation in the tympanic membrane, etc.,
or subjective criteria, such as a sense of improved hearing,
lessening of discomfort or pain, etc.
[0192] Optionally, the deformity is a perforation. Optionally,
repairing a tympanic membrane includes totally or partially
covering the perforation with a patch.
[0193] Optionally, a patch as described herein is placed or
implanted in-situ with an insertion instrument for implanting a
tympanic membrane patch. Optionally, insertion instruments for
implanting a tympanic membrane patch are known to one of skill in
the art.
[0194] Reference is now made to FIGS. 8A-8F which illustrate
various views of an applicator 800 for repairing a perforated
tympanic membrane, in accordance with an embodiment. FIG. 8A
illustrates a cross-section of the entire applicator 800 having a
proximally disposed handle 802 and distally disposed deployment
stem 804. FIG. 8B-8D illustrates detailed cross-sectional views of
handle 802, and FIGS. 8E-8F illustrate a detailed cross-sectional
and perspective view, respectively, of the distal tip of stem 804.
Applicator 800 is substantially similar to applicator 100 described
above, and it is to be understood the description that follows
relates to the differences between applicator 800 and applicator
100, and that unless otherwise specified, their structure and
function are substantially the same.
[0195] Referring to FIG. 8A, handle 802 is provided with a
deployment control mechanism comprising actuators 834 and 840, and
860. Deployment stem 804 may include multiple nested, telescoping
sleeves connected to handle 802.
[0196] Referring to FIGS. 8E-8F, the multiple nested and
telescoping sleeves may include an inner sleeve 818, a middle
sleeve 820 encasing inner sleeve 818, and an outer sleeve 822
encasing middle sleeve 820, similar to sleeves 118, 120, and 122
described above. Two patches, a distally disposed patch 808D
superimposed with a proximally disposed patch 808P may be affixed
to the distal end of the deployment stem 804. Distal patch 808D may
be affixed via a distal actuation filament 826D embedded within the
inner sleeve 818 of deployment stem 804, thereby affixing distal
patch 808D to the distal end of the inner sleeve 818, and proximal
patch 808P may be affixed via a proximal actuation filament 826P
embedded within middle sleeve 820, thereby affixing proximal patch
808P to the distal end of the middle sleeve 820. Filaments 826P and
826D may be made of any fiber suitable for withstanding a tensile
force, such as but not limited to metallic wire, or thread, such as
may be made of nylon or other suitable material.
[0197] Distal patch 808D may be disposed with a distal patch cord
838Db that engages with distal filament 826D within inner sleeve
818, and proximal patch 808P may be disposed with a proximal patch
cord 838Pb that engages with proximal filament 826P within middle
sleeve 820, external to inner sleeve 818, thereby securing patches
808D and 808P to the distal ends of sleeves 818 and 820,
respectively. Cords 838Db and 838Pb may correspond to cord 138
described above. As with patch 108, cords 838Db and 838Pb may have
a wider distal ends 838Da and 838Pa attaching cords 838Db and 838Pb
to disks 836D and 836P of patches 808D and 808P, respectively, and
which may allow pulling any of patches 808D and 808P proximally by
pulling on filaments 826D and 826P, and/or by retracting sleeves
818 and 820 proximally Patches 808D and 808P are constructed from a
resilient material that flexes to fit through the perforation, and
restores its original shape when emerging from the perforation.
[0198] Optionally, the filaments may engage with the cords as
follows: a proximal end 838Dc of distal patch cord 838Db may loop
through a looped distal end 826Da of the distal filament 826D in
the inner sleeve 818, and the proximal end 838Pc of the proximal
patch cord 838Pb may loop through a looped distal end 826Pa of the
proximal filament 826P in the middle sleeve 820. Proximal ends
838Dc and 838Pc may be unattached, such that withdrawing filaments
826D and 826P may unravel the engagement. Filaments 826D and 826P
may each be configured as a doubled over filament that is fused
along its length proximally, leaving only a relatively small
unfused portion at the distal end, to form loops 826Da and
826Pa.
[0199] Deployment actuators 834 and 860 may control the
filament-based deployment system as follows:
[0200] Referring to FIGS. 8A-8D, actuator 860 may be positioned
with an elongated niche 860a within handle 802, allowing actuator
860 to slide distally and proximally within niche 860a. Actuator
860 may be integrally connected to a case 860b, such that sliding
actuator 860 along niche 860a moves case 860b distally and
proximally, accordingly. Case 860b may enclose a debridement
mechanism comprising a motor 844 and a gear wheel mechanism,
comprising two engaged gear wheels 858a and 858b, mechanically
connected to a blade pushing tube 854, which is in turn connected
to spring 828 that is connected to outer sleeve 822, similar to
spring 128 and sleeve 122 described above. Referring to FIG. 8E,
outer sleeve 822 connects to middle sleeve 820 via a pin 862
sandwiched between two disks 864a-b. It may be appreciated that
other connecting means may be used. Thus sliding actuator 860
distally and proximally within niche 860a advances and retracts
blade pushing tube 854 which advances and retracts outer and middle
sleeves 822 and 820 over bend 806 via spring 828, accordingly.
Optionally, inner sleeve 818 is not connected to sleeves 822 and
820, and moves independently. Optionally, a strengthening tube (not
shown) is nested between the middle and outer sleeves 820 and 822,
extending from blade pushing tube 854 distally. Spring 828 may
encase the strengthening tube.
[0201] The operation of actuator 834 is illustrated in FIG. 8D. The
proximal ends of filaments 826D and 826P may be each be anchored in
handle 802 at filament bosses 846D and 846P, respectively. Springs
850D and 850P, each positioned distally to bosses 846D and 846P and
enclosing filaments 826D and 826P, respectively, are provided to
exert tension on filaments 826D and 826P responsive to actuator
834. Filament 826P may terminate at distally disposed boss 846P,
and filament 826D may extend proximally via a tube 852D and
terminate at proximally disposed boss 846D. Actuator 834 may be
mechanically connected to bosses 846P and 846D via triggers 848P
and 848D, such that a controlled downwards compression by actuator
834 pushes triggers 848P and 848D downwards, pushing bosses 846P
and 846D, and exerting a tension on filaments 826D and 826P via
springs 850D and 850P, accordingly. This tension retracts filaments
826D and 826P proximally, and unravels the proximal ends 838Dc,
838Dc of cords 838Db, 838Pb from the looped distal ends of
filaments 826D and 826P, shown in FIG. 8E, causing distal patch
cord 838Db and the proximal patch cord 838Pb to disengage from
distal filament 826D and proximal filament 826P. This releases the
distal patch and the proximal patch from the deployment stem
804.
[0202] Optionally, actuator 834 may be configured with multiple
settings (not shown) that allow activating triggers 848P and 848D
either separately, or together to control the retraction of
filaments 826D and 826P, accordingly.
[0203] It may be appreciated that any of the features of device
100, such as but not limited to any of the rotation mechanisms
provided for rotating any of sleeves 118, 120 may be implemented
with device 800 for rotating any of sleeves 818, 820
accordingly.
[0204] Referring back to FIG. 8A, applicator 800 may be further
provided with a debridement mechanism activated by actuator 840
configured with handle 802. The debridement mechanism includes
blade pushing tube 854 and spring 828 mechanically connected to
outer sleeve 822, and at least one protruding blade 810 disposed at
the distal end of outer sleeve 822. Optionally, blade 810 is a
single, concave arc-shaped blade such as shown in FIG. 8F.
Alternatively, the at least one protruding blade may be configured
as the convex blade pair 110a-b described above. Actuator 840
controls a power supply, such as battery 842, provided to drive
motor 844. A gear wheel mechanism, comprising two engaged gear
wheels 858a and 858b, mechanically connects motor 844 to blade
pushing tube 854, transferring a rotation by motor 844 to sleeve
822 via blade pushing tube 854. Thus, activation by actuator 840
causes motor 844 to rotate thereby rotating protruding blade 810
disposed on sleeve 822, and causing a debridement of the
circumference of the perforation of tympanic membrane when blade
822 is positioned at the tympanic membrane. Optionally, actuator
840 operates as a push button to activate the debridement.
[0205] Advantageously, the curvature of protruding blade 810
controls the penetration depth of blade 810 into the perforation.
Similarly, the debridement mechanism may include a penetration
depth controlling mechanism that limits the penetration depth of
blade 810 by limiting the advancement of the outer sleeve 822
relative to inner sleeve 818. For example, the length of niche 860a
may serve as a penetration depth controlling mechanism. As with the
debridement mechanism of applicator 100, the debridement mechanism
of applicator 800 may include a niche, such as may be formed
between blade 810 and the outer surface of outer sleeve 822 for
collecting any debrided tissue.
[0206] Reference is now made to FIGS. 9A-9H, which illustrate a
method for repairing a perforated tympanic membrane using the
filament-based deployment system of applicator 800. The
filament-based deployment system may deploy patch 808D distally, at
the internal side of a perforated tympanic membrane in the middle
ear, and deploy patch 808P proximally, at the external side of the
perforated tympanic membrane in the outer ear, thereby sandwiching
the tympanic membrane between distally disposed patch 808D and the
proximally disposed patch 808P.
[0207] Referring to FIG. 9A, deployment stem 804 may introduce the
two patches 808D and 808D into the ear canal 200, such as via a
speculum, 210, and penetrate the perforated tympanic membrane 202
with at least distally disposed patch 808D, via the inner
sleeve.
[0208] Referring the FIG. 9B, optionally, the perforated tympanic
membrane 202 may be penetrated with both the distal patch together
with the proximal patch, by inserting the middle sleeve encasing
the inner sleeve through the perforation. The two patches may be
constructed from a resilient material that flexes to fit through
the perforation, and restores its original shape when emerging from
the perforation. Optionally, the tympanic membrane may be
penetrated with the distal end of stem 804 comprising the inner,
middle, and outer sleeves 818, 820, and 822, with the distal ends
of the three sleeves substantially aligned distally, bringing blade
810 into contact with the edge of the perforation.
[0209] Referring to FIG. 9C, actuator 840 may be activated to
perform a debridement of the circumference of the perforation. The
debridement may be performed prior to the final deployment of the
patches, to allow blood released from the debridement to
subsequently serve as a glue for securing the patches to the
tympanic membrane. Optionally the blade is concave, and the
deployment stem is maneuvered to bring a concave edge of the blade
with the edge of the perforation. With the blade 810 positioned
thus, the outer sleeve may be rotated, thereby rotating the
debridement blade about the circumference of the perforation.
Optionally, debrided tissue resulting from the debridement may be
collected in a niche formed between blade 810 and sleeve 810.
[0210] Referring to FIG. 9D, once the debridement is complete,
actuator 860 may be retracted proximally within niche 860a,
retracting outer sleeve 822 and middle sleeve 820 relative to the
inner sleeve 818, to evacuated blade 810 and sleeves 822 and 820
from the middle ear through the debrided perforation. This serves
to retract the proximal patch 808P from the middle ear through the
perforation of the debrided tympanic membrane, and position the
proximal patch 808P at the external side of the perforated tympanic
membrane in the outer ear.
[0211] The proximal patch may flex to fit through the perforation
(FIG. 9D), and restore its shape on emerging in the outer ear (FIG.
9E). The proximal patch 808P may possess a low surface tension
towards the distal patch 808D, and thus patches 808P and 808D don't
have a tendency to attach or adhere to each other.
[0212] Referring to FIGS. 9E-9F, the distal patch 808D is now
positioned at the internal side 204 of the perforated tympanic
membrane 202 in the middle ear, and the proximal patch 808P is
positioned at the external side 206 of the perforated tympanic
membrane in the outer ear. At this stage, the distal patch 808D is
still affixed to the inner sleeve 818, and positioned in the inner
ear, with the tympanic membrane 202 positioned between the two
patches (FIG. 9E).
[0213] Referring to FIG. 9F, the entire applicator may be
retracted, retracting the deployment stem and pulling the inner
sleeve with the distal patch 808D until the distal patch is flush
with the internal side 204 of the perforated tympanic membrane
202.
[0214] Referring to FIG. 9G, actuator 860 may be advanced distally
within niche 860a, advancing sleeves 820 and 822 relative to the
inner sleeve 818 until the proximal patch 808P is flush against the
external side of the perforated tympanic membrane 206. Referring to
FIG. 9H, actuator 834 may be pressed, exerting a tension on
filaments 826D and 826D, disengaging the distal patch cord 838Db
from the distal filament 826D and the proximal patch cord 838Pb
from the proximal filament 826D, releasing the distal patch 808D
and the proximal patch 808P from the deployment stem 804. The
deployment stem 804 may be retracted from the ear canal 200
completing the ffdeployment of the distal patch at the inner side
of the tympanic membrane, and the proximal patch at the outer side
of the tympanic membrane, serving to seal the perforation on both
sides.
[0215] In the figures, elements are not always provided with
reference numbers; a certain element, for example, may be provided
with a reference number in one of more figures, and be shown
without that reference number in other one or more figures--merely
for reasons of brevity. Since all figures in this application show
the same device, it is intended that an element having the same
shape and appearing in different figures, sometimes with a
reference number and sometimes not--be interpreted as the same
element.
[0216] The present invention has been described using non-limiting
detailed descriptions of embodiments thereof that are provided by
way of example and are not intended to limit the scope of the
invention. It should be understood that features and/or steps
described with respect to one embodiment may be used with other
embodiments and that not all embodiments of the invention have all
of the features and/or steps shown in a particular figure or
described with respect to one of the embodiments. Variations of
embodiments described will occur to persons of the art.
[0217] It is noted that some of the above described embodiments may
describe the best mode contemplated by the inventors and therefore
may include structure, acts or details of structures and acts that
may not be essential to the invention and which are described as
examples. Structure compounds and acts described herein are
replaceable by equivalents which perform the same function, even if
the structure or acts are different, as known in the art.
Therefore, the scope of the invention is limited only by the
elements and limitations as used in the claims. When used in the
following claims, the terms "comprise", "include", "have" and their
conjugates mean "including but not limited to".
* * * * *