`(12) Patent Application Publication (10) Pub. No.: US 2007/0038298 A1
`Sulner et al.
`(43) Pub. Date:
`Feb. 15, 2007
`
`US 2007003 8298Al
`
`(54) REPAIR OF TYMPANIC MEMBRANE USING
`PLACENTA DERIVED COLLAGEN
`BIOFABRIC
`
`(76) Inventors: Joseph W. Sulner, Paramus, NJ (US);
`Janice Smiell, MorristoWn, NJ (US);
`Sharon L. ‘Bourke, PiscataWay, NJ
`(Us); Pamcla A- MurPhy,
`Hlllsborough, NJ (US)
`
`Correspondence Address;
`JONES D AY
`222 EAST 415T ST
`NEW YORK NY 10017 (Us)
`’
`
`(21) App1_ NO;
`
`11/479,801
`
`(22) Filed;
`
`Jun. 29, 2006
`
`Related US. Application Data
`
`(60) Provisional application No. 60/696,167, ?led on Jun.
`30, 2005.
`
`Pubhcatlon Classl?catlon
`
`(51) Int Cl
`(200601)
`A61F 2/18
`(52) us. Cl. ......................................... .. 623/10; 623/2372
`
`(57)
`
`ABSTRACT
`
`The present invention provides a method of repairing a
`tympanic membrane deformity, such as a tympanic mem
`brane perforation, commonly referred to as tympanoplasty
`or myringoplasty, using a collagen biofabric. The collagen
`biofabric is preferably laminated. The invention further
`provides kits comprising one or more pieces of collagen
`biofabric, for example laminated collagen biofabric, for the
`repair of a tympanic membrane.
`
`
`
`US 2007/0038298 A1
`
`Feb. 15, 2007
`
`REPAIR OF TYMPANIC MEMBRANE USING
`PLACENTA DERIVED COLLAGEN BIOFABRIC
`
`[0001] This application claims bene?t of Us. Provisional
`Application No. 60/696,167, ?led Jun. 30, 2005, Which is
`hereby incorporated by reference herein in its entirety.
`
`l. FIELD OF THE INVENTION
`
`[0002] The present invention relates to the repair of the
`tympanic membrane, commonly referred to as tympano
`plasty or myringoplasty, using a collagen biofabric.
`
`2. BACKGROUND OF THE INVENTION
`
`[0003] The ?rst component of the middle ear to receive
`sound Waves is the tympanic membrane, also knoWn as the
`eardrum. Sound Waves striking the tympanic membrane are
`transmitted through a series of tiny bonesithe malleus,
`incus and stapesito the cochlea, Where the sound Waves are
`sensed and processed. The tympanic membrane itself is
`living tissue.
`[0004] Tympanic membrane deformities, such as perfora
`tions, interfere With the transmission and perception of
`sound. Perforations are usually caused by trauma or infec
`tion. Examples of traumatic causes of perforated eardrums
`include open hand bloWs to the ear (i.e., boxing the ears);
`skull fractures; sudden explosions; objects such as a bobby
`pin or cotton sWab pushed too far into the ear canal; hot slag
`from Welding or acid entering the ear canal, and other
`traumas. Middle ear infections can cause spontaneous rup
`ture (tear) of the eardrum, resulting in a perforation. In this
`circumstance, called otitis media With perforation, there may
`be infected or bloody drainage from the ear. A hole in the
`tympanic membrane may also be caused by surgical proce
`dures, such as tympanotomy or myringotomy. A small hole
`may remain in the eardrum after a previously placed pres
`sure equalization tube either falls out or is removed by the
`physician.
`[0005] Whatever the cause of the deformity of the tym
`panic membrane, hoWever, repair of the membrane is desir
`able. Repair of tympanic membrane perforations is accom
`plished, generally, in a procedure knoWn as tympanoplasty
`or myringoplasty. The tWo are similar; hoWever, aside from
`repair of the tympanic membrane itself, tympanoplasty
`additionally implies remediation of pathology or pathologies
`of the middle ear cleft, such as chronic infection, choleas
`toma, or ossicular chain problems. Typically, in tympano
`plasty or myringoplasty, the hole in the tympanic membrane
`is repaired by means of a graft. Typical graft materials have,
`to date, included natural materials such as temporalis fascia,
`tragal perichondrium, skin, periosteum, loose overlay tissue,
`fat, vein tissue, human amniotic membrane, and homolo
`gous dura; and non-natural materials such as silastic, paper
`and te?on sheets. Aside from repair of the tympanic mem
`brane, one main purpose of tympanoplasty is the creation of
`a middle ear space that contains air. Given this purpose, it is
`important that the material used to repair the tympanic
`membrane resists, or displays a loW proclivity for, forming
`adhesions or promoting infection.
`[0006] Generally, a perforated tympanic membrane is
`treated as folloWs. Working With a microscope, the edges of
`the eardrum are debrided to freshen the edges to stimulate
`groWth, and then the occluding material, generally a thin
`
`patch or graft, is placed over the eardrum perforation so as
`to overlap onto the intact portions of the tympanic mem
`brane. Commonly, the patch is a small section of cigarette
`paper, Which is thought to provide a stent for the ingroWth
`of epithelial cells to ?ll the perforation. Usually, after closure
`of the tympanic membrane, hearing improvement is noted.
`Several applications of a patch (up to three or four) may be
`required before the perforation closes completely. If a paper
`patch does not provide prompt or adequate closure of the
`hole in the eardrum, or if attempts With paper patching are
`not successful, surgery, for example, myringoplasty or tym
`panoplasty, is considered. Not all otolaryngologists, hoW
`ever, agree that placement of a paper patch on a perforated
`tympanic membrane is an adequate treatment, hoWever,
`citing a relatively high failure rate.
`
`3. SUMMARY OF THE INVENTION
`
`[0007] The present invention provides methods and com
`positions for repair of tympanic membranes. For example,
`the present invention provides methods and compositions
`for repair of a tympanic membrane injury or deformity. In
`one embodiment, the present invention provides a method of
`repairing a perforated tympanic membrane, comprising con
`tacting said tympanic membrane With a collagen biofabric.
`In another speci?c embodiment, said contacting is suf?cient
`to occlude the perforation. In a more speci?c embodiment,
`said perforation is a central perforation. In another more
`speci?c embodiment, said perforation is a marginal perfo
`ration. In another speci?c embodiment, said perforation has
`not healed spontaneously Within tWo months of developing
`the perforation. In a speci?c embodiment, the proteins
`making up the collagen biofabric substantially retain their
`native conformations, e.g., the collagen biofabric is not
`protease-treated. In another speci?c embodiment, the pro
`teins of said collagen biofabric are not cross-linked, e.g., the
`collagen biofabric is not ?xed. In another speci?c embodi
`ment, the collagen biofabric is substantially dry prior to said
`contacting, that is, comprises about 20% or less Water by
`Weight. In another speci?c embodiment, said collagen bio
`fabric is a single layer. In another speci?c embodiment, said
`collagen biofabric is a laminate of tWo or more layers. In
`another speci?c embodiment, said collagen biofabric is
`trimmed prior to said contacting. In another speci?c embodi
`ment, said collagen biofabric is about 2><2 cm prior to
`trimming. In another speci?c embodiment, said collagen
`biofabric is about 3x3 cm prior to trimming. In another
`speci?c embodiment, said collagen biofabric is about 2x3
`cm prior to trimming. In another speci?c embodiment, said
`collagen biofabric is hydrated prior to contacting With the
`tympanic membrane. In another speci?c embodiment, the
`collagen biofabric is betWeen about 2 micrometers and about
`150 micrometers in thickness in the dry state. In a more
`speci?c embodiment, said biofabric is about 10 to about 50
`microns in thickness in the dry state. In another speci?c
`embodiment, the biofabric is about 40 to about 50 microns
`in thickness in the dry state. In a more speci?c embodiment,
`the collagen biofabric that is betWeen about 2 micrometers
`to about 150 micrometers in thickness in the dry state is a
`laminate of tWo or more layers. In the above embodiments,
`the ranges indicate average thicknesses, and are not absolute
`limits to thickness. In another embodiment, said collagen
`biofabric is contacted With the tympanic membrane through
`
`
`
`US 2007/0038298 A1
`
`Feb. 15, 2007
`
`use of an applicator. In another embodiment, the invention
`provides one or more sheets of collagen biofabric in a sterile
`double-peel pouch.
`[0008] 3.1 De?nitions
`[0009] As used herein, “collagen biofabric” generally
`means a collagen-containing, placenta-derived amniotic or
`chorion membrane material that can be used as a ?lm or
`sheet. A preferred collagen biofabric is the vacuum-dried,
`non-?xed, non-protease-treated amniotic membrane mate
`rial described in Hariri, U.S. Application Publication U.S.
`2004/0048796, Which is hereby incorporated in its entirety,
`and that is produced by the methods described therein, and
`herein (see Examples 1, 2). The collagen biofabric is pref
`erably made from the amnion, but may be made from the
`chorion, or both amnion and chorion.
`
`[0010] As used herein, the term “bioactive compound”
`means any compound or molecule that causes a measurable
`effect on one or more biological systems in vitro or in vivo.
`
`4. DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0011] The present invention provides methods of repair
`ing a tympanic membrane deformity, and, more speci?cally,
`of performing a tympanoplasty or myringoplasty, using a
`collagenous amniotic and/or chorionic membrane material,
`herein referred to as a collagen biofabric.
`[0012] 4.1 Repair of Tympanic Membrane Using Collagen
`Biofabric
`
`[0013] The present invention provides a method for the
`repair of a tympanic membrane using a collagen biofabric.
`In one embodiment, the tympanic membrane to be repaired
`has a deformity. The deformity may be naturally-occurring,
`for example, as the result of disease or infection, or may be
`an injury. In various embodiments, the deformity can be, for
`example, a perforation, e.g., an acute perforation or a
`chronic perforation (a perforation lasting longer than, for
`example, 2 months), partial or total loss of collagen in the
`tympanic membrane, partial or total loss of normal tympanic
`membrane stiffness, an atelectatic tympanic membrane (i.e.,
`tympanic membrane in Which the natural collagenous layer
`that stilfens the membrane is lost partially or totally), a
`deformity relating to cholesteatoma or tumor involvement of
`the middle ear, 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.
`
`[0014] Repair of a tympanic membrane deformity may, for
`example, encompass contacting the tympanic membrane
`With a collagen biofabric for a time suf?cient to heal the
`tympanic membrane deformity, for a time suf?cient to
`measurably improve one or more aspects of the tympanic
`membrane deformity, or for a time suf?cient to lessen the
`Worsening of one or more aspects of the tympanic mem
`brane deformity, as compared to a tympanic membrane not
`contacted With a collagen biofabric.
`
`[0015] As used herein, “aspects of a tympanic membrane
`deformity” encompasses objectively measurable criteria,
`such as ability of the tympanic membrane to transmit sound,
`
`hearing loss in decibels, appearance of the tympanic mem
`brane 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.
`
`[0016] In one embodiment, the deformity is a perforation.
`Such a perforation may, for example, be caused accidentally,
`by trauma, by infection, or may be caused deliberately, for
`example, a perforation caused by insertion of one or more
`tubes alloWing drainage of ?uids in the middle ear past the
`tympanic membrane and out the auditory canal (e.g., per
`foration(s) to alloW a myringotomy tube installation, or a
`perforation caused by surgical removal of diseased or dam
`aged tissue). The perforation may be acute, or the perfora
`tion may be chronic, that is, has been in existence for tWo
`months or more.
`
`[0017] In one embodiment of repairing a tympanic mem
`brane, a tympanic membrane having a perforation is con
`tacted With a collagen biofabric such that the collagen
`biofabric partially or totally occludes the perforation. The
`perforation to be occluded may be a central perforation, that
`is, a perforation of any siZe that does not involve the margin
`of the tympanic membrane (i.e., the periphery seated in the
`auditory canal), or a marginal perforation (i.e., a perforation
`touching upon, or largely involving, the margin of the
`tympanic membrane). In another embodiment, only the
`tympanic membrane is perforated, and no other ear structure
`is perforated or damaged. In another embodiment, occlusion
`of the perforation is an adjunct to at least one other surgical
`procedure involving the outer, middle, or inner ear. In
`another embodiment, the repair of the tympanic membrane
`is a tympanoplasty. In another embodiment, the repair of the
`tympanic membrane is a myringoplasty.
`
`[0018] The bene?ts of closing a tympanic membrane
`perforation include prevention of Water entering the ear
`While shoWering, bathing or sWimming (Which could cause
`ear infection), improved hearing, and diminished tinnitus. It
`also might prevent the development of cholesteatoma (skin
`cyst in the middle ear), Which can cause chronic infection
`and destruction of ear structures.
`
`[0019] Tympanoplasty and myringoplasty are generally
`outpatient procedures. The otolaryngologist may approach
`repair of a tympanic membrane perforation either through
`the auditory canal (trans-canal approach), or via a post
`auricular incision folloWed by folding the ear forWard to
`expose the tympanic membrane (post-auricular approach).
`
`[0020] Before attempting any correction of the perfora
`tion, a hearing test is generally performed, and the patient is
`evaluated for Eustachian tube function, as partial or com
`plete loss of Eustachian tube function can exacerbate a
`tympanic membrane puncture and interfere With the adher
`ence of a graft to the tympanic membrane. Repair of a
`perforated tympanic membrane generally comprises placing
`an occluding material on the membrane. The patient is
`evaluated for complications, such as extension of squamous
`epithelium through the perforation and into the middle ear
`space. In such instances, tympanoplasty or myringoplasty is
`preferably accompanied, Where possible, by remediation of
`the complication.
`
`[0021] The present invention encompasses repair of a
`tympanic membrane With collagen biofabric either as a ?rst
`
`
`
`US 2007/0038298 A1
`
`Feb. 15, 2007
`
`or subsequent therapy. That is, the collagen biofabric may be
`used to repair a tympanic membrane deformity, such as a
`perforation, before other remedial measures are tried. Alter
`natively, repair of a tympanic membrane With collagen
`biofabric may be performed after one or more other remedial
`measures have been tried and failed.
`[0022] In one embodiment, repair of a tympanic mem
`brane With collagen biofabric may additionally comprise
`applying an anti-infective agent to the graft and/ or surround
`ing ear canal. Thus, in one embodiment, the invention
`provides a method of repairing a tympanic membrane com
`prising contacting the tympanic membrane With collagen
`biofabric and an anti-infective agent. The anti-infective
`agent can be contacted either prior to, concurrently With, or
`subsequent to contacting the tympanic membrane With the
`collagen biofabric. The anti-infective agent can be present
`separate from, or as an integral part of, the collagen biofab
`ric. For example, the anti-infective agent can be present on
`the surface of the collagen biofabric, or can be impregnated
`in the collagen biofabric. In a speci?c example, the anti
`infective agent is an antibiotic, a bacteriostatic agent, anti
`viral compound, a virustatic agent, antifungal compound, a
`?ngistatic agent, or an antimicrobial compound. In a speci?c
`embodiment, the anti-infective agent is ionic silver. In a
`more speci?c embodiment, the ionic silver is contained
`Within a hydrogel. Ionic silver hydrogel is a preferred
`anti-infective agent because it is broad spectrum, With no
`knoWn bacterial resistance; its application and removal are
`pain-free, and the hydrogel supports autolytic debridement.
`In a preferred embodiment, the collagen biofabric is impreg
`nated With silver ions prior to application to the tympanic
`membrane. In another embodiment, the collagen biofabric is
`impregnated With silver ions after application of the biofab
`ric to the tympanic membrane, for example, by application
`of ear drops.
`[0023] The invention further provides a method of repair
`ing a tympanic membrane comprising contacting the tym
`panic membrane With collagen biofabric and a plurality of
`stem or progenitor cells. Preferred stem cells include, for
`example, mesenchymal stem cells and the placenta-derived
`stem cells disclosed in United States Application Publication
`Nos. US 2003/0032179 and US 2003/0180269 US, each of
`Which is hereby incorporated in its entirety herein. In one
`embodiment, the collagen biofabric may be contacted With
`the stem or progenitor cells prior to contacting the tympanic
`membrane With the collagen biofabric. For example, col
`lagen biofabric may be prepared prior to application on the
`tympanic membrane by disposing stem or progenitor cells
`on the surface of, or Within, the collagen biofabric and
`alloWing the stem or progenitor cells sufficient time to attach
`to the collagen biofabric. The stem or progenitor cells can,
`for example, be disposed onto the surface of, or Within, the
`collagen biofabric at least, or no more than, 30 minutes, 1,
`2, 3, 4, 5, 6, 7, 8, 9, l0, l2, l4, l6, 18, 20, 22, or 24 hours
`prior to application of the collagen biofabric onto the
`tympanic membrane. In another embodiment, the collagen
`biofabric may be contacted With the stem or progenitor cells
`after application of the collagen biofabric to the tympanic
`membrane. In another embodiment, a the invention provides
`a method of treating a tympanic membrane comprising
`contacting the tympanic membrane With a plurality of stem
`or progenitor cells, and contacting the tympanic membrane
`With collagen biofabric so that the collagen biofabric covers
`the tympanic membrane and stem or progenitor cells.
`
`[0024] The number of stem or progenitor cells disposed
`onto the tympanic membrane, or onto the surface of the
`collagen biofabric, in any embodiment may vary, but may be
`at least 1x106, 3x106, 1x107, 3x107, 1x108, 3x108, 1x109,
`3x109, 1x10“), 3x10”, l><l0n, 3><l0ll, or l><l0l2; or may
`be no more than 1x106, 3x106, 1x107, 3x107, 1x108, 3x108,
`1x109, 3x109, 1x10“), 3x10“), l><l01l, 3><l0l1, or 1x10”;
`stem or progenitor cells. Thus, in speci?c embodiments, the
`invention provides a method of repairing a tympanic mem
`brane comprising contacting said tympanic membrane With,
`in either order, (a) collagen biofabric, and (b) a plurality of
`stem or progenitor cells comprising 1x106, 3x106, 1x107,
`3x107, 1x108, 3x108, 1x109, 3x109, 1x10“), 3x10“),
`l><l0n, 3><l0l1, or 1x10”; stem or progenitor cells. In other
`speci?c embodiments, the invention provides a method of
`treating a tympanic membrane comprising contacting the
`tympanic membrane, in either order, (a) collagen biofabric,
`and (b) a plurality of stem or progenitor cells comprising no
`more than 1x106, 3x106, 1x107, 3x107, 1x108, 3x108,
`1x109, 3x109, 1x10“), 3x10“), l><l01l, 3><l0l1, or 1x10”;
`stem or progenitor cells. In a more speci?c embodiment,
`said plurality of stem cells comprises tWo or more different
`stem or progenitor cell types.
`
`[0025] The invention further provides that the use of
`collagen biofabric to repair a tympanic membrane deformity
`may be the sole treatment of the tympanic membrane, or
`may be in addition to another therapies or treatment used
`simultaneously in the course of treating or repairing a
`tympanic membrane. For example, the invention provides
`for the repair of a tympanic membrane comprising contact
`ing the tympanic membrane With a collagen biofabric, and
`treating the tympanic membrane using an additional therapy
`not comprising contacting the tympanic membrane With a
`collagen biofabric, Where the contacting and the additional
`therapy individually or together cause a measurable
`improvement in, maintenance of, or lessening of the Wors
`ening of, at least one aspect of a tympanic membrane
`deformity, as compared to a tympanic membrane not con
`tacted With a collagen biofabric.
`
`[0026] The invention further provides for the use of col
`lagen biofabric to repair an ear condition in conjunction With
`repair of a tympanic membrane. For example, the collagen
`biofabric can be used to reconstruct or repair the outer or
`middle ear structures, including the auditory canal and
`middle ear chamber. The collagen biofabric, for example,
`may be used to repair or line the mastoid cavity, particularly
`Where mastoid reconstruction is indicated in addition to
`tympanoplasty. In one embodiment, the collagen biofabric
`may be used to line the mastoid cavity Where the mastoid
`cavity comprises exposed bone, that is, bone With no cov
`ering epithelial cell layer. In another embodiment, the col
`lagen biofabric may be used as a oval WindoW graft in stapes
`surgery, either alone or in conjunction With tympanoplasty
`or myringoplasty.
`[0027] 4.2 Collagen Biofabric
`[0028] 4.2.1 Description
`[0029] The collagen biofabric used to repair a tympanic
`membrane may be derived from the amniotic membrane of
`any mammal, for example, equine, bovine, porcine or catar
`rhine sources, but is most preferably derived from human
`placenta. In a preferred embodiment, the collagen biofabric
`is substantially dry, i.e., is 20% or less Water by Weight. In
`
`
`
`US 2007/0038298 A1
`
`Feb. 15, 2007
`
`another preferred embodiment, the collagen biofabric retains
`the native tertiary and quaternary structure of the amniotic
`membrane, i.e., has not been protease-treated. In another
`preferred embodiment, the collagen biofabric contains no
`collagen and other structural proteins that have been arti?
`cially crosslinked, e.g., chemically crosslinked, that is, the
`preferred collagen biofabric is not ?xed. A preferred col
`lagen biofabric is the dried, non-?xed, non-protease-treated
`amniotic membrane material described in Hariri, U.S. Appli
`cation Publication U.S. 2004/0048796, Which is hereby
`incorporated in its entirety, and that is produced by the
`methods described therein, and herein (see Examples 1, 2).
`HoWever, the methods of the present invention can utiliZe
`any placenta-derived collagen material made by any proce
`dure.
`
`[0030] In a preferred embodiment, the collagen biofabric
`used in the treatment or repair of a tympanic membrane is
`translucent. In other embodiments, the collagen biofabric is
`opaque, or is colored or dyed, e.g., permanently colored or
`dyed, using a medically-acceptable dyeing or coloring
`agent; such an agent may be adsorbed onto the collagen
`biofabric, or the collagen biofabric may be impregnated or
`coated With such an agent. In this embodiment, any knoWn
`non-toxic, non-irritating coloring agent or dye may be used.
`[0031] When the collagen biofabric is substantially dry, it
`is about 0.1 g/cm2 to about 0.6 g/cm2. In a speci?c embodi
`ment, a single layer of the collagen biofabric is at least 2
`microns in thickness. In another speci?c embodiment, a
`single layer of the collagen biofabric used to repair a
`tympanic membrane is approximately 10-40 microns in
`thickness, but may be approximately 2-150, 2-100 microns,
`5-75 microns or 7-60 microns in thickness in the dry state.
`
`[0032] In one embodiment, the collagen biofabric is prin
`cipally comprised of collagen (types I, III and IV; about 90%
`of the matrix of the biofabric), ?brin, ?bronectin, elastin,
`and may further comprise glycosaminoglycans and/or pro
`teoglycans. In certain embodiments, the collagen biofabric
`can comprise non-structural components, such as, for
`example, one or more groWth factors, e.g., platelet-derived
`groWth factors (PDGFs), vascular-endothelial groWth factor
`(VEGF), ?broblast groWth factor (FGF) and transforming
`groWth factor-[31. The composition of the collagen biofabric
`may thus be ideally suited to encourage the migration of
`?broblasts and macrophages, and thus the promotion of
`Wound healing.
`
`[0033] The collagen biofabric may be used in a single
`layered format, for example, as a single-layer sheet or an
`un-laminated membrane. Alternatively, the collagen biofab
`ric may be used in a double-layer or multiple-layer format,
`e.g., the collagen biofabric may be laminated. Lamination
`can provide greater stiffness and durability during the heal
`ing process. The collagen biofabric may be, for example,
`laminated as described beloW (see Section 4.2.7).
`[0034] The collagen biofabric may further comprise col
`lagen from a non-placenta source. For example, one or more
`layers of collagen biofabric may be coated or impregnated
`With, or layered With, puri?ed extracted collagen. Such
`collagen may be obtained, for example, from commercial
`sources, or may be produced according to knoWn methods,
`such as those disclosed in US. Pat. Nos. 4,420,339, 5,814,
`328, and 5,436,135, the disclosures of Which are hereby
`incorporated by reference.
`
`[0035] The collagen biofabric used to repair a tympanic
`membrane may comprise one or more compounds or sub
`stances that are not present in the placental material from
`Which the collagen biofabric is derived. The collagen bio
`fabric can comprise non-naturally-occuriing amounts of one
`or more compounds or substances that are normally present
`in the placental material from Which the collagen biofabric
`is derived. For example, the collagen biofabric may be
`impregnated With a bioactive compound, such as those listed
`in Section 4.2.2, beloW. Such bioactive compounds include,
`but are not limited to, small organic molecules (e.g., drugs),
`antibiotics (such as Clindamycin, Minocycline, Doxycy
`cline, Gentamycin), hormones, groWth factors, anti-tumor
`agents, anti-?ugal agents, anti-viral agents, pain medica
`tions, anti-histamines, anti-in?ammatory agents, anti-infec
`tives including but not limited to silver (such as silver salts,
`including but not limited to silver nitrate and silver sulfa
`diaZine), elemental silver, antibiotics, bactericidal enZymes
`(such as lysoZyme), Wound healing agents (such as cytok
`ines including but not limited to PDGF, TGF; thymosin),
`hyaluronic acid as a Wound healing agent, Wound sealants
`(such as ?brin With or Without thrombin), cellular attractant
`and scaffolding reagents (such as added ?bronectin) and the
`like. In a speci?c example, the collagen biofabric may be
`impregnated With at least one groWth factor, for example,
`?broblast groWth factor, epithelial groWth factor, etc. The
`biofabric may also be impregnated With small organic mol
`ecules such as speci?c inhibitors of particular biochemical
`processes e.g., membrane receptor inhibitors, kinase inhibi
`tors, groWth inhibitors, anticancer drugs, antibiotics, etc.
`Impregnating the collagen biofabric With a bioactive com
`pound may be accomplished, e.g., by immersing the col
`lagen biofabric in a solution of the bioactive compound of
`the desired concentration for a time suf?cient to alloW the
`collagen biofabric to absorb and to equilibrate With the
`solution.
`[0036] In other embodiments, the collagen biofabric may
`be combined With a hydrogel to form a composite. 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,
`Eu}: JPharm. Biopharm. 50(1): 27-46; Nguyen et al., 2002,
`Biomalerials, 23(22): 4307-14; Henincl et al., 2002, Adv
`Drug Deliv. Rev 54(1): 13-36; Skelhorne et al., 2002, Med.
`Device. Technol. 13(9): 19-23; Schmedlen et al., 2002,
`Biomalerials 23: 4325-32; all of Which are incorporated
`herein by reference in their entirety. In a speci?c embodi
`ment, the hydrogel composition is applied on the collagen
`biofabric, i.e., disposed on the surface of the collagen
`biofabric. The hydrogel composition for example, may be
`sprayed onto the collagen biofabric or coated onto the
`surface of the collage biofabric, or the biofabric may be
`soaked, bathed or saturated With the hydrogel composition.
`In another speci?c embodiment, the hydrogel is sandWiched
`betWeen tWo or more layers of collagen biofabric. In an even
`more speci?c embodiment, the hydrogel is sandWiched
`betWeen tWo layers of collagen biofabric, Wherein the edges
`of the tWo layers of biofabric are sealed so as to substantially
`or completely contain the hydrogel.
`[0037] The hydrogels useful in the methods and compo
`sitions of the invention can be made from any Water
`interactive, or Water soluble polymer knoWn in the art,
`including but not limited to, polyvinylalcohol (PVA), poly
`
`
`
`US 2007/0038298 A1
`
`Feb. 15, 2007
`
`hydroxyehthyl methacrylate, polyethylene glycol, polyvinyl
`pyrrolidone, hyaluronic acid, alginate, collagen, gelatin,
`dextran or derivatives and analogs thereof.
`
`[0038] In some embodiments, the collagen biofabric of the
`invention comprises one or more bioactive compounds and
`is combined With a hydrogel. For example, the collagen
`biofabric can be impregnated With one or more bioactive
`compounds prior to being combined With a hydrogel. In
`other embodiments, the hydrogel composition is further
`impregnated With one or more bioactive compounds prior to,
`or after, being combined With a collagen biofabric of the
`invention, for example, the bioactive compounds described
`in Section 4.2.2, beloW.
`
`[0039] 4.2.2 Bioative Compounds
`
`[0040] The collagen biofabric used in the methods of the
`invention may comprise (e. g., be impregnated With or coated
`With) one or more bioactive or medicinal compounds, such
`as small organic molecules (e.g., drugs), antibiotics, antivi
`ral agents, antimicrobial agents, anti-in?ammatory agents,
`antiproliferative agents, cytokines, enZyme or protein inhibi
`tors, antihistamines, and the like. In various embodiments,
`the collagen biofabric may be coated or impregnated With
`antibiotics (such as Clindamycin, Minocycline, Doxycy
`cline, Gentamycin), hormones, groWth factors, anti-tumor
`agents, anti-?ngal agents, anti-viral agents, pain medications
`(including
`XYLOCAINE®, Lidocaine,
`Procaine,
`Novocaine, etc.), antihistamines (e.g., diphenhydramine,
`BENADRYL®, etc.), anti-in?ammatory agents, anti-infec
`tives including but not limited to silver (such as silver salts,
`including but not limited to silver nitrate and silver sulfa
`diaZine), elemental silver, antibiotics, bactericidal enZymes
`(such as lysoZome), Wound healing agents (such as cytok
`ines including but not limited to PDGF (e.g.,
`REGRANEX®), TGF; thymosin), hyaluronic acid as a
`Wound healing agent, Wound sealants (such as ?brin With or
`Without thrombin), cellular attractant and scaffolding
`reagents (such as ?bronectin), and the like, or combinations
`of any of the foregoing, or of the foregoing and other
`compounds not listed. Such impregnation or coating may be
`accomplished by any means knoWn in the art, and a portion
`or the Whole of the collagen biofabric may be so coated or
`impregnated.
`[0041] The collagen biofabric, or composites comprising
`collagen biofabric, may comprise any of the compounds
`listed herein, Without limitation, individually or in any
`combination. Any of the biologically active compounds
`listed herein, and others useful in the context of the sclera or
`eye, may be formulated by knoWn methods for immediate
`release or extended release. Additionally, the collagen bio
`fabric may comprise tWo or more biologically active com
`pounds in different manners; e.g., the biofabric may be
`impregnated With one biologically active compound and
`coated With another. In another embodiment, the collagen
`biofabric comprises one biologically active compound for
`mulated for extended release, and a second biologically
`active compound formulated for immediate release.
`
`[0042] Wound healing, including the healing of tympanic
`membranes, including perforated tympanic membranes,
`requires adequate nutrition, particularly the presence of iron,
`Zinc, vitamin C, arginine, and the like. Thus, the collagen
`biofabric may be impreg
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