(12) United States Patent
`Lee et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,383,092 B2
`Feb. 26, 2013
`
`USOO8383 092B2
`
`(54) BIOADHESIVE CONSTRUCTS
`(75) Inventors: Bruce P. Lee, Madison, WI (US); Laura
`Vollenweider, Middleton, WI (US);
`John L. Murphy, Madison, WI (US);
`Fangmin Xu, Middleton, WI (US);
`Jeffrey L. Dalsin, Madison, WI (US);
`Jeanne Virosco, Madison, WI (US);
`William Lew, Mendota Heights, MN
`(US): Jed White, Madison, WI (US)
`
`O
`O
`(73) Assignee: SNNER'ssion Sub, Inc.,
`glon,
`
`c
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 320 days.
`
`(21) Appl. No.: 12/568,527
`
`(22) Filed:
`
`Sep. 28, 2009
`
`(65)
`
`O
`O
`Prior Publication Data
`US 2010/O137902 A1
`Jun. 3, 2010
`
`Related U.S. Application Data
`(63) Continuation-in-part of application No. 12099,254,
`filed on Apr. 8, 2008, which is a continuation-in-part of
`application No. 1 1/676,099, filed on Feb. 16, 2007,
`now Pat. No. 7,732,539, and a continuation-in-part of
`application No. 1 1/834,651, filed on Aug. 6, 2007, now
`Pat. No. 7,622,533.
`(60) Provisional application No. 61/100,560, filed on Sep.
`26, 2008, provisional application No. 61/100,738,
`filed on Sep. 28, 2008, provisional application No.
`60/910,683, filed on Apr. 9, 2007.
`
`(51) Int. Cl.
`(2006.01)
`A6 IK3I/74
`(52) U.S. Cl. ................... 424/78.27;606/213; 424/78.08
`(58) Field of Classification Search ................ 424/78.27
`See application file for complete search history.
`
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`JP
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`(Continued)
`
`OTHER PUBLICATIONS
`
`Lee et al. Biological Adhesives, 2006.257-277.*
`
`(56)
`
`References Cited
`
`(Continued)
`
`U.S. PATENT DOCUMENTS
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`
`Primary Examiner — Michael G. Hartley
`Assistant Examiner — Sean R Donohue
`riva
`(74) Attorney, Agent, or Firm — Casimir Jones S.C.
`
`(57)
`ABSTRACT
`The invention describes Substrates, such as prosthetics, films,
`nonwovens, meshes, etc. that are treated with a bioadhesive.
`he bioadhesi
`includ
`1
`b
`hat h
`The bioa nesive inclu es polymeric Substances that ave
`phenyl moieties with at least two hydroxyl groups. The bio
`adhesive constructs can be used to treat and repair, for
`example, hernias and damaged tendons.
`
`8 Claims, 13 Drawing Sheets
`
`EX. 1022
`APPLE INC. / Page 1 of 57
`
`

`

`US 8,383,092 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
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`
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`2005/056708
`6, 2005
`2010/091300
`8, 2010
`
`OTHER PUBLICATIONS
`Oxlund et al. Collagen deposition and mechanical strength of colon
`anastomoses and skin incisional wounds of rats, J Surg Res. Nov.
`1996;66(1):25-30.
`Jorgensen et al., Dose-response study of the effect of growth hormone
`on mechanical properties of skin graft wounds, J Surg Res. Mar.
`1995:58(3):295-301.
`daSilva, L.F.M., T.N.S.S. Rodrigues, M.A.V. Figueiredo, M.F.S.F. de
`Moura, and J.A.G. Chousal, Effect of AdhesiveType and Thickness
`on the Lap Shear Strength J. Adh., 2006. 82: p. 1091-1115.
`Santillan-Doherty, P. R. Jasso-Victoria, A. Sotres-Vega, R. Olmos,
`J.L. Arreola, D. Garcia, B. Vanda, M. Gaxiola, A. Santibanez, S.
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`Research, 1996. 9(1): p. 45-55.
`Burger, J.W.A., J.A. Halm, A.R. Wijsmuller, S. ten Raa, and J. Jeekel,
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`Lo Menzo, E., J.M. Martinez, S.A. Spector, A. Iglesias, V.
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`196(5): p. 715-9.
`* cited by examiner
`
`EX. 1022
`APPLE INC. / Page 2 of 57
`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 1 of 13
`
`US 8,383,092 B2
`
`Figure
`
`Schematic representation of A
`gointercialiy awaiiatie, nor-adhesive
`biologic mesh and 8) the proposed
`biologic mesh coated with Nerites'
`ascissive.
`
`
`
`Figure 2
`
`{:
`-(-CH
`C:-
`'8
`
`
`
`}
`R
`or
`o,
`{-CH (-ch.
`:
`8 :
`six
`
`:
`
`w
`
`o
`--ch-
`{:
`
`a 3-3
`
`a
`
`V
`
`iyiraghatic,
`Axitxsix8,
`assy
`i-ysiogiic
`Eicitiesek
`&isitio:
`Cherica stricities of
`450 and 280, espectively 8
`
`-
`is worn-s-cooch,
`OA
`
`itygiophobie.
`3iassy
`x8::::
`A and 5A2, whese , , and xate 37,
`
`**********************************************************************
`
`
`
`EX. 1022
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`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 2 of 13
`
`US 8,383,092 B2
`
`Figure 3
`
`iOOf A Derivative
`
`
`
`
`
`|
`
`C:- Degradabie
`tinkages
`Gerberal structure of vedhesive,
`
`s: Medhes ive-022
`
`:
`
`eciesiwei
`s www.gwww:
`:
`88:
`s:
`8:
`&
`fire day
`in vitro degradation of cured Medhesive hydrogeis
`as followed by the percent dry weight remaining in
`the adhesive.
`
`EX. 1022
`APPLE INC. / Page 4 of 57
`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet3 of 13
`
`US 8,383,092 B2
`
`Figure 5
`
`e
` 2
`
`or
`»
`3
`oft
`“
`eo
`es eS of
`
`{A} Paak stress saquired to sepanate hyo ploces of adhered collagen sheels in lap shaar mode and. (B) burst
`strength: adhesion last performed! or eplagen sheets: Mode of failure: A= Adhesive failure: Cs Cohesive
`talure: T = Ocllagen substraia tear # > slatintoally ciferont fram Tisseet VA: « = olatiatioally dierent fron
`OvuadraSeal-OH. (p= 0.05}
`
`Figure 6
`
`
`
`Hho LY4PES6Syeed-o-Poh—olTPEPEG of} al
`
`
`Omsggg7© Norn O-4g07OG" OngenaOo cil
`ml
`=
`my
`moe ees4
`
`on
`HO
`po
`
`na @
`Medhesive-024
`
`
`
`Gy
`%
`860
`sed deGoPEGGBR
`
`HO
`res
`HorNe
`a
`ae
`
`ity
`t
`GO yw
`@
`oO
`a
`Boy.
`Lot goPGkollGoh2.4.PEGwot egyPORigdoe?
`Z
`%,
`a
`2080
`Riyeds:
`yadeed
`
`
`
`Medhesive-027
`
`Chemical structures of adhesive palyniers lo be tested as adhesive coatings applied to bolagke mash.
`
`EX. 1022
`APPLEINC./ Page 5 of 57
`
`EX. 1022
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`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 4 of 13
`
`US 8,383,092 B2
`
`Figure 7
`
`Oxicizia:
`Ragent
`
`
`
`Hydrophobic
`3:33
`
`sesssssssssss
`
`Scheatic of the fox3sed ioadhesive biologic prosthetic estedded with
`oxidizing reagest. As th&acirasive is fehydrated, 8 the Sciabilizei &xidging
`feagent is eieased arid oxidizes the catechci, (C) resting is covalent crossiik
`foratia between tire catechoi and farcticaragraags presett or the tissue
`Siriace,
`
`Figure 8
`
`A.
`
`Bigkggies
`8.338 & \
`8si Sista:
`Acisesika
`
`8ixiegic
`w8S
`
`st
`St::::::::::
`
`
`
`^ (gening in
`& Sist:
`Ridityw
`
`Scientatics of Alap sheat and Bixirst streagh test setups.
`
`EX. 1022
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`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 5 of 13
`
`US 8,383,092 B2
`
`
`
`Figure 9
`o
`
`8:Strašict of siggotiag& 8:it:38&ic agent actities &ncio; regair,
`
`Figure 10
`
`Left blank intentionally
`
`EX. 1022
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`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 6 of 13
`
`US 8,383,092 B2
`
`Figure ill
`
`iss&ew 38:a::c: eites:
`
`herite:S-2
`
`Neries-3. heritask
`
`issee: Wi: 8:33xx: 888s.
`
`Nefies-
`
`888S-S 88;i&ssa
`
`s
`
`
`
`8
`
`50
`
`
`
`200
`
`88838
`
`isse: i:
`
`N888s
`
`series
`
`*&fies-S
`
`8:88-8
`
`Adhesion tests test its from a jap seat adhesios test, a -peet test, and c.
`burst strength test. hiode of faitise: , sixture of aciesive aid cohesive
`failife, A, 3chesive faire, C, x:8sive failife: i, Sibstrate tear.
`
`EX. 1022
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`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 7 of 13
`
`US 8,383,092 B2
`
`Figure 12
`
`les------
`(-)-les-to-n-in-a-ra-n-
`8
`I.
`s: so
`
`Nerites-4
`
`-PEGoo--- litrecio-polio r
`
`:
`
`... x:
`
`Sr.
`
`Neries
`
`-PEGeo-lu-
`
`s
`
`:
`
`t
`
`x
`
`PEGeotectoo-region).pcao
`
`y
`
`x : y - $8: 3
`
`HN
`
`E.
`
`i N --Nui
`o-
`
`\-
`wo-i-
`
`Nrisi
`
`K.
`
`ics---,
`
`3.
`
`'^^^ 8.
`
`
`
`-3
`c -8;
`
`^a
`Nerites
`
`- l ~). -- s
`
`3. r
`K.
`
`-r
`
`rx
`
`;
`
`ty
`
`:
`
`S.
`8.
`DC^^ -8
`
`r\
`
`\-, :
`
`Neries-8.
`Cihetical strictures of aciesive polyai's to be tested as as adhesive coating (33
`Coliage; the:bates.
`
`EX. 1022
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`
`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet8 of 13
`
`US 8,383,092 B2
`
`OH
`
`Figure 13
`
`OH
`
`OH
`
`OH
`
`Cle
`
`°
`
`cht
`
`SS
`
`°
`
`Cite
`
`9
`
`cH
`
`9
`
`
`
`
`
`OH
`OH. A :
`OH
`OH
`meteNNJopopethen OTJc~My
`wocthoudy{7}/ owpyarte fiegull9}/ ~~pthth
`ou
`A C.,
`aS
`C |
`
`oH=©6@C-(PEG-DOPA-Boc), OH OH C-(PEG-DOPA,), OH
`
`
`
`PEG 10K — (D)4
`PEG 10K - (D,)4
`(a)
`(b)
`
`Hs
`
`CH
`
`OH
`
`
`(HA.
`\fn oo? Via
`HY
`Oe
`
`
`
`-
`
`
`
`
`
`HN cw CH U, MESof\ Jtoo ors wrens } H
`
`
`
`
`:
`ae
`eo
`;
`9
`G
`9°
`9
`
`UK LRoy
`KAA ut
`tL
`oh/ \fo
`(ou
`H th CH ree } tr M
`hy ( en CH NT H
`3
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`
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`
`OH
`
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`
`NA
`
`C-(PEG-DOPA;-Lys2),
`PEG 10K — (DL),
`
`OH
`
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`
`(¢)
`
`oH CH,
`
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`N
`
`CH:
`
`mi
`
`oO
`
`c
`
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`
`m
`
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`Oo
`
`2
`2 Lo too I
`cylnf \/ \4 why Jot,
`CH,
`E
`H
`m
`m H
`CH,
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`OH Ss
`
`CH
`CH»
`
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`N
`
`oO
`Qo
`
`OH
`
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`
`C-(PEG-DOHA),
`(d) PEG 10K — (DH), m=56
`(g) PEG 20K - (DH), m=113
`g
`
`oH
`
`EX. 1022
`APPLEINC. / Page 10 of 57
`
`EX. 1022
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`

`

`U.S. Patent
`
`Feb. 26, 2013
`
`Sheet 9 of 13
`
`US 8,383,092 B2
`
`Figure 13 (cont.)
`
`OH
`
`OH
`
`OH
`
`OH
`
`CH2
`
`O
`O
`
`H
`
`ck-o'-- /-(-)-o-ch.
`c--i-o-n- }/ \{ Y1so in-ch,
`
`56
`O
`
`56
`
`O
`
`56 O
`O
`
`56
`
`H
`
`CH2
`
`CH2
`
`OH
`
`OH
`
`OH
`
`OH
`
`C-(PEG-DMu).
`PEG 1 OK - (DMu)
`(e)
`
`OH
`
`OH
`
`OH
`
`OH
`
`H
`H CH2
`cline "cho
`or /(-no Tch C II-N-CH,
`CH-N-I- -chi-of- }/ \{ Y-solich-Elti-ch,
`
`CH,
`
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`U.S. Patent
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`Feb. 26, 2013
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`Sheet 10 of 13
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`US 8,383,092 B2
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`O.O.O. OOO 223 O5O w
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`Lap shear adhesion tests performed on collagen backing coated with Medhesive-024 and
`compared to adhesive joints adhered with commercially available tissue adhesives.
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`U.S. Patent
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`Feb. 26, 2013
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`Sheet 11 of 13
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`US 8,383,092 B2
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`Figure 15
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`Burst strength tests performed on collagen backing coated with Medhesive-024.
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`U.S. Patent
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`Feb. 26, 2013
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`Sheet 12 of 13
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`US 8,383,092 B2
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`Figure 16
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`U.S. Patent
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`Feb. 26, 2013
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`Sheet 13 of 13
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`US 8,383,092 B2
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`Figure 18
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`US 8,383,092 B2
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`1.
`BOADHESIVE CONSTRUCTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application claims the benefit of U.S. provi
`sional application Ser. No. 61/100,560 filed Sep. 26, 2008,
`and U.S. provisional application Ser. No. 61/100,738 filed
`Sep. 28, 2008, the contents of which are incorporated in their
`entirety herein by reference. The present application also
`claims the benefit of U.S. application Ser. No. 12/099,254,
`filed Apr. 8, 2008, which claims the benefit of U.S. provi
`sional application Ser. No. 60/910,683 filed on Apr. 9, 2007,
`U.S. application Ser. No. 1 1/676,099, filed Feb. 16, 2007, and
`U.S. application Ser. No. 1 1/834,651, filed Aug. 6, 2007, the
`contents of which are incorporated in their entirety herein by
`reference including any provisional applications referred to
`therein for a priority date(s).
`
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`REFERENCETO FEDERAL FUNDING
`
`The project was funded in part by NIH (1R43AR056519
`01A1, 1R43DK083199-01, and 2R44DK083199-02), and
`NSF (IIP-0912221) grants. NMR characterization was per
`formed at NMRFAM, which is supported by NIH
`(P41RR02301, P41GM66326, P41GM66326, P41RR02301,
`RR02781, RR08438) and NSF (DMB-8415048, OIA
`9977486, BIR-9214394) grants. The government has certain
`rights in the invention.
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`
`FIELD OF THE INVENTION
`
`The invention relates generally various Substrates, such as
`prosthetics, films, nonwovens, meshes, etc. that are treated
`with a bioadhesive. The bioadhesive includes polymeric sub
`stances that have phenyl moieties with at least two hydroxyl
`groups. The bioadhesive constructs can be used to treat and
`repair, for example, hernias and damaged tendons.
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`BACKGROUND OF THE INVENTION
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`these biologic implants become a site for remodeling via
`fibroblast migration, followed by Subsequent native collagen
`deposition.
`In addition to mesh type, effective immobilization of the
`mesh against the abdominal wall is also critical to the Success
`of the hernia repair. Currently, both synthetic and biologic
`meshes are held in place with sutures and staples. While these
`fixation methods demonstrate variable Success, their usage is
`believed to be a source of nerve damage and chronic discom
`fort. Thus, finding an effective alternative to sutures and metal
`Staples would dramatically enhance the long-term biocom
`patibility of these meshes.
`Tendon and ligament injuries have been occurring with
`increasing frequency over the last several decades. While
`methods for the fixation of torn tendons and ligaments have
`improved, none has proven ideal. The existing methods of
`using Sutures alone or Sutures with a variety of graft materials
`can create weak points at the Sutures and require immobili
`zation for a period of time after repair, before rehabilitation
`can begin. The evidence generated by the medical community
`is that earlier rehabilitation increases the likelihood that the
`repair of such injuries will be successful. A new method for
`repairing tendon and ligament injuries that would allow ear
`lier rehabilitation and fewer incidences of post-operative
`pain, Surgical complications, and rerupture of the repaired
`tissues is clearly needed.
`Therefore, a need exists for improved materials and meth
`ods that overcome one or more of the current disadvantages.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention surprisingly provides unique bioad
`hesive constructs that are Suitable to repair or reinforce dam
`aged tissue.
`The constructs include a suitable Support that can be
`formed from a natural material. Such as collagen or man made
`materials such as polypropylene and the like. The Support can
`be a film, a membrane, a mesh, a non-woven and the like. The
`support need only help provide a surface for the bioadhesive
`to adhere. The Support should also help facilitate physiologi
`cal reformation of the tissue at the damaged site. Thus the
`constructs of the invention provide a site for remodeling via
`fibroblast migration, followed by Subsequent native collagen
`deposition.
`The bioadhesive is any polymer that includes multihy
`droxyphenyl groups, referred to herein a DHPD's. The poly
`merbackbone can be virtually any material as long as the
`polymer contains DHPD's that are tethered to the polymer via
`a linking group or a linker. Generally, the DHPD comprises at
`least about 1 to 100 weight percent of the polymer (DHPp),
`more particularly at least about 2 to about 65 weight percent
`of the DHPp and even more particularly, at least about 3 to
`about 55 weight percent of the DHPp. Suitable materials are
`discussed throughout the specification.
`In certain embodiments an oxidant is included with the
`bioadhesive film layer. The oxidant can be incorporated into
`the polymer film or it can be contacted to the film at a later
`time. A solution could be sprayed or brushed onto either the
`adhesive surface or the tissue substrate surface. Alternatively,
`the construct can be dipped or Submerged in a solution of
`oxidant prior to contacting the tissue Substrate. In any situa
`tion, the oxidant upon activation, can help promote crosslink
`ing of the multihydroxyphenyl groups with each other and/or
`tissue. Suitable oxidants include periodates and the like.
`The invention further provides crosslinked bioadhesive
`constructs or hydrogels derived from the compositions
`described herein. For example, two DHDP moieties from two
`
`Surgical prostheses, meshes, and grafts are commonly
`used in Surgical procedures that include tendon and ligament
`repair, hernia repair, cardiovascular Surgery, as well as certain
`dental Surgical procedures. These prosthetic materials are
`fixated through the use of sutures, staples, or tacks. While
`Such fixation methods have demonstrated Success in immo
`bilizing Surgical prostheses, they are also a source of existing
`problems associated with each Surgical procedure. In some
`instances, Sutures may not be practical in certain situations
`where there is limited space or light source needed for sutur
`ing.
`Hernia repair is one of the most commonly performed
`Surgeries in the US. Although the use of prosthetic mesh as a
`reinforcement has significantly improved Surgical outcomes,
`the rate of hernia recurrence remains as high as 30-50%.
`Moreover, current prosthetic materials are associated with
`numerous complications, including increased risk of infec
`tion, prosthetic shrinkage and host foreign body reactions.
`Such reactions often lead to changes in prosthetic mesh textile
`properties and result in a diminished postoperative patient
`quality of life. Recent advances in tissue engineering have
`seen the introduction of various biologic prosthetic meshes.
`These biologic meshes are derived from human or animal
`tissue modified both to preserve the structural framework of
`the original tissue and to eliminate cells potentially capable of
`instigating a foreign body reaction. Following implantation,
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`US 8,383,092 B2
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`separate polymer chains can be reacted to form a bond
`between the two DHDP moieties. Typically, this is an oxida
`tive/radical initiated crosslinking reaction wherein oxidants/
`initiators such as NaIO, NaIO, FeIII salts, (FeCl), Mn III
`salts (MnCl), H2O, oxygen, an inorganic base, an organic
`base oran enzymatic oxidase can be used. Typically, a ratio of
`oxidant/initiator to DHDP containing material is between
`about 0.2 to about 1.0 (on a molar basis) (oxidant:DHDP). In
`one particular embodiment, the ratio is between about 0.25 to
`about 0.75 and more particularly between about 0.4 to about
`0.6 (e.g., 0.5). It has been found that periodate is very effec
`tive in the preparation of crosslinked hydrogels of the inven
`tion. Additionally, it is possible that oxidation “activates' the
`DHPD(s) which allow it to form interfacial crosslinking with
`appropriate Surfaces with functional group (i.e. biological
`tissues with —NH2. —SH, etc.)
`Typically, when the DHDP containing construct is treated
`with an oxidant/initiator as described herein, the coating gels
`(crosslinks) within 1 minute, more particularly within 30
`seconds, most particularly under 5 seconds and in particular
`within 2 seconds or less. For example, QuadraSeal-D4
`(PEG10k-(D)) (FIG.13b) gelled within2 seconds or less at
`a IO:DOPA mole ratio of 0.25 or higher.
`The use of the bioadhesive constructs eliminates or reduces
`the need to use staples, Sutures, tacks and the like to secure or
`repair damaged tissue, for example, Such as herniated tissue
`or torn ligaments or tendons.
`The bioadhesive constructs of the invention combine the
`unique adhesive properties of multihydroxy (dihydroxyphe
`nyl)-containing polymers with the biomechanical properties,
`bioinductive ability, and biodegradability of biologic meshes
`to develop a novel medical device for hernia repair. A thin film
`of biodegradable, water-resistant adhesive will be coated onto
`a commercially available, biologic mesh to create an adhesive
`bioprosthesis. These bioadhesive prosthetics can be affixed
`over a hernia site without Sutures or staples, thereby poten
`tially preventing tissue and nerve damage at the site of the
`repair. Both the synthetic glue and the biologic meshes are
`biodegradable, and will be reabsorbed when the mechanical
`Support of the material is no longer needed; these compounds
`prevent potential long-term infection and chronic patient dis
`comfort typically associated with permanent prosthetic mate
`rials. Additionally, minimal preparation is required for the
`proposed bioadhesive prosthesis, which can potentially sim
`plify Surgical procedures. The adhesive coating will be char
`acterized, and both adhesion tests and mechanical tests will
`be performed on the bioadhesive biologic mesh to determine
`the feasibility of using such a material for hernia repair.
`Additionally, the unique adhesive properties of dihydrox
`yphenyl-containing polymers can be combined with the bio
`mechanical properties, bioinductive ability, and biodegrad
`ability of a collagen membrane to develop a novel
`augmentation device for tendon and ligament repair. These
`bioadhesive tapes can be wrapped around or placed over a
`torntendon orligament to create a repair stronger than Sutures
`alone. This new method of augmentation Supports the entire
`graft Surface by adhering to the tissue being repaired, as
`opposed to conventional repair methods, which use Sutures to
`attach the graft at only a few points. Securing the repaired
`tissue more effectively means that patients can potentially
`begin post-operative rehabilitation much sooner, a critical
`development, as early mobilization has been found to be
`crucial for regenerating well organized and functional col
`lagen fibers in tendons and ligaments. The collagen mem
`branes will be coated with biomimetic synthetic adhesive
`65
`polymers (described herein) to create a bioadhesive collagen
`tape. The adhesive coating will be characterized, and both
`
`4
`adhesion and mechanical tests will be performed on the bio
`adhesive collagen tape to determine the feasibility of using
`Such a material to augment tendon and ligament repair.
`While multiple embodiments are disclosed, still other
`embodiments of the present invention will become apparent
`to those skilled in the art from the following detailed descrip
`tion. As will be apparent, the invention is capable of modifi
`cations in various obvious aspects, all without departing from
`the spirit and scope of the present invention. Accordingly, the
`detailed descriptions are to be regarded as illustrative in
`nature and not restrictive.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 provides a schematic representation of a bioadhe
`sive construct of the invention.
`FIG. 2 provides suitable bioadhesive materials for a con
`Struct.
`FIG.3 is a general structure for one type of bioadhesive of
`the invention.
`FIG. 4 provides degradation information regarding several
`of the bioadhesives of the invention.
`FIG. 5 provides physical data on several of the constructs
`of the invention and commercially available materials.
`FIG. 6 provides the chemical structure of two of the bio
`adhesives used in the constructs of the invention.
`FIG. 7 provides a schematic of how the bioadhesive con
`struct can function.
`FIG. 8 is a diagram of lap shear and burst test setups.
`FIG. 9 provides examples of how a bioadhesive construct
`can be applied to a tendon.
`FIG. 10 left intentionally blank.
`FIG. 11, provides adhesion test results of several bioadhe
`sive constructs of the invention and a commercial product.
`FIG. 12 provides chemical structures of several of the
`bioadhesive coatings.
`FIG. 13 provides chemical structure of several of the bio
`adhesive coatings.
`FIG. 14 provides lap shear adhesion tests performed on
`bioadhesive constructs of the invention.
`FIG. 15 provides burst strengths for a bioadhesive con
`struct of the invention.
`FIG. 16 depicts a surgical mesh coated with a bioadhesive
`coating described in the specification.
`FIG. 17 provides a mesh coated with adhesive pads.
`FIG. 18 provides schematics of A) construct with 100%
`area coverage, B) a patterned construct with 2 circular
`uncoated areas with larger diameter, and C), a patterned con
`struct with 8 circular uncoated areas with smaller diameter.
`
`DETAILED DESCRIPTION
`
`In the specification and in the claims, the terms “including
`and "comprising are open-ended terms and should be inter
`preted to mean “including, but not limited to... These terms
`encompass the more restrictive terms “consisting essentially
`of and “consisting of
`It must be noted that as used herein and in the appended
`claims, the singular forms “a”, “an', and “the include plural
`reference unless the context clearly dictates otherwise. As
`well, the terms “a” (or “an”), “one or more' and “at least one'
`can be used interchangeably herein. It is also to be noted that
`the terms “comprising”, “including”, “characterized by and
`"having can be used interchangeably.
`Unless defined otherwise, all technical and scientific terms
`used herein have the same meanings as commonly under
`stood by one of ordinary skill in the art to which this invention
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`5
`belongs. All publications and patents specifically mentioned
`herein are incorporated by reference in their entirety for all
`purposes including describing and disclosing the chemicals,
`instruments, statistical analyses and methodologies which are
`reported in the publications which might be used in connec
`tion with the invention. All references cited in this specifica
`tion are to be taken as indicative of the level of skill in the art.
`Nothing herein is to be construed as an admission that the
`invention is not entitled to antedate such disclosure by virtue
`of prior invention.
`General Applications
`In one embodiment, adhesive compounds of the present
`invention provide a method of adhering a first Surface to a
`second Surface in a subject. In some embodiments, the first
`and second surfaces are tissue surfaces, for example, a natural
`tissue, a transplant tissue, or an engineered tissue. In further
`embodiments, at least one of the first and second Surfaces is an
`artificial surface. In some embodiments, the artificial surface
`is an artificial tissue. In other embodiments, the artificial
`Surface is a device or an instrument. In some embodiments,
`adhesive compounds of the present invention seal a defect
`between a first and second Surface in a subject. In other
`embodiments, adhesive compounds of the present invention
`provide a barrier to, for example, microbial contamination,
`infection, chemical or drug exposure, inflammation, or
`metastasis. In further embodiments, adhesive compounds of
`the present invention stabilize the physical orientation of a
`first surface with respect to a second surface. In still further
`embodiments, adhesive compounds of the present invention
`reinforce the integrity of a first and second surface achieved
`by, for example, Sutures, staples, mechanical fixators, or
`mesh. In some embodiments, adhesive compounds of the
`present invention provide control of bleeding. In other
`embodiments, adhesive compounds of the present invention
`provide delivery of drugs including, for example, drugs to
`control bleeding, treat infection or malignancy, or promote
`tissue regeneration.
`The bioadhesive constructs described hereincan be used to
`repair torn, herniated, or otherwise damaged tissue. The tis
`Sue can vary in nature but includes cardiovascular, vascular,
`epithelial, ligament, tendon, muscle, bone and the like. The
`constructs can be utilized with general Surgical techniques or
`with more advanced laparoscopic or arthroscopic Surgery
`techniques. Once the constructs are applied to the damaged/
`injured site, they can be directly adhered to the tissue. Alter
`natively and in addition to the adherence of the adhesive to the
`tissue, Staples, Sutures or tacks and the like can also be used to
`help secure the construct.
`In addition to tendon and ligament repair and hernia repair,
`the bioadhesive construct could potentially be utilized in car
`diovascular surgery. Over 600,000 vascular grafts are
`implanted annually to replace damaged blood vessels. Coro
`nary artery bypass grafting (CABG) is the most common
`methodofreplacing diseased blood vessels. When no suitable
`autologous vessels are available, there are several synthetic
`materials used for prosthetic vascular grafts such as PTFE,
`polyurethane and Dacron. Such materials have been used in
`cardiovascular repair since the early 1950s. In addition to
`synthetic grafts, collagen has been investigated with some
`Success for use as a cardiovascular