U.S. patent application number 10/515164 was filed with the patent office on 2005-10-27 for biomedical adhesive.
This patent application is currently assigned to Commonwealth Scientific & Industrial Research Organisation. Invention is credited to Hughes, Timothy Charles.
Application Number | 20050238692 10/515164 |
Document ID | / |
Family ID | 29286127 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050238692 |
Kind Code |
A1 |
Hughes, Timothy Charles |
October 27, 2005 |
Biomedical adhesive
Abstract
The biomedical adhesives of the invention provide a reactive
surface to adhere or crosslink to tissue and may be used, for
example, as ready-to-use corneal onlay in ophthalmic surgery. The
invention provides a method for bonding a bulk material to a
corresponding nucleophilic or electrophilic surface including
attaching a multifunctionally activated bulk material compound to
the bulk material and contacting a functional group of the compound
with the surface under conditions permitting covalent linkage
between the bulk material and the functional group.
Inventors: |
Hughes, Timothy Charles;
(Victoria, AU) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Commonwealth Scientific &
Industrial Research Organisation
|
Family ID: |
29286127 |
Appl. No.: |
10/515164 |
Filed: |
May 27, 2005 |
PCT Filed: |
May 21, 2003 |
PCT NO: |
PCT/AU03/00612 |
Current U.S.
Class: |
424/427 ;
427/2.24 |
Current CPC
Class: |
A61L 27/34 20130101;
A61L 27/34 20130101; C08L 71/02 20130101; C08F 290/02 20130101;
C08L 71/02 20130101; A61L 27/18 20130101; A61F 2/14 20130101; C08F
290/062 20130101; A61L 27/18 20130101; A61L 2430/16 20130101 |
Class at
Publication: |
424/427 ;
427/002.24 |
International
Class: |
A61L 002/00; A61F
002/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 21, 2002 |
EP |
02011173.8 |
Claims
1. A method for bonding an inorganic or organic bulk material to a
nucleophilic or electrophilic surface including: attaching a
multifunctionally activated compound to the bulk material, the
compound selected to be electrophilic or nucleophilic opposite to
the surface; then contacting the multifunctionally activated
compound with the surface under conditions permitting covalent
linkage between the surface and the multifunctionally activated
compound.
2. A method according to claim 1 in which the bulk material
combined with the multifunctionally activated compound is
dehydrated before contacting the surface.
3. A method according to claim 1 in which the multifunctionally
activated compound includes an activated ester or amide.
4. A method according to claim 3, wherein the multifunctionally
activated compound is of formula R.sub.13-D-R.sub.12 wherein D is a
bivalent organic radical, which is unsubstituted or substituted by
one or more carboxy or carboxy derivative groups; R.sub.12 is a
carboxy derivative group; and R.sub.13 is a further reactive group
selected from the group consisting of a carboxy, carboxy
derivative, isocyanato, isothiocyanato and epoxy group.
5. A method according to claim 4, wherein D is an optionally
branched C.sub.1-C.sub.12-alkylene; a radical of a dendrimer or
star-bust polymer; a radical of a polyethylene glycol; a radical of
a polyvinyl alcohol; or a radical of a hyperbranched polyester
resin, preferably the radical of a polyethylene glycol.
6. A method according to claim 4, wherein R.sub.12 and R.sub.13 are
each an activated ester group.
7. A method according to claim 1 wherein the multifunctionally
activated compound is polyethylene glycol that is di-substituted
with succinimidyl propionate, succinimidyl succinate or
succinimidyl succinamide, and is first reacted with nucleophilic
groups on the surface of the bulk material.
8. A method according to claim 1 in which the multifunctionally
activated compound includes a carboxy derivative group selected
from a group consisting of: 4
9. A method according to claim 1 in which the carboxy derivative
group is 5
10. A method according to claim 1 in which the bulk material
combined with the multifunctionally activated compound is washed to
remove excess multifunctionally activated compound before
contacting the surface.
11. A method according to claim 1 in which a natural or synthetic
polymer is comprising co-reactive groups is first bonded to the
bulk material.
12. A method according to claim 11 in which the natural or
synthetic polymer is selected from the group consisting of
cell-adhesive glycoproteins like collagens (various types),
fibronectin, vitronectin, laminin, poly(ethyl imine), amino
dextran, PAMAM dendrimers, poly(allyl amine), poly(vinyl alcohol),
poly(arylic acid) and poly(methacrylic acid).
13. A method according to claim 10 in which the natural or
synthetic polymer is collagen.
14. A bioadhesive material attached to a bulk material for bonding
the bulk material to a biological surface, the bioadhesive
comprising a multifunctionally activated compound reactable with
nucleophilic or electrophilic functional groups of the surface.
15. A bioadhesive according to claim 14 in which the
multifunctionally activated compound is bound to a natural or
synthetic polymer bound to the bulk material.
16. A bioadhesive according to claim 15 in which the
multifunctionally activated compound is of formula
R.sub.13-D-R.sub.12 (j) wherein D is a bivalent organic radical,
which is unsubstituted or substituted by one or more carboxy or
carboxy derivative groups; R.sub.12 is a carboxy derivative group;
and R.sub.13 is a further reactive group selected from the group
consisting of a carboxy, carboxy derivative, isocyanato,
isothiocyanato and epoxy group.
17. A biomedical device for attaching to a biological surface by a
bioadhesive including a biocompatible organic or inorganic bulk
material to which a multifunctionally activated compound has been
bound, the bound multifunctionally actived compound being capable
of being stored anhydrously.
18. A biomedical device according to claim 17 in which the
multifunctionally activated compound is of formula
R.sub.13-D-R.sub.12 (j) wherein D is a bivalent organic radical,
which is unsubstituted or substituted by one or more carboxy or
carboxy derivative groups; R.sub.12 is a carboxy derivative group;
and R.sub.13 is a further reactive group selected from the group
consisting of a carboxy, carboxy derivative, isocyanato,
isothiocyanato and epoxy group, one or more of the groups being
hydralytically unstable.
19. A biomedical device according to claim 18 further comprising a
natural or synthetic polymer having co-reactive groups.
20. A biomedical device according to claim 18, wherein D is an
optionally branched C.sub.1-C.sub.12-alkylene; a radical of a
dendrimer or star bust polymer; a radical of a polyethylene glycol;
a radical of a polyvinyl alcohol; or a radical of a hyperbranched
polyester resin, preferably the radical of a polyethylene
glycol.
21. A biomedical device according to claim 18, wherein R.sub.12 and
R.sub.13 are each an activated ester group.
22. A biomedical device according to claim 17 wherein the
multifunctionally activated compound is polyethylene glycol that is
di-substituted with succinimidyl propionate, succinimidyl succinate
or succinimidyl succinamide, and is first reacted with nucleophilic
groups on the surface of the bulk material.
23. A biomedical device according to claim 17 in which the
multifunctionally activated compound includes a carboxy derivative
group selected from a group consisting of: 6
24. A biomedical device according to claim 17 in which the carboxy
derivative group is 7
25. A biomedical device according to any one of claims 17 further
comprising a natural or synthetic polymer.
26. A biomedical device according to claim 17 stored anhydrously
prior to use wherein one or more of the groups of the
multifunctionally activated compound are unreacted.
27. A biomedical device according to claim 23, stored anhydrously
prior to use wherein one or more of the groups of the
multifunctionally activated compound are unreacted.
28. A biomedical device according to claim 17, the device being an
opthalmic device, a contact lens, a corneal onlay, a corneal inlay,
a lenticule or an intraocular lens.
29. A process for applying a bioadhesive to a surface of a
biomedical device comprising a biocompatible organic or inorganic
bulk material including the steps of if the surface is not
nucleophilic or electrophilic, applying nucleophilic or
electrophilic functional groups to the surface, covalently bonding
to the surface a multifunctionally activated compound, the compound
selected to be electrophilic or nucleophilic opposite to the
fuctional groups, washing the surface of unbound multifunctionally
activated compound.
30. A process for applying a bioadhesive to a surface of a
biomedical device comprising a biocompatible organic or inorganic
bulk material including the steps of if the surface is not
nucleophilic or electrophilic, applying nucleophilic or
electrophilic functional groups to the surface, covalently bonding
the functional groups to a natural or synthetic polymer comprising
co-reactive groups, covalently coupling to the natural or synthetic
polymer a multifunctionally activated compound, the compound
selected to be electrophilic or nucleophilic opposite to the
co-reactive groups, washing the natural or synthetic polymer of
unbound multifunctionally activated compound.
31. A process according to claim 29, wherein the multifunctional
compound is of formula R.sub.13-D-R.sub.12 (j) wherein D is a
bivalent organic radical, which is unsubstituted or substituted by
one or more carboxy or carboxy derivative groups; R12 is a carboxy
derivative group: and R13 is a further reactive group selected from
the group consisting of a carboxy, carboxy derivative, isocyanato,
isothiocyanato and epoxy group.
32. A process according to claim 29, wherein the biocompatible
organic or inorganic bulk material is a PFPE polymer.
33. A process according to claim 30, wherein the biocompatible
organic or inorganic bulk material is a PFPE Polymer.
34. The use of a biomedical device according to claim 17 as an
intraocular lens for the implantation into or onto the cornea.
35. The use of a biomedical device according to claim 23 as an
intraocular lens for the implantation into or onto the cornea.
Description
[0001] The present invention relates to a biomedical adhesive.
Particularly, it relates to a ready-to-use adhesive for an organic
or inorganic biocompatible bulk material in biological
applications. One suitable use of the adhesive is binding a corneal
onlay or inlay under ambient conditions to the corneal basement
membrane or corneal stromal tissue.
[0002] It is desirable in many applications, especially in the
biomaterial and medical field to adhere biomaterials and other
biocompatible materials or devices to tissue. Tissue is defined as
any part of the body, living or dead. A biomedical device that can
be glued directly to tissue and attains sufficient interfacial bond
strength is attractive because it may obviate the need for surgical
methods such as suturing. Useful applications include the adhesion
of drug delivery devices to the epidermis, the gluing of
anti-adhesion barriers for surgery and the adhesion of synthetic
onlays or inlays to the cornea. Conventional surgical adhesives are
often not suitable for a wide range of adhesive applications.
Currently cyanoacrylates and fibrin glues are used clinically as
soft tissue adhesives. However the brittleness of the cured
adhesives, the potential toxicity of their biodegradation products
and the lack of control over cure time are the major drawbacks of
cyanoacrylates. Slow curing, poor mechanical strength and infection
risk are disadvantages of fibrin-based glues.
[0003] A variety of different methods for the bonding of devices to
tissue have been disclosed in the prior art. For example, U.S. Pat.
No. 5,354,336 describes a method for sealing lenticules onto a
corneal surface comprising the steps of placing the lenticule to
the correct position, applying a polymerizable collagen composition
onto the lenticule and the corneal surface to form a collagen
coating over the lenticule and the corneal surface and polymerizing
the coating in the presence of an initiator thereby sealing the
lenticule onto the corneal surface. However said glues have not yet
proven satisfactory mainly because of severe handling problems. For
example, the surgeon always has to mix the glue components shortly
prior to use. Once the premixing has taken place, only a limited
time period is available for using the glue depending on the glue's
specific curing time; this puts time-pressure on the surgeon.
Following the attachment of the lenticule onto the cornea,
excessive glue has to be removed carefully otherwise glue residues
may inhibit the normal function of biological tissue. Further
disadvantages of the known glues are, for example, insufficient
mechanical stability and adhesive duration.
[0004] Reference to any prior art in the specification is not, and
should not be taken as, an acknowledgment or any form of suggestion
that this prior art forms part of the common general knowledge in
Australia or any other country.
[0005] It will be understood that the term "comprises" or its
grammatical variants as used in this specification and claims is
equivalent to the term "includes" and is not to be taken as
excluding the presence of other elements or features.
[0006] Biomedical adhesives may be given different names, including
"bioadhesive", "biological adhesive" and "surgical adhesive" among
others. In this specification, such terms are used interchangeably,
and all refer to compositions which are biocompatible and which
result in temporary or permanent bonding of two surfaces, where at
least one of the surfaces is biological and/or bonding is in a
biological environment.
[0007] The term "bulk material" is used in this specification to
refer to biocompatible organic or inorganic material. This includes
for example polymers from which biomedical devices are formed,
prostheses, etc. The bulk material would usually be a solid
phase.
[0008] Surprisingly, it now has been found that a biomedical
adhesive can be formed with broad applicability and reduced adverse
biological reaction.
[0009] The present invention therefore relates to a biomedical
adhesive comprising multifunctionally activated functional
groups.
[0010] In one form of the invention, there is provided a method for
bonding a bulk material to a nucleophilic or electrophilic surface
including attaching a multifunctionally activated functional group
to the bulk material and then contacting the functional group with
the nucleophilic surface under conditions permitting covalent
linkage between the surface and the functional group.
[0011] As would be appreciated, the compound and the surface can be
either electrophilic or nucleophilic, as long as each is the
opposite of the other so as to enable reaction between them--such a
pair of reactive groups may be called "corresponding" (eg, an
activated ester and an amino group).
[0012] The conditions are selected to be as convenient as possible.
The temperature range is preferably between 0.degree. C. and
60.degree. C., most preferably body temperature (ie, about
37.degree. C.). Ambient pressure is suitable. In some cases, there
is also desirably sufficient surrounding fluid to facilitate or
permit sufficient movement of the reactive groups (or the longer
molecules to which they are attached) such that they come into
close enough proximity for the covalent linkage to form.
[0013] The invention also provides a bioadhesive attached to a bulk
material for bonding the bulk material to a biological surface, the
bioadhesive comprising a multifunctionally activated compound
reactable with nucleophilic or electrophilic functional groups.
[0014] The multifunctionally activated functional group is
preferably an activated ester or amide.
[0015] The invention also provides a bioadhesive covalently linking
a bulk material with a biological surface, the adhesive being
formed by the curing of a multifunctionally activated functional
group.
[0016] The invention also provides a biomedical device for
attaching to a biological surface including a biocompatible organic
or inorganic bulk material to which a multifunctionally activated
compound has been bonded.
[0017] The invention is also directed towards a method of preparing
a device comprising a bulk material combined with a bioadhesive
which may be stored anhydrously prior to use, comprising attaching
the multifunctionally activated functional group to the bulk
material and then dehydrating the device.
[0018] The invention also provides a process for applying a
bioadhesive to a surface of a biomedical device comprising the
steps of
[0019] providing a biomedical device comprising a biocompatible
organic or inorganic bulk material
[0020] if the surface has inadequate functional groups on its
surface, applying surface functional groups to the surface, and
[0021] covalently coupling a multifunctionally activated compound
comprising at least one carboxy derivative group and at least one
additional functional group that is co-reactive to the surface
functional groups.
[0022] The invention is particularly directed towards a bioadhesive
for in vivo use. The invention can be used to adhere, for example,
synthetic materials to which the bioadhesive multifunctionally
activated compound is attached to any appropriate nucleophilic or
electrophilic surface of an animal (including humans). A common
nucleophilic surface to which such articles may be attached is
collagen, or any other lysine-rich polypeptide (whether natural or
synthetic).
[0023] The incorporation of collagen into a device according to the
invention is optional. Collagen may confer other properties on the
biomedical device useful or desirable for its intended purpose.
Collagen may be bonded to the biomedical device of the invention by
the same surface functional groups as bind the multifunctionally
activated compound or otherwise.
[0024] The invention has particular application to biomedical
devices made from a bulk material which is strongly hydrophobic.
Such materials are known to be difficult to adhere in a biological
environment. As detailed in a preferred embodiment, hydrophobic
surfaces may first be treated by the addition of surface functional
groups (such as aldehydes) by known processes (such as plasma
deposition).
[0025] Suitable multifunctionally activated functional groups
include carboxy derivative groups, such as, for example, carboxylic
halides, for example --COCl or --COBr; carboxylic anhydrides;
lactones; carboxylic amides; or preferably carboxylic esters. A
preferred group of carboxy derivative groups are esters, in
particular activated esters or amides.
[0026] The reactive groups may be selected from a class of esters,
which are highly reactive towards nucleophiles. Active esters or
other reactive groups derived from carboxylic acids or amides
undergo elimination reactions with nucleophiles to form stable
adducts as follows:
[0027] General reaction (1) describes the elimination reaction of
nucleophiles (Nu) with an active ester (AE). General reaction (2)
describes the elimination reaction of nucleophiles (Nu) with a
reactive group (XG). 1
[0028] in which
[0029] X=halogen;
[0030] Y=H, alkyl, or optionally active ester or reactive
group;
[0031] Nu=nucleophile (e.g. amine, thiol)
[0032] These reactions can be applied as a curing reaction for
adhesives, when di- or poly-functional reagents are used. Thus, if
Z contains more than one nucleophilic group and Y contains more
than one active ester or reactive group, then a cross-linked
polymer results that has the properties of an adhesive. If the
substrate to be glued contains nucleophilic groups (e.g. amines in
collagen-coated articles or ophthalmic tissue), then direct bonding
to the active ester or reactive group can occur and the formulation
acts as a bioadhesive.
[0033] The reactive groups can be in the form of a multifunctional
dendritic polymer, a multifunctionalized comb like polymer, the
terminating ends of a linear polymer or other multifunctional
polymer where there is at least one reactive group per polymer
chain as follows: 2
[0034] Careful choice in the spacer component enables the synthesis
of a bioadhesive that supports or inhibits cell growth, or is
biodegradable or non-biodegradable. The bioadhesives can also
contain other materials, such as inert biocompatible fillers, to
improve the viscosity and to result in porosity after leaching.
[0035] An activated ester or amide is, for example, a radical of
formula 3
[0036] A preferred carboxy derivative group according to the
invention is an activated ester group of formula (g), (e) or, in
particular, of formula (h).
[0037] Multifunctionally activated compounds are, for example,
compounds of formula
R.sub.13-D-R.sub.12 (j),
[0038] wherein
[0039] D is a bivalent organic radical, which may be substituted,
for example, by one or more carboxy or carboxy derivative
groups;
[0040] R.sub.12 is a carboxy derivative group; and
[0041] R.sub.13 is a further reactive group, for example a carboxy,
a carboxy derivative, isocyanato, isothiocyanato or epoxy
group.
[0042] Examples of bivalent organic radicals D are, for example, an
optionally branched C.sub.1-C.sub.12-alkylene; a radical of
dendrimer or star bust polymer; a radical of a polyethylene glycol;
a radical of a polyvinyl alcohol, for example, a polyvinyl alcohol
with pendant polymerisable groups as described in WO 96/24075; or a
radical of a hyperbranched polyester resin as described by M.
Johansson and A. Hult in Journal of Coatings Technology, 67, No.
849, 35 (1995). D is preferably a bivalent radical of a
polyethylene glycol, for example a radical of formula
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.f--, wherein f is
an integer of, for example, from 2 to 250.
[0043] R.sub.12 is a carboxy derivative group, wherein the above
given meanings and preferences apply. R.sub.13 is independently
preferably a carboxy derivative group, wherein the above given
meanings and preferences apply. Most preferably, R.sub.12 and
R.sub.13 are identical.
[0044] In one embodiment, the multifunctionally activated compound
is polyethylene glycol that is di-substituted with succinimidyl
propionate, succinimidyl succinate or succinimidyl succinimide, or
the known derivatives of these functional groups.
[0045] The method of attaching a multifunctional compound of
formula (O) to a bulk material surface provided with a natural or
synthetic polymer comprising co-reactive functional groups depends
on the nature of the reactive groups being present in compound (j)
and at the natural or synthetic polymer. The reactions are known
per se, for example, from textbooks of organic chemistry.
[0046] For example, in case that a compound of formula (j) with a
carboxy, amide or ester group R.sub.13 is to be coupled to a
natural or synthetic polymer containing amino, thiol or hydroxy
groups, the reaction may be carried out under the conditions that
are customary for ester or amide formation. It is preferred to
carry out the esterification or amidation reaction in the presence
of an activating agent, for example N-ethyl-N'-(3-dimethyl
aminopropyl)carbodiimide (EDC), N-hydroxy succinimide (NHS) or
N,N'-dicyclohexyl carbodiimide (DCC).
[0047] In case that a compound of formula (O) with an anhydride
group R.sub.13 is to be coupled to a natural or synthetic polymer
containing amino, thiol or hydroxy groups the reaction may be
carried out as described in organic textbooks, for example in an
aprotic solvent, for example one of the above-mentioned aprotic
solvents, at a temperature from room temperature to about
100.degree. C.
[0048] In case that a compound of formula (j) with an activated
ester or amide group R.sub.13 is to be coupled to the surface of a
bulk material or to a natural or synthetic polymer containing
amino, thiol or hydroxy groups, the reaction may be carried out,
for example, at room temperature or at elevated temperature, for
example at about 20 to 100.degree. C., in an aprotic medium.
[0049] In case that a compound of formula (j) with an isocyanato
group R.sub.13 is to be coupled to a natural or synthetic polymer
containing amino or hydroxy groups, the reaction may be carried out
in an inert organic solvent such as acetonitrile, an optionally
halogenated hydrocarbon, for example petroleum ether,
methylcyclohexane, toluene, chloroform, methylene chloride and the
like, or an ether, for example diethyl ether, tetrahydrofurane,
dioxane, or a more polar solvent such as DMSO, DMA,
N-methylpyrrolidone or even a lower alcohol or water, at a
temperature of from 0 to 100.degree. C., preferably from 0 to
50.degree. C. and particularly preferably at room temperature,
optionally in the presence of a catalyst, for example a tertiary
amine such as triethylamine or tri-n-butylamine,
1,4-diazabicyclooctane, or a tin compound such as dibutyltin
dilaurate or tin dioctanoate. In addition, the reaction of the
isocyanato groups with amino groups may also be carried out in an
aqueous solution in the absence of a catalyst. It is advantageous
to carry out the above reactions under an inert atmosphere, for
example under a nitrogen or argon atmosphere.
[0050] In case that a compound of formula (j) with an epoxy group
R.sub.13 is to be coupled to a natural or synthetic polymer
containing amino, thiol or hydroxy groups, the reaction may be
carried out, for example, at room temperature or at elevated
temperature, for example at about 20 to 100.degree. C., in an
aprotic medium using a base catalyst, for example
Al(O--C.sub.1-C.sub.6-alkyl).sub.3 or
Ti(O--C.sub.1-C.sub.6-alkyl).sub.4.
[0051] In a preferred embodiment of the invention, the bulk
material forms a biomedical device. The device may be obtainable by
a process comprising the steps of
[0052] providing a biomedical device comprising a biocompatible
organic bulk material and having surface functional groups on its
surface, and
[0053] covalently coupling the surface functional groups with a
natural or synthetic polymer comprising co-reactive groups, and
[0054] covalently coupling a multifunctionally activated compound
comprising at least one carboxy derivative group and at least one
additional functional group that is co-reactive to the co-reactive
groups of the natural or synthetic polymer.
[0055] Examples of bulk materials that may be coated according to
the process of the invention are natural or synthetic organic
polymers, or laminates, composites or blends of said materials.
Some examples of polymers are polyaddition and polycondensation
polymers (polyurethanes, epoxy resins, polyethers, polyesters,
polyamides, polycarbonates and polyimides); vinyl polymers
(polyacrylates, polymethacrylates, polystyrene, polyethylene,
polyacrylamides and halogenated derivatives thereof, polyvinyl
acetate and polyacrylonitrile); elastomers (silicones,
polybutadiene and polyisoprene); or modified or unmodified
biopolymers (collagen, cellulose, chitosan and the like).
[0056] Another preferred group of bulk materials are those
conventionally used for the manufacture of biomedical devices, e.g.
contact lenses, intraocular lenses or artificial cornea, which are
not hydrophilic per se. Such materials are known to the skilled
artisan and may comprise for example polysiloxanes,
perfluoropolyethers (PFPE), fluorinated poly(meth)acrylates or
equivalent fluorinated polymers derived e.g. from other
polymerizable carboxylic acids, polyalkyl (meth)acrylates or
equivalent alkylester polymers derived from other polymerizable
carboxylic acids, or fluorinated polyolefines, such as fluorinated
ethylene propylene, or tetrafluoroethylene, preferably in
combination with specific dioxols, such as
perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk
materials are e.g. Lotrafilcon A, Neofocon, Pasifocon, Telefocon,
Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon or
Teflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which
are copolymers of about 63 to 73 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of
tetrafluoroethylene, or of about 80 to 90 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of
tetrafluoroethylene.
[0057] Another preferred group of biocompatible polymers are those
being conventionally used for the manufacture of biomedical
devices, e.g. contact lenses, which are hydrophilic per se, since
hydrophilic groups, e.g. carboxy, carbamoyl, sulfate, sulfonate,
phosphate, amine, ammonium or hydroxy groups, are inherently
present in the material. Such materials are known to the skilled
artisan and comprise for example polyhydroxyethyl acrylate,
polyhydroxyethyl methacrylate (HEMA), polyvinyl pyrrolidone (PVP),
polyacrylic acid, polymethacrylic acid, polyacrylamide,
poly-N,N-dimethyl acrylamide (DMA), polyvinyl alcohol, copolymers
for example from two or more monomers from the group hydroxyethyl
acrylate, hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylic
acid, methacrylic acid, acrylamide, N,N-dimethyl acrylamide, vinyl
alcohol, vinyl acetate and the like, polyalkylene glycols such as
polyethylene glycols, polypropylene glycols or
polyethylene/polypropylene glycol block copolymers. Typical
examples are e.g. Polymacon, Tefilcon, Methafilcon, Deltafilcon,
Bufilcon, Phemfilcon, Ocufilcon, Focofilcon, Etafilcon, Hefilcon,
Vifilcon, Tetrafilcon, Perfilcon, Droxifilcon, Dimefilcon,
Isofilcon, Mafilcon, Nelfilcon or Atlafilcon.
[0058] An even more preferred group of bulk materials are, for
example, porous polymers with improved wettability and cell growth
ability as described in U.S. Pat. No. 6,015,609, WO 97/35906, WO
97/35905, WO 00/49058 or in WO 00/15686. Polymers incorporating
charged units or zwitterions (such as described WO 00/15686) are
also useful in this invention, and the contents of that
specification are herein incorporated by reference. Additional
examples are provided in European Patent Application no.
02011173.8, the contents of which are herein incorporated by
reference. PFPE macromonomers and the synthesis of polymers
therefrom are known e.g. from PCT applications WO 96/31546 or WO
97/35906.
[0059] The bulk material network can, if desired, be reinforced by
addition of a crosslinking agent, that is not a PFPE polymer, for
example by a polyunsaturated crosslinking comonomer. Examples of
typical crosslinking comonomers are allyl (meth)acrylate, lower
alkylene glycol di(meth)acrylate, poly(lower alkylene) glycol
di(meth)acrylate, lower alkylene di(meth)acrylate, divinyl ether,
divinyl sulfone, di- and trivinylbenzene, trimethylolpropane
tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, bisphenol A
di(meth)acrylate, methylenebis(meth)acrylamide, triallyl phthalate
and diallyl phthalate. Polyunsaturated perfluoroalkyl crosslinkers
of formula
Q-CH.sub.2--(CF.sub.2).sub.q--CH.sub.2-Q (k),
[0060] wherein for Q the above given meanings and preferences
apply, and q is an integer of, for example, from 1 to 20 and
preferably from 1 to 12, are the preferred additional crosslinking
comonomers. If a crosslinking comonomer is used, the amount used is
in the range of from 0.01 to 40% of the expected total weight of
polymer, preferably the comonomer is in the range of 0.1 to 30%,
and more preferably in the range of 0.1 to 20%. Preferably the
polymerization mixture does not contain a crosslinking monomer.
[0061] The preferred bulk materials of the invention may be
obtained by copolymerizing one or more PFPE macromonomers, one or
more charged monomers or a suitable precursor thereof and optional
further comonomers and/or additives to afford a transparent polymer
in the presence of a suitable initiator. Standard methods well
known in the art for effecting polymerization may be utilized, with
free radical polymerization being preferred. Free radical
polymerization can be simply carried out by radiating (using
ultra-violet light) monomer mixtures containing a UV initiator,
such as benzoin methylether, in an appropriate container or vessel.
The mixture is irradiated for a sufficient time to enable
polymerization between monomers to take place. Alternatively,
thermal initiation using a thermal initiator such as
azobisisobutyronitrile, can be employed. If a precursor of the
zwitter-ionic monomer is used, the copolymer after the irradiation
may be treated with a suitable reagent in order to convert the
precursor units into zwitter-ionic units.
[0062] The polymerization mixture can be converted to a polymer
neat or in the presence of one or more solvents. While the
structure of the components of the polymerization mixture has the
most significant effect on the resulting modulus, the choice of
solvent and comonomer also has an effect. Useful solvents include
those selected from the following classes: esters, alcohols,
ethers, and halogenated solvents. Fluorinated solvents are
particularly useful and their use in combination with other
solvents (in ratios varying from 1:9 to 9:1) from the classes above
is especially desirable. Solvent concentrations of between 0-70%
w/w, particularly 30-80% w/w, especially 55% in the polymerization
mixture are desirable. Preferred solvents include acetates,
particularly isopropyl acetate and tert-butyl acetate,
2-(trifluoromethyl)-2-propanol, chlorofluoroalkanes, particularly
trichlorotrifluoroethane, and perfluorinated alkanes, such as
perfluoro-1,3-dimethylcyclohexane, 2,2,3,3-tetrafluor-1-propanol,
2',3',4',5',6'-pentafluoroacetophenone,
1,1,1-trifluoro-3,4-pentadione, 2',3',4',5',6'-pentafluorobenzyl
alcohol and the like. A particular preferred solvent is water or an
aqueous solution comprising, for example, one or more organic
solvents, for example a C.sub.1-C.sub.4-alkanol such as methanol or
ethanol, or a fluorinated alkane. Water may be 1 to 70% w/w,
preferably 2 to 50% w/w and particularly preferably 3 to 30% w/w,
in each case based on the entire formulation.
[0063] The bulk materials may form porous substrates. Porosity may
be provided by the inherent porosity of the material.
Alternatively, pores may be introduced into the polymers by various
procedures such as those disclosed in PCT applications WO 00/15686.
In case of porous bulk materials, a polar solvent, for example
water, a C.sub.1-C.sub.4-alkanol, and/or a surfactant, preferably a
fluorinated surfactant, may be incorporated into the polymerization
mixture. The use of surfactants is an effective means of
controlling the size and density of the pores. Non-ionic
surfactants containing fluorine are preferred. Particularly
preferred surfactants include commercially available fluorinated
surfactants such as Zonyl (DuPont) and Fluorad (3M). Zonyl
surfactants, which are made of a perfluorinated hydrophobic tail
and hydrophilic poly(ethylene oxide) head group, are a particularly
preferred surfactant for use in the process of the present
invention.
[0064] Suitable bulk materials are those obtainable by
copolymerizing one or more macromonomers comprising at least one
PFPE unit, wherein the above-given meanings and preferences apply,
and at least one zwitter-ionic monomer or a precursor thereof,
wherein again the above-given meanings and preferences apply, in an
aqueous solution and, if a zwitter-ionic monomer precursor has been
used, converting the precursor units into charged units after the
copolymerization reaction. A particular preferred reaction medium
in this context is an aqueous solution comprising a
C.sub.1-C.sub.4-alkanol, in particular methanol or ethanol, a
fluorinated surfactant and optionally a fluorinated alkane.
[0065] The surface of the bulk material may inherently contain
functional groups or may be provided with covalently attached
functional groups, for example, by plasma deposition, particularly
if it is hydrophobic. The method of coating a surface by plasma
deposition is known to the skilled artisan and is described in,
e.g. WO 98/52620 and WO 00/29548. Typical examples of reactive
groups being introduced to the surface of the bulk material by
plasma surface preparation include aldehyde groups, amino groups,
hydroxy groups, carboxy groups, carbonyl groups, sulfonic acid
groups, sulfonyl chloride groups and groups able to be replaced by
amino or hydroxy groups, such as halo groups. Aldehyde groups,
thiol groups, amino groups, hydroxy groups and carboxy groups are
preferred.
[0066] Examples of the natural or synthetic polymer used are
cell-adhesive glycoproteins like collagens (various types),
fibronectin, vitronectin, laminin, poly(ethyl imine), amino
dextran, PAMAM dendrimers, poly(allyl amine), poly(vinyl alcohol),
poly(arylic acid) and poly(methacrylic acid). Collagen and
collagen-like proteins are preferred. The coupling of cell-adhesive
glycoproteins to plasma polymers covalently bound to the underlying
bulk material is known and described, for example, in WO
00/29548.
[0067] Moreover, biomedical devices according to the invention
comprising a preferred bulk material, that is a bulk material
obtainable by copolymerizing a macromonomer comprising at least one
PFPE unit and a zwitter-ionic monomer in an aqueous solution, offer
the additional advantage, that unlike other hydrophobic materials,
for example those disclosed in WO 00/15686, they may be hydrated
very easily. Accordingly, the biomedical devices of the invention
may be dehydrated after their preparation and stored for extended
periods without loss of adhesive activity. Such a biomedical
device, for example an onlay, is then immediately ready for use, by
just placing it in water for a short period, typically for about 1
to 10 minutes and particularly for about 2 minutes, which is
sufficient to re-hydrate both the bulk material and the coating (so
as to re-activate the hydrolytically unstable functional groups of
the multifunctionally activated compound). All of these advantages
naturally apply not only to contact lenses but also to other
biomedical mouldings according to the invention as mentioned
before.
[0068] In a further preferred form of the invention, biomedical
devices (such as corneal inlays and onlays or lenticules) are
formed from a polymer as described above, and then dried and stored
in anhydrous conditions. This maintains the multifunctionally
activated compounds' unreacted reactive groups such that they can
bond to tissue upon implantation or affixation of the device to
tissue, after re-hydration to increase polymer chain mobility.
[0069] The biomedical devices of the present invention such as in
particular corneal onlays and inlays may be fixed on the cornea by
just placing the device in intimate contact with the corneal tissue
for a certain time period, for example for about 5 to 30 minutes
and especially for 10 to 20 minutes. Such onlays and inlays are
easier to handle, since the use thereof does not involve, for
example, a premixing of glue components or time pressure upon the
surgeon due to specific curing times of the glue components. In
addition, no tedious removal of excess glue after fixing onto the
cornea is necessary, and the previous problem of inhibition of
overgrowth by glue residues does not exist.
[0070] Preferably, the cornea is previously prepared for the
attachment of an onlay, for example, by removing the epithelial
cell layers of the cornea by scraping and/or washing the eye, for
example, with ethanol/water mixtures. Ideally the cornea surface
and the lenticule are dried with surgical sponges or the like. It
is desirable to minimise the fluid and air between the lenticule
and the cornea surface. Excess fluid and air may be removed by
applying pressure across the membrane using a rolling action with a
surgical instrument. Such onlays provide a new route towards
implanting a corneal onlay onto a cornea which is easy to perform,
does not affect the wearers vision, and is safe. In particular, a
mechanically stable fixation of the implant on the cornea is
obtained which lasts for a period of time sufficient for normal
biological function to recover after surgery. This may include the
chance to allow the epithelial cells to recover, grow over the
implant and thus fix it in a persistent manner.
[0071] The invention is particularly suitable for corneal inlays
where cell growth ability is less important. Cell growth ability
may be impeded by higher charged unit content, such as over 10%
w/w, although this may be overcome by surface modification of the
inlay (eg collagen attachment). The inlay may be implanted using
known techniques. For example, an incision may be made in the
stroma, into which the re-hydrated inlay is placed. The inlay then
attaches to the stroma through reaction of the re-activated
functional groups of the multifunctionally activated compound with
no additional material being required. Polymers with charged unit
content of around 20% are useful for this application.
[0072] The present invention is further described by the following
non-limiting examples. If not specified otherwise, all parts are by
weight. Temperatures are in degree Celsius.
EXAMPLE 1
Preparation of a Self-Hydrating PFPE Material
[0073] The following formulation was prepared in a glass vial
furnished with a stirrer. The components were added in order of
decreasing hydrophilicity and mixed well, prior to the addition of
the photoinitiator. After the addition of the photoinitiator
(Darocur 1173), the mixing was continued for a further five
minutes. The resulting solution was then placed in polypropylene
moulds and polymerised for 3 hours under the irradiation of broad
spectrum UV lamps. (1 mW/cm.sup.-2). The polymers (20 mm diameter
disc 50 to 250 microns thick) were removed from the mold and placed
through a general extraction procedure to remove any unpolymerised
components. This procedure consists of a 2.times.24 h soaking in a
fluorinated solvent such as Vertrel XF (DuPont), TCTFE (Aldrich) or
HFE 7100 (3M), then 2.times.24 hr immersion in isopropyl acetate
and subsequent immersion for 2.times.24 h in methanol. The polymers
were then hydrated by a graded solvent change from methanol to
ethanol (2.times.24 hr), 75% ethanol/water (2.times.24 hr), 50%
ethanol/water (2.times.24 hr), 25% ethanol/water (2.times.24 hr),
then pure water or saline (2.times.24 hr). This assists in
extracting unpolymerised monomers/solvents/surfactants.
[0074] Examples 1 to 4 used a combination of Part A and Part B for
polymerisation as follows:
[0075] Part A consisted of (parts by weight):
1 PFPE macromonomer #1 4.5 PFPE macromonomer #2 0.5 Ethanol 2.5
PFDMCH 3.0
[0076] Part B consisted of a 50% (w/w) solution of
[2-(methacryloyloxy)eth- yl]dimethyl(3-sulfopropyl)-ammonium inner
salt (zwitterion) in water.
2 Component Amount Part A 1.749 Part B 0.143 Surfactant Zonyl FSK
0.1841 Darocur 1173 0.0024 EWC (%) 27.5 Optical Clarity 95.6 (%)
Porosity (A.sub.280) 0.815
[0077] Explanation of Abbreviations:
[0078] PFPE macromonomer #1: perfluorinated macromer obtained by
endcapping a perfluoropolyether diol (Ausimont, Italy,
M.sub.w=2000) with isocyanatoethyl methacrylate as described in
Chaouk H. et al., J. Appl. Polym. Sci., 2001, 80, 1756;
[0079] PFPE macromonomer #2: perfluorinated macromer obtained by
endcapping a perfluoropolyether diol (Ausimont, Italy,
M.sub.w=1000) with isocyanatoethyl methacrylate as described in
Chaouk H. et al., J. Appl. Polym. Sci., 2001, 80, 1756;
[0080] Zonyl FSK, FSA, FSO100 and FSN100=non-ionic fluorinated
surfactants (DuPont);
[0081] Darocur.RTM.1173=photoinitiator (Ciba Speciality
Chemicals).
[0082] PFDMCH=perfluorodimethylcyclohexane
[0083] Equilibrium water contents (EWC) (expressed as percentages)
and porosity measurements are measured as reported by Chaouk H. et
al, J. Appl. Polym. Sci., 2001, 80, 1756.
[0084] Optical haze (%) is measured using a Gardner PG-5500 digital
photometric unit. Optical clarity is calculated by subtracting
optical haze from 100%.
EXAMPLE 2
Surface Modification of a "Self-Hydrating" Bulk Material
[0085] The formulation of Example 1 was covalently coated, both
sides, with type 1 collagen according to the procedure disclosed in
WO 00/29548. The collagen coated materials were then exchanged from
phosphate buffered saline (PBS) to MilliQ water, then 100% ethanol
and finally acetonitrile. The acetonitrile was then replaced by dry
acetonitrile. 250 .mu.l of poly(ethylene glycol) di(succinimidyl
propionate) solution (582 mg, Shearwater Polymers, dissolved in 1.2
ml of dry acetonitrile) were added to each of the acetonitrile
equilibrated collagen coated self-hydrating polymer samples in
separate vials. After 20 minutes of incubation, 3 samples (samples
1,2,3) were evaporated to dryness using a rotary evaporator.
Another 3 samples (4,5,6) had the excess crosslinker solution
removed with a pipette. Dry acetonitrile (2 ml) was added to these
vials and they were gently shaken before removing excess
acetonitrile solution with a pipette. The three samples (samples
4,5,6) were then evaporated to dryness using a rotary evaporator.
All samples were stored under vacuum over P.sub.2O.sub.5 until
used, in this case seven days later, although lenticules made in
this manner could be stored much longer.
EXAMPLE 3
Adhesive Testing of a "Self-Hydrating" Biomedical Device
[0086] The dried surface-modified lenticules of Example 45 are
hydrated by placing them in water. The use of hot water sped up the
hydration process. The hydration process may be performed using PBS
instead of water or aqueous mixtures. Once hydrated, the lenticules
were surface dried using lint-free tissue paper and then placed on
a freshly debrided bovine cornea. Excess fluid and bubbles were
expelled from under the lenticule by gently wiping across the
anterior surface of the lenticule. The lenticule was allowed to
cure for 15 to 19 minutes before the adhesion was assessed using a
vacuum tester (a detachment threshold>5.5 means that the
adhesion is greater than what was able to be tested using the
vacuum tester):
3 hydration time cure time detachment Sample (minutes) (minutes)
threshold 1 2 16 >5.5 2 2 15 >5.5 3 2 15 >5.5 4 2 15
>5.5 5 2 17 3.5 6 2 19 >5.5
EXAMPLE 4
Adhesive Modification Prior to Implantation
[0087] Poly(ethylene glycol) di(succinimidyl propionate) (50 mg,
Shearwater Polymers) was dissolved in water for irrigation (125
.mu.l, Baxter products) within 30 seconds by vigorous mixing. A
hydrated but surface dried double sided collagen coated
perfluoropolyether lenticule was cast in a contact lens mould. The
concave cup of the lenticule was filled with poly(ethylene glycol)
di(succinimidyl propionate) solution. After two minutes the
solution was removed by pipettor and the excess poly(ethylene
glycol) di(succinimidyl propionate) solution was removed by washing
the modified lenticule for 4 minutes in water (for irrigation, 25
ml, Baxter products). The lenticules were then surface dried using
lint free tissue paper. The modified lenticules were then placed on
a freshly debrided feline cornea. Excess fluid and bubbles were
expelled from under the lenticule by gently wiping across the face
of the lenticule. The lenticules were allowed to cure for 10
minutes before antibacterial cream is applied to the eyes and the
cat is allowed to gain consciousness. Six lenticules adhered to
feline cornea for between 14 and 90 days. In one case, the
epithelium completely covered the lenticule by day 12
post-implantation. The lenticule remained adhered to the cornea and
fully epithelized beyond day 90. After adhesive failure the wound
beds re-epithelized within a normal time period indicating the
adhesive did not induce permanent damage to the cornea.
[0088] It will be understood that the invention disclosed and
defined herein extends to all alternative combinations of two or
more of the individual features mentioned or evidence from the text
or drawings. All of these different combinations constitute various
alternative aspects of the invention.
* * * * *