U.S. patent application number 11/725190 was filed with the patent office on 2007-10-04 for intraocular lens implant.
Invention is credited to Michael R. Carrasco, Curtis W. Frank, Won-Gun Koh, David Myung, Jaan Noolandi, Christopher Ta.
Application Number | 20070233240 11/725190 |
Document ID | / |
Family ID | 36149013 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070233240 |
Kind Code |
A1 |
Frank; Curtis W. ; et
al. |
October 4, 2007 |
Intraocular lens implant
Abstract
The present invention provides a hydrogel-based intraocular lens
(IOL) implant that can covalently attach to a lens capsule on
implantation into an eye. The inventive IOL has a high refractive
index, high elasticity, and is of a similar size to a naturally
occurring lens. In addition, the IOL can be implanted in a smaller,
dehydrated state, allowing the IOL to be placed in the lens capsule
with a small incision (up to about 1/10 the volume of the IOL).
Exposure to fluid can then initiate rapid swelling of the dried
polymer to the shape and dimensions of a natural lens, with full
occupation of the lens capsule. Upon equilibrium swelling, the IOL
can then make contact with the inner aspect of the lens capsule and
covalently bind to it. By this attachment process, the IOL may
accommodate in a manner identical to that of the natural lens.
Inventors: |
Frank; Curtis W.;
(Cupertino, CA) ; Ta; Christopher; (Saratoga,
CA) ; Myung; David; (Santa Clara, CA) ;
Noolandi; Jaan; (Palo Alto, CA) ; Carrasco; Michael
R.; (Sunnyvale, CA) ; Koh; Won-Gun; (Kyunggi
Yongin, KR) |
Correspondence
Address: |
LUMEN INTELLECTUAL PROPERTY SERVICES, INC.
2345 YALE STREET, 2ND FLOOR
PALO ALTO
CA
94306
US
|
Family ID: |
36149013 |
Appl. No.: |
11/725190 |
Filed: |
March 16, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11243952 |
Oct 4, 2005 |
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11725190 |
Mar 16, 2007 |
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11409218 |
Apr 20, 2006 |
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11725190 |
Mar 16, 2007 |
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11243952 |
Oct 4, 2005 |
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11725190 |
Mar 16, 2007 |
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11636114 |
Dec 7, 2006 |
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11725190 |
Mar 16, 2007 |
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11243952 |
Oct 4, 2005 |
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11725190 |
Mar 16, 2007 |
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11409218 |
Apr 20, 2006 |
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11725190 |
Mar 16, 2007 |
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11639049 |
Dec 13, 2006 |
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11725190 |
Mar 16, 2007 |
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11243952 |
Oct 4, 2005 |
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11725190 |
Mar 16, 2007 |
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11409218 |
Apr 20, 2006 |
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11725190 |
Mar 16, 2007 |
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60783601 |
Mar 17, 2006 |
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60616262 |
Oct 5, 2004 |
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60673172 |
Apr 20, 2005 |
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60673600 |
Apr 21, 2005 |
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60843942 |
Sep 11, 2006 |
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60783307 |
Mar 17, 2006 |
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60843942 |
Sep 11, 2006 |
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Current U.S.
Class: |
623/6.59 |
Current CPC
Class: |
A61L 27/3813 20130101;
A61L 27/26 20130101; A61L 27/54 20130101; A61L 27/26 20130101; C12N
2533/30 20130101; A61L 2300/25 20130101; A61L 27/26 20130101; A61L
2300/602 20130101; A61L 2300/252 20130101; C08L 33/08 20130101;
C08L 71/02 20130101; A61L 27/3839 20130101; A61K 35/44 20130101;
A61L 27/3804 20130101; A61F 2/142 20130101; A61L 27/52 20130101;
A61F 2/145 20130101; C12N 5/0621 20130101; A61L 2430/16
20130101 |
Class at
Publication: |
623/006.59 |
International
Class: |
A61F 2/16 20060101
A61F002/16 |
Claims
1. An intraocular lens implant, comprising: (a) a hydrogel; and (b)
active functional groups covalently linked to a surface of said
hydrogel, wherein said active functional groups mediate covalent
binding of said intraocular lens implant to an eye's lens capsule
upon implantation of said intraocular lens implant into said lens
capsule.
2. The intraocular lens implant as set forth in claim 1, wherein
said active functional groups comprise N-hydroxysuccinimide.
3. The intraocular lens implant as set forth in claim 1, wherein
said active functional groups are covalently linked to said surface
of said hydrogel through a photoreactive azide.
4. The intraocular lens implant as set forth in claim 3, wherein
said photoreactive azide comprises 5-Azido-2-nitrobenzoic acid
N-hydroxysuccinimide ester.
5. The intraocular lens implant as set forth in claim 1, wherein
said active functional groups covalently bind to proteins in said
lens capsule.
6. The intraocular lens implant as set forth in claim 5, wherein
said proteins are at least one of collagen, collagen type I and
collagen type III
7. The intraocular lens implant as set forth in claim 1, wherein
said active functional groups covalently bind to said lens capsule
via free amines on proteins present in said lens capsule.
8. The intraocular lens implant as set forth in claim 1, wherein
said hydrogel can swell from a dehydrated state to a rehydrated
state within about 2 hours.
9. The intraocular lens implant as set forth in claim 1, wherein
the weight and volume ratios of said hydrogel in a dehydrated
versus a hydrated state are between about 10:90 and about
40:60.
10. The intraocular lens implant as set forth in claim 1, wherein
water content of said hydrogel in a dehydrated state is between
about 0 and about 30%.
11. The intraocular lens implant as set forth in claim 1, wherein
water content of said hydrogel in a rehydrated state is between
about 60 and about 90%.
12. The intraocular lens implant as set forth in claim 1, wherein
said hydrogel is a homopolymer, copolymer or interpenetrating
network based on at least one of poly(ethylene glycol),
poly(acrylic acid), poly(vinyl alcohol), poly(2-hydroxy
ethylacrylate), poly(2-hydroxyethyl methacrylate), poly(methacrylic
acid) and their derivatives.
13. The intraocular lens implant as set forth in claim 1, wherein
said hydrogel has an elastic modulus of between about 1 kPa and
about 250 kPa.
14. The intraocular lens implant as set forth in claim 1, wherein
said hydrogel has a refractive index of between about 1.33 to about
1.42.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Patent Application No. 60/783,601, filed Mar. 17, 2006, which is
incorporated herein by reference.
[0002] This application is a continuation-in-part of U.S. patent
application Ser. No. 11/243,952, filed Oct. 4, 2005, which claims
priority from U.S. Provisional Patent Application No. 60/616,262,
filed Oct. 5, 2004, and from U.S. Provisional Patent Application
No. 60/673,172, filed Apr. 20, 2005, all of which are incorporated
by reference herein.
[0003] This application is also a continuation-in-part of U.S.
application Ser. No. 11/409,218, filed Apr. 20, 2006, which claims
priority from U.S. Provisional Patent Application No. 60/673,600,
filed Apr. 21, 2005, and which is a continuation-in-part of U.S.
patent application Ser. No. 11/243,952, filed Oct. 4, 2005, all of
which are incorporated by reference herein.
[0004] This application is also a continuation-in-part of U.S.
patent application Ser. No. 11/636,114, filed Dec. 7, 2006, which
claims priority from U.S. Provisional Application Nos. 60/843,942,
filed on Sep. 11, 2006, and 60/783,307, filed Mar. 17, 2006, both
of which are incorporated herein by reference. U.S. patent
application Ser. No. 11/636,114 is a continuation-in part of U.S.
patent application Ser. No. 11/243,952, filed Oct. 4, 2005, and of
U.S. application Ser. No. 11/409,218, filed Apr. 20, 2006, both of
which are incorporated by reference herein.
[0005] This application is also a continuation-in-part of U.S.
application Ser. No. 11/639,049, filed Dec. 13, 2006, which claims
priority from U.S. Provisional Patent Application No. 60/843,942,
filed Sep. 11, 2006, both of which are incorporated herein by
reference. U.S. application Ser. No. 11/639,049 is a
continuation-in part of U.S. patent application Ser. No.
11/243,952, filed Oct. 4, 2005 and of U.S. application Ser. No.
11/409,218, filed Apr. 20, 2006
FIELD OF THE INVENTION
[0006] The present invention relates generally to intraocular lens
implants. More particularly, the present invention relates to
intraocular lens implants that can covalently bind to a lens
capsule.
BACKGROUND
[0007] Cataract extraction is among the most commonly performed
operations in the United States and the world. There are an
estimated 20 million people worldwide who suffer from cataracts. In
the United States alone, 1.5 million people have cataract surgery
each year. Following removal of a cataractous lens, an intraocular
lens (IOL) implant is typically implanted within the lens capsule
in order to mimic the refractive function of healthy natural
lens.
[0008] Current IOLs are made from hard and non-swellable materials
such as poly(methyl methacrylate) (PMMA) and silicone, which do not
accommodate when placed in the eye. They are typically secured
within the lens capsule through two polymeric haptics, which extend
radially from the device. The most recent innovation involves
"foldable" IOLs that permit smaller incisions during their
implantation. Some are able to facilitate accommodation, but not by
the eye's natural mechanism. Another concern with current IOLs is
their inability to prevent secondary opacification of the posterior
capsule, thus requiring laser treatment. Accordingly, there is a
need in the art to develop an IOL implant that can be implanted
with a small incision, can prevent secondary opacification of the
posterior capsule, and that can accommodate by the eye's natural
mechanism.
SUMMARY OF THE INVENTION
[0009] The present invention provides a hydrogel-based intraocular
lens (IOL) implant that can covalently attach to a lens capsule on
implantation into an eye. The covalent binding of the IOL to the
lens capsule is preferably mediated by active functional groups
covalently linked to a surface of a hydrogel, for example through a
photoreactive azide. The active functional groups are preferably
N-hydroxysuccinimide functional groups tethered to the surface of
the hydrogel. This tethering may be accomplished by use of a
bifunctional chemical linker such as 5-azido-2-nitrobenzoic acid
N-hydroxysuccinimide ester. Exposure to UV light converts the azide
group of this linker to reactive nitrene groups that bind to the
surface of hydrogels. This leaves the N-hydroxysuccinimide (NHS)
groups free to form peptide linkages with proteins in the lens
capsule via free amines on the lens capsule proteins. For example,
the NHS groups may bind to collagen, such as collagen type I and
collagen type III, which is naturally present in the lens capsule.
The adhesion of the hydrogel to proteins by this esterification
process occurs rapidly in aqueous solution at pH 7.4 if the
materials are brought into close, sustained contact.
[0010] Preferably, the IOL has a high refractive index, high
elasticity, and is of a similar size to a naturally occurring lens.
Also preferably, the IOL can be implanted in a smaller, dehydrated
state, allowing the IOL to be placed in the lens capsule with a
small incision (up to about 1/10 the volume of the IOL). Exposure
to fluid can then initiate rapid swelling of the dried polymer to
the shape and dimensions of a natural lens, with full occupation of
the lens capsule. Upon equilibrium swelling, the IOL can then make
contact with the inner aspect of the lens capsule and covalently
bind to it via the active-ester surface functionalization of the
hydrogel. By this attachment process, the IOL will be in a position
to accommodate in a manner identical to that of the natural
lens.
BRIEF DESCRIPTION OF THE FIGURES
[0011] The present invention together with its objectives and
advantages will be understood by reading the following description
in conjunction with the drawings, in which:
[0012] FIG. 1 shows a schematic of swelling of an IOL according to
the present invention on implantation into a lens capsule.
[0013] FIG. 2 shows time-dependence of the water content of a
single network PEG hydrogels and PEG/PAA IPNs with different
amounts of acrylic acid (AA). The hydrogels were placed in
deionized water in the dry state at time=0 and then weighed at
regular intervals.
[0014] FIG. 3 shows appearance of a PEG/PAA IPN based on PEG MW
4600 in the dried state (a) and after being immersed for 40 minutes
in PBS, pH 7.4.
[0015] FIG. 4 shows a schematic of covalent binding of an IOL
according to the present invention to a lens capsule.
[0016] FIG. 5 shows binding of collagen-fluorescein isothiocyanate
(FITC) to an IOL according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention provides a hydrogel-based IOL capable
of covalently binding to a lens capsule upon implantation into an
eye. The hydrogel may be composed of any polymer capable of rapid
swelling upon hydration. A schematic of swelling of an IOL on
implantation into a lens capsule is shown in FIG. 1. FIG. 1A shows
a dehydrated IOL 110 that has been implanted through incision 120
in cornea 122 into lens capsule 130. In FIG. 1B, dehydrated IOL
becomes partially hydrated 112 on exposure to the aqueous
environment of the lens capsule 130. In FIG. 1C, the IOL is fully
swollen 114 within lens capsule 130. Fully swollen IOL 114 can then
be controlled by zonules 140 to accommodate the curvature of the
lens to different distances.
[0018] Preferably, the hydrogel can swell from a dehydrated state
to a rehydrated state within about 2 hours. Also preferably, the
volume and weight ratios of dehydrated versus rehydrated hydrogel
are between about 10:90 (dry:swollen) and about 40:60
(dry:swollen). The water content of a dehydrated hydrogel is
preferably between about 0 and about 30%, whereas the rehydrated
water content of the hydrogel is preferably between about 60 and
about 90%. FIG. 2 shows time-dependence of the water content of a
single network PEG hydrogels and PEG/PAA IPNs with different
amounts of acrylic acid (AA). The hydrogels were placed in
deionized water in the dry state at time=0 and then weighed at
regular intervals. This graphs shows that both single network PEG
hydrogels and PEG/PAA IPNs swell rapidly in deionized water. FIG. 3
shows that PEG/PAA IPNs also swell rapidly under physiological
conditions. (FIG. 3A shows the hydrogel in a dehydrated state. FIG.
3B shows the hydrogel 40 minutes after hydration with PBS pH 7.4. A
penny is shown in both parts of the figure for comparison of
size).
[0019] The IOLs are preferably made of homopolymer, copolymer, or
interpenetrating networks based on poly(ethylene glycol) (PEG)
and/or poly(acrylic acid) (PAA). Due to their high degree of
hydrophilicity, polymer networks of PEG and PAA rapidly swell upon
exposure to water. Moreover, at physiologic pH (7.4 to 7.6), the
carboxylic acid groups on PAA (pKa 4.7) ionize, causing the polymer
chains to repel each other and the network to take up even more
water. Both PEG and PAA are biocompatible. Other polymer components
suitable for practicing the invention include PEG and PAA
derivatives as well as poly(vinyl alcohol), poly(2-hydroxy
ethylacrylate), poly(2-hydroxyethyl methacrylate), poly(methacrylic
acid) and their derivatives.
[0020] The hydrogels can be polymerized in elliptical molds or
reshaped after polymerization by lathing or by use of lasers such
as a femtosecond laser. A typical hydrated lens is about 9.5 mm
wide and 4.0-4.5 mm thick. Partially dehydrated lenses can be
around 7.0 mm wide and 2.0 mm thick, and fully dehydrated lenses
can be as small as 2.0 mm wide and less than 1.0 mm thick.
[0021] When PAA is polymerized in the presence of an existing
PEG-diacrylate hydrogel network, an interpenetrating polymer
network (IPN) structure is formed. These materials exhibit
reversible, reproducible, swelling behavior with dehydration and
hydration in aqueous solution. Details on PAA/PEG IPNs can be found
in U.S. patent application Ser. No. 11/243952, which is
incorporated by reference herein.
[0022] Like a human lens, hydrogels based on PEG and PAA have a low
elastic modulus at physiologic pH, which allows IOLs made from
these materials to accommodate by ciliary muscle-mediated
circumferential tension on the lens capsule. High MW PEG macromers
(.gtoreq.8000) have low elastic moduli and are suitable for use in
these devices. In addition, PAA polymers with low crosslinking
density (.ltoreq.mol 1%) and high water content (.gtoreq.80%) have
low elastic moduli. The preferred elastic modulus values are on the
order of between about 1 kPa and about 250 kPa. Table 1 shows
hydrogels of varying polymer composition and formulation. Depending
on the type of polymer (PEG or PAA), its molecular weight (8000 kDa
or 14000 kDa), or whether it is a homopolymer, copolymer, or an
interpenetrating network, hydrogels of various rehydrated water
content (84%-96%), tensile strength (.sigma..sub.max) and elastic
modulus (E.sub.0) values (50 kPa-250 kPa) can be synthesized. The
water content of a given hydrogel can be raised or lowered by
changing the molecular weight or relative composition of the
components of a hydrogel, or by simply changing the amount of
polymer precursor (monomer) at the time of polymerization. The
elastic modulus of the human lens is roughly 1 kPa. TABLE-US-00001
TABLE 1 Properties of PEG and PAA-based hydrogels specimen WC (%)
.sigma..sub.max (MPa) E.sub.o (MPa) PAA 95.5 .+-. 1.7 0.068 .+-.
0.015 0.050 .+-. 0.001 PEG(8.0k) 90.5 .+-. 1.2 0.273 .+-. 0.036
0.199 .+-. 0.075 PEG(14.0k) 95.1 .+-. 1.2 0.073 .+-. 0.070 0.062
.+-. 0.005 PEG(14.0k)/PAA* 84.3 .+-. 1.7 0.247 .+-. 0.046 0.177
.+-. 0.013 PEG(8.0k)-co-PAA** 90.54 .+-. 0.08 0.275 .+-. 0.025
0.250 .+-. 0.013 *interpenetrating network **copolymer network
[0023] Preferably, the hydrogels are engineered to match the
refractive index of the human lens (1.42) by modulation of the
relative content of PEG (1.46), PAA (1.52) and water (1.33). The
refractive index of the hydrogel can be modulated in either of two
ways: (1) by increasing the relative polymer content and/or (2) by
the addition of high refractive index additives as either a filler
material or as a co-polymeric element. By increasing the content of
PEG and PAA relative to water, the refractive index of the material
will be higher due to a greater proportion of materials (relative
to water) with high refractive index. The range of preferred
refractive index values are from about 1.33 to about 1.42. The
swollen weight ratios of water to polymer in these combinations can
range from about 1:1 to about 1:10.
[0024] To mediate covalent binding of the IOL to the lens capsule,
an azide-active-ester chemical containing a photoreactive azide on
one end and an N-hydroxysuccinimide (NHS) group (which can
covalently bind to cell adhesion proteins and peptides) on the
other end can be used. An example of such a linker is
5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester. Another
example of a bifunctional linker is
6-(4-azido-2-nitrophenylamino)hexanoic acid N-hydroxysuccinimide
ester, which has a longer spacer arm between the reactive end
groups. In addition, novel spacer arms that are both longer and
more hydrophilic can be synthesized by conjugating
5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester with
amine-terminated PEG macromers, which can then be further
functionalized to possess NHS moieties that can bind to
protein/peptides. In one example, 5 mg of 5-azido-2-nitrobenzoic
acid N-hydroxysuccinimide ester is dissolved in 1 mL of
N,N-dimethylformamide (DMF) (See Matsuda et al. (1990) in a paper
entitled "Development of micropatterning technology for cultured
cells" and published in "ASAIO Transactions 36(3):M559-562"). This
solution is then evenly spread over the hydrogel surface and
exposed to UV for 5 minutes after the hydrogel surface is
air-dried. Upon UV irradiation, the phenyl azide group reacts to
form covalent bonds with the hydrogel surface. The irradiated
surfaces are then thoroughly rinsed with solvent to remove any
unreacted chemicals from the surface. This results in hydrogels
with exposed NHS end groups on the surface. These exposed NHS end
groups can then covalently bind to a lens capsule upon implantation
of the IOL into the lens capsule, as shown in FIG. 4.
[0025] In FIG. 4, swollen IOL 410, which has been functionalized
with 5-azido-2-nitrobenzoyloxy-N-hydroxysuccinimide, makes
sustained contact with lens capsule 420. This in turn allows the
functionalized IOL to covalently bind 430 to the lens capsule 420.
Preferably, the functionalized IOL covalently binds to the lens
capsule through free amines on proteins present in the lens
capsule.
[0026] Hydrogels that have been functionalized with
5-azido-2-nitrobenzoyloxy-N-hydroxysuccinimide can bind collagen, a
protein normally found in the lens capsule, as shown in FIG. 5. In
FIG. 5A, an IOL according to the present invention was incubated in
a 0.1% collagen-FITC solution for 24 hours at 37 degrees C. In
contrast to FIG. 5B, which was not reacted with collagen-FITC, FIG.
5A shows binding of collagen-FITC to the surface of the IOL. In
this experiment, collagen type I was used.
[0027] IOLs according to the present invention may be used for any
condition whereby the natural lens is damaged, missing, or
defective. Examples include lens replacement for people suffering
from cataracts and for people with age-related hardening of the
lens (presbyopia).
[0028] In addition, IOLs according to the present invention
preferably prevent secondary opacification of the posterior
capsule. It does so by eliminating the potential space between the
lens capsule and the lens element in which opacification typically
occurs in vivo.
[0029] As one of ordinary skill in the art will appreciate, various
changes, substitutions, and alterations could be made or otherwise
implemented without departing from the principles of the present
invention. Accordingly, the scope of the invention should be
determined by the following claims and their legal equivalents.
* * * * *