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The present invention addresses the treatment of ocular conditions by the enhancement of lens regeneration. Enhancement of lens regeneration is accomplished by the administration of a composition comprising a polysiloxane polymer having functional acryl groups useful in the preparation of intraocular lenses (IOLs).
1. A method comprising enhancing regeneration of lens cells in a mammal after endocapsular extraction by filling a lens capsule bag of said mammal with an injectable lens material comprising a polysiloxane polymer wherein said injectable lens material has a viscosity for being injected through standard cannula and said polysiloxane polymer has functional acryl groups at terminal ends of said polymer.
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wherein R1 and R2 are independently C1-C6 alkyl; R3 is phenyl; R4 is phenyl or C1-C6 alkyl; R5 is CF3 (CH2)x wherein x is 1-5; R6 is C1-C6 alkyl or fluoroalkyl; I is in the molar fraction range of 0 to 0.95; m is in the molar fraction range of from greater than 0 to 0.7; and n is in the molar fraction range of from greater than 0 to 0.65.
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11. A kit comprising (i) a polysiloxane polymer; and (ii) instructional materials wherein said instructional materials direct the use of said polysiloxane polymer in enhancing regeneration of lens cells.
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wherein R1 and R2 are independently C1-C6 alkyl; R3 is phenyl; R4 is phenyl or C1-C6 alkyl; R5 is CF3 (CH2)x wherein x is 1-5; R6 is C1-C6 alkyl or fluoroalkyl; I is in the molar fraction range of 0 to 0.95; m is in the molar fraction range of from greater than 0 to 0.7; and n is in the molar fraction range of from greater than 0 to 0.65.
The present application is a continuation-in-part of U.S. Pat. No. 10/881,426 filed Jun. 30, 2004.
The present invention addresses the treatment of ocular conditions by the enhancement of lens regeneration. Enhancement of lens regeneration is accomplished through the administration of a composition comprising a polysiloxane polymer having functional acryl groups that is useful in the preparation of intraocular lenses (IOLs).
A cataract is the clouding of a natural eye lens, the part of the eye that focuses light onto the retina to produce clear, sharp images. The lens is contained in a sealed bag or capsule. As old lens cells die they become trapped within the capsule, and, over time, the accumulation of these cells causes the lens to cloud, so that light is no longer focused properly onto the retina and images appear blurred or fuzzy. For most people, cataracts are a natural result of aging.
A process called extracapsular cataract extraction with implantation of an intraocular lens (IOL) is currently the most common method for the treatment of cataracts. This process involves removing the natural dysfunctional lens and replacing it with an artificial lens. This procedure is less than ideal, however, because the current synthetic IOLs are unable to accommodate appreciably, and secondary opacification of the posterior capsule (i.e. secondary cataracts) is a common occurrence following the procedure.
Importantly, after removal, in some situations eye lenses can regenerate over time. Ideally then, it a regenerated natural lens could replace a suitable biodegradable material, the reformed regenerated lens could have the same or similar natural focusing power as the normal young lens and could be able to accommodate visually. Alternatively, if naturally regenerating lens epithelial cells could be directed to grow in a regularly organized pattern around a suitably flexible and biocompatible polymeric lens, the resultant bilenticular system might also be able to accommodate. Therefore, there is a need in the art for a regenerated lens (with or without a suitably flexible and biocompatible polymeric lens) which would have properties of the natural lens including clarity, protein content, histology, focusing power, spectral transmission, accommodative ability, configuration, shape and structure.
One approach to forming a lens following cataract extraction has been to use accommodative refill lenses. Accommodative refill lenses are created by injecting low viscosity liquids (such as silicone oils or low temperature vulcanizing (LTV) silicone elastomers) into the len's capsular bag through a small incision. After injection, these low viscosity liquids polymerize under forming pressure to create a lens of the required shape. This technique uses the form of the capsular bag as a mold. Various drawbacks associated with this technique remain to date, however, preventing its beneficial use in all patients. The present invention provides beneficial methods of using new materials to create accommodative refill lenses and to enhance natural lens regeneration.
The present invention provides methods of enhancing lens regeneration using materials comprising polysiloxane polymers. Surgeons or researchers can inject the material into a capsular bag to form a lens or scaffold onto and around which lens cells can regenerate and organize.
Specifically, in one embodiment according to the present invention the invention is a method comprising enhancing regeneration of lens cells in a mammal after endocapsular extraction by filling a lens capsule bag of the mammal with an injectable lens material comprising a polysiloxane polymer wherein the injectable lens material has a viscosity for being injected through standard cannula and the polysiloxane polymer has functional acryl groups at terminal ends of the polymer.
In another embodiment of the methods, the endocapsular extraction occurs through a capsulorrhexis that is 3 millimeters or less.
Embodiment of the presently described methods can also further comprise one or more of: (i) inserting a foldable intraocular lens into the capsule bag of the mammal; (ii) positioning a contact lens or similar polymeric material in the form of a permeable or semi-permeable disc shaped lens between the anterior capsule and the injectable lens material; (iii) administering hyaluronic acid to the capsule bag of the mammal; (iv) administering hyaluronidase to the capsule bag of the mammal; and (v) inserting at least one collagen patch in the capsule bag of the mammal.
In another embodiment of the methods, the injectable lens material further comprises a photoinitiator and is capable of being photopolymerized into a solid intraocular lens.
In yet another embodiment of the methods, the polysiloxane polymer has a backbone of the general formula:
The present invention also includes kits. Kits according to the present invention can comprises instructional materials and one or both of (i) a polysiloxane polymer; and (ii) a photocurable polysiloxane polymer and wherein the kit can also comprise one or more of (i) hyaluronic acid; (ii) hyaluronidase; (iii) a collagen patch; (iv) an intraocular lens; and (v) a contact lens or similar polymeric material in the form of a permeable or semi-permeable disc shaped lens. The instructional materials of these kits instruct the use of the included components in enhancing the regeneration of lens cells. In alternative embodiments, the instructional materials can also direct that the endocapsular extraction occurs through a capsulorrhexis that is 3 millimeters or less in length.
In another embodiment of the kits, the polysiloxane polymer has a backbone of the general formula:
Enhance lens regeneration: As used herein, �enhance lens regeneration� and variants of the same phrase include increasing the probability of a lens regenerating after extracapsular lens extraction wherein the lens will have less haze, less striae or fewer folds than it otherwise would have had without a described treatment or is a regenerative lens that is more clear than it otherwise would have been with a described treatment.
Functional acryl groups: As used herein, �functional acryl groups� include polysiloxane molecules having functional groups attached thereto including an acryl group moiety, so as to become acryl-bearing, by acryl attachment to the siloxane monomers of the polysiloxane backbone, its terminal ends, or both. The acryl groups in these functional groups can be linked to the silicone atoms by spacers. Examples of functional acryl groups include, without limitation, acrylamidopropyl, methacrylamidopropyl, acryloxyhexyl and methacryloxyhexyl. In one embodiment, the functional acryl groups are attached to the terminal ends of polysiloxane molecules, as exemplified by, without limitation, acrylamidopropyl-, methacrylamidopropyl-, acryloxyhexyl- and methacryloxyhexyl-terminated polysiloxanes. Those skilled in the art can consider numerous such alternatives which maintain the basic function of having an acryl group for subsequent crosslinking/polymerization of the polysiloxane molecules into larger network together with a photoinitiator. In the same manner it is also to be understood that the meaning of acryl group includes acryl or substituted acryl, such as, without limitation, methacryl, moieties attached through a variety of linkages including ester, amide and urethane linkages, or functional analogues of acryl capable of undergoing crosslinking reactions with a photoinitiator.
The present invention is based on the concept that the natural lens is capable of controlled or enhanced organic cellular or biological regeneration following endocapsular lens and/or cataract extraction. In various embodiments, the present invention provides methods to contribute to the production of a regenerated lens with properties similar to that of the natural lens, including, without limitation, clarity, protein content, histology, focusing power, spectral transmission and accommodative ability. In one embodiment, the natural regenerating lens tissue can be directed to grow in a more natural or regular pattern around a suitably flexible and biocompatible polymeric lens.
The concept of implanting a suitably flexible polymeric lens compatible with naturally regenerating lens tissue was previously suggested by studies in which Acuvue� contact lenses (etafilcon A, 58% H20; available from Johnson & Johnson Vision Care, Inc., Jacksonville, Fla.) were modified for intralenticular implantation in the rabbit eye. While normal regeneration was noted in one eye, the results were inconsistent and the nucleus of most regenerated lenses contained a star-shaped opacity related to the irregular growth pattern and misalignment of the earliest lens fibers.
In numerous studies, lenses that have been regenerated following endocapsular lens extraction in New Zealand Albino rabbits have been irregular in shape, appearing primarily doughnut-shaped. The newly formed lenses are irregular in shape as a result of the lack of lens growth at the site of the anterior capsulotomy and its adhesion to the posterior capsule. These regenerated lenses have had variable translucency because of irregular alignment of newly formed fibers, which may partly result from irregular proliferation of cells in zones of wrinkling or folding of the lens capsule in the early postoperative period. To improve the transparency of the regenerated lenses and their therapeutic utility, investigators have attempted to mimic the embryonic environment with limited success.
The various embodiments of the present invention reaffirm past findings in the art showing lens regeneration and demonstrate that regeneration of the lens can be enhanced through the use of polysiloxane polymer containing compositions. Certain embodiments according to the present invention also incorporate the use of hyaluronic acid to further enhance lens regeneration. Embodiments according to the present invention can also enhance lens regeneration by restoring lens capsule integrity following the administration of polysiloxane polymer containing compositions
The following in vivo studies evaluated the use of polysiloxane polymers following endocapsular lens extraction in young and old New Zealand white rabbits.
General Materials
The polysiloxane polymer material used in the presently described studies was obtained from AMO (Groningen, Holland) and corresponded to composition AS4-11, CS0402014. Silicone plugs (4.5 mm) were also obtained from AMO (Groningen, Holland). �Shark Tooth� Phaco needles, (LAMINAR� Flow Phaco Tip15�/45�) and infusion sleeve (20 gauge, OPO154520L) were also obtained from AMO (Santa Ana, Calif.). Healon 5 was obtained from AMO (Uppsala, Sweden).
General Methods
The general health and acceptability of animals used in the following studies was established prior to surgery. A total of 7 New Zealand white rabbits were used in three studies. During surgery, rabbits were anesthetized with about 5 mg/kg xylazine and about 50 mg/kg ketamine HCl, intramuscularly. The surgical eye was dilated with 1% cyclopentolate and 10% phenylephrine; eyelashes were trimmed; and the ocular area was disinfected with povidone iodine. A wire lid speculum was inserted to retract the lids, and a corneal incision was made at 12:00 with a 2.85 mm keratome. Healon S was injected to maintain anterior chamber depth and an about 2-3 mm continuous curvilinear capsulorrhexis was performed. A 20 gauge phacoemulsification tip was inserted through the corneal wound and endocapsular lens extraction was performed by phacoemulsification and irrigation/aspiration with BSS mixed with 5% heparin (Solo Pak Lab. Inc., Elk Groove Village, Ill.) and 1.100,000 epinephrine (Anpro Pharmaceutical, Arcadia, Calif.). Considerable care was taken to remove all lens cortical material by diligent irrigation and aspiration. A 4.5 mm silicone plug was inserted into the capsule bag and maneuvered behind the anterior capsulotomy and the polysiloxane polymer material was injected into the capsule bag using a 20 gauge cannula. At the completion of the procedure, the corneal incision was closed with 10-0 nylon sutures and 0.25 ml (20 mg) of gentamicin and 0.1 ml of dexamethasone (2 mg) was injected subconjunctivally every 3 days for two weeks.
The overall positional stability of the silicone plug was evaluated based on the slit lamp observation of placement in the capsule bag. Observations of conjunctiva, corneal pathology, anterior chamber cells, flare and fibrin, posterior synechiae, capsular bag shape, and percent lens regrowth in the capsule bag were recorded.
All slit lamp findings were graded on a scale of 0 to 4 (0=none, 1+=trace, 2+=mild, 3+=moderate, 4+=severe). Throughout the experimental period, rabbits were observed for any abnormal clinical signs, including any abnormal ocular findings such as pain, excessive hyperemia or discharge. Grading of the ocular findings was based on the methods of McDonald and Shadduck (McDonald, T. O., and Shadduck, J. A. Eye Irritation. Advances in Modern Toxicology, Vol. 4, pp. 162-166. Dermatotoxicology and Pharmacology. Eds. Marzulli and Maibach. Washington: Hemisphere, 1977) which is incorporated by reference herein for all that it teaches regarding the grading of ocular findings. All observations were recorded on a Slit Lamp Examination form. Grading for each of these parameters was done as follows:
Cornea: Scores recorded for the cornea reflect the greatest severity of corneal edema/cloudiness observed. Severity of corneal cloudiness was graded as follows:
Cells in the anterior chamber: The presence/absence of cells in the anterior chamber was monitored as follows:
Anterior chamber flare: Anterior chamber flare was graded on the intensity of the Tyndall phenomenon and was scored by comparing the normal Tyndall effect observed when the slit lamp passes through the lens with that seen in the anterior chamber:
Fibrin in the anterior chamber: The presence/absence of fibrin in the anterior chamber was monitored as follows:
Posterior Synechia: The presence/absence of iris adhesion to the lens capsule is known as posterior synechia and was graded as follows:
At the end of the studies, animals were euthanized by an injection of sodium pentobarbital (Eutha-6, Western Medical Supply Co., Inc.) into the marginal ear vein. At all times animals were treated in accordance with USDA guidelines and the ARVO Resolution on the Use of Animals in Research.
The study described in Example 1 evaluated: (i) posterior capsule opacification when a foldable silicone IOL in combination with the polysiloxane polymer material is used and (ii) the surgical technique for performing endocapsular extraction through a small 2 mm capsulorrhexis in an older rabbit with a hard lens.
In this study, rabbit 71719 (New Zealand white female; weight 2.4 kg) was 3 months old and rabbits 71565 and 71566 (New Zealand white females; weight 3.5 kg) were 3 years old.
Rabbit 71719 OD, OS: Uneventful endocapsular lens extractions were performed through a 2.0 mm capsulorrhexis using a 20 gauge phaco needle with Healon 5 for anterior chamber maintenance. During phaco, the capsulorrhexis stretched and a 4.5 mm silicone plug was positioned under the capsulorrhexis. In 71719 OD, the polysiloxane polymer material containing a few small bubbles was injected with a 20 gauge cannula on a 3 cc syringe. In 71719 OS, a SI-40NB IOL devoid of haptics was inserted into the capsule bag with the Silver Insertion System and the polysiloxane polymer material was injected into capsule bag in front of the IOL.
Rabbits 71565 and 71566: In these 3 year old large rabbits, the lens nucleus density was estimated to be 3-4+. Endocapsular lens extractions were performed through a 2.0 mm capsulorrhexis using a 21 gauge Shark Tooth Phaco needle with Healon 5 for anterior chamber maintenance. The Phaco time for 71565 OD was 20 minutes. The Phaco time for 71565 OS was 18 minutes. Following lens removal, rabbit 71565 was euthanized. The Phaco time for 71566 OD was 13 minutes. After multiple attempts a 4.5 mm silicone plug was placed under the stretched capsulorrhexis and 0.3 cc of the polysiloxane polymer material was injected into the capsule bag. Slit lamp biomicroscopy was performed on Days 0, 1, 7, 15, 18, 26, 44, 74 and 107.
Immediately postoperative, all wounds were intact. Trace conjunctival injection, corneal haze and edema were noted at day 1 which resolved by one week. Trace anterior chamber flare was seen at day 1-5 which resolved by 2 weeks. Mild posterior synechiae to the capsulorrhexis was seen in all eyes. Severe synechiae was noted in one eye at days 7-26. The anterior capsulorrhexis was sealed by the 4.5 mm silicone plug and/or the Acuvue contact lens throughout the study, except in 2 eyes. In rabbit eye 71719 OS (SI-40 IOL) the polysiloxane polymer material and SI40NB IOL was noted to extrude into the anterior chamber at Day 26.
Results for Rabbit #71719 OD:
Results for Rabbit #71719 OS:
Results for Rabbit #71566 OD:
In two separate eyes a SI40NB IOL or an Acuvue contact lens were placed intracapsularly prior to injection of the polysiloxane polymer material, The SI40NB IOL was noted to rest against the posterior capsule and was associated with trace anterior and posterior capsule haze immediately postoperative. As time progressed the polysiloxane polymer material and the SI40NB IOL were extruded into the anterior chamber for no apparent reason. The Acuvue� contact lens was noted to rest against the clear anterior capsule for the two month follow-up period. It is of note that the Acuvue�/polysiloxane polymer material eye had the only clear anterior capsule (devoid of haze, striae or folds) in the 3 studies (see
Hard Lens Removal Through Small Capsulorrhexis
Three year old large rabbits have a large lens with a nuclear density estimated to be 3-4+. These lenses are thought to be very similar to the adult cataractous lens with a 3-4+ nuclear density. In this study, the hard lens was able to be removed through a 2.0 mm capsulorrhexis using a 21 gauge Shark Tooth Phaco needle. However, the phaco time was exceedingly long, averaging from 13 to 20 minutes. It is important to note that these lenses were much larger than the human lens (maybe as much as twice the size of the human lens) and therefore one would anticipate being able to reduce the total phaco time to 5 to 10 minutes in the human eye.
This study evaluated the implantation of an Acuvue� contact lens in combination with the polysiloxane polymer material. The New Zealand white female rabbit (Rabbit 71891) was about 3-4 months old at time of surgery and weighed 2.6 kg.
Rabbit 71891 OD, OS: Uneventful endocapsular lens extractions were performed through a 2.0 (OD) to 2.5 mm (OS) capsulorrhexis using a 20 gauge phaco needle with Healon 5 for anterior chamber maintenance. During phaco the capsulorrhexis stretched and a 4.5 mm silicone plug was positioned under the capsulorrhexis. In the right eye, an Acuvue� contact lens was cut to 6.5 mm and placed into the capsule bag with forceps. The polysiloxane polymer material (0.25 cc) was then injected under the contact lens which assisted the silicone plug in preventing polysiloxane polymer leakage. In the left eye, the polysiloxane polymer material (0.15 cc) was injected into the capsule bag with slight leakage.
Slit lamp biomicroscopy was performed Days 0, 21, 38 and 53. Immediately postoperative, all wounds were intact. Trace to mild corneal haze and edema were noted day 1 and resolved by one week.
Results for Rabbit #71891 OD
Results for Rabbit #71891 OS
Example 3 was designed to quantitate the amount of polysiloxane polymer material required to fill the capsule bag of 3 month old New Zealand white rabbits. The rabbits used in this study were 3-4 months old and weighed 2.5-2.6 kg.
Rabbits 72823 OD, 72824 OD, 72825 OD: Uneventful endocapsular lens extractions were performed through a 3.0 capsulorrhexis using a 21 gauge phaco needle with Healon 5 for anterior chamber maintenance. A 4.5 mm silicone plug was placed into the capsular bag and 0.2 cc, 0.1 cc and 0.2 cc of the polysiloxane polymer material was injected into the capsule bag of rabbit 72823 OD, 72824 OD and 72825 OD, respectfully. Minimal air bubbles and polysiloxane polymer leakage were noted. Slit lamp biomicroscopy was performed on Days 0, 5, 26 and 57.
Immediately postoperative, all wounds were intact. Trace anterior chamber flare was seen at day 1-5 which resolved by 2 weeks. Mild anterior chamber fibrin was noted in one eye at day 1 and a small polysiloxane polymer material bubble was seen in one eye. In rabbit 72824 OD the silicone plug and polysiloxane polymer material also protruded into the anterior chamber at day 26.
Results for Rabbit #72823 OD
Results for Rabbit #72824 OD
Results for Rabbit #72825 OD
Immediately postoperative, the capsule bags were clear and distended with the clear polysiloxane polymer material. The polysiloxane polymer material used remained clear in all studies throughout the follow-up period (for as long as 107 days). Underfilling of the capsule bag was noted in some eyes. In particular, 0.1 cc of the polysiloxane polymer material was not enough to fill the capsule bag and was associated with slippage of the silicone plug and extrusion of polysiloxane polymer material into the anterior chamber. Rather, about 0.2 cc of polysiloxane polymer material was required to fill the capsule bag of these 3-4 months old New Zealand white rabbits, weighing 2.5-2.6 kg.
Immediately postoperative, trace posterior capsule haze was noted in most eyes and gradually progressed with striae and folds also noted. Posterior capsule lens regrowth was first noted at day 26 and gradually progressed surrounding the polysiloxane polymer material. In general lens regrowth was clear anterior and peripheral to the polysiloxane polymer material and more irregular and opaque posterior to the polysiloxane polymer material. By one week varying degrees of anterior capsule haze, striae and folds were noted in all eyes except the one eye with the Acuvue� against the anterior capsule (
In summary, the results of the described studies indicated that: (i) endocapsular lens extraction could be performed through a small 2.0 mm capsulorrhexis in the hard lens (3-4+) of 3 year old large rabbits; (ii) a clear anterior capsule devoid of haze, striae or folds was noted in the one eye with the Acuvuee contact lens positioned between the anterior capsule and polysiloxane polymer material; (iii) the polysiloxane polymer material was an intralenticular lens with clear regenerative lens material surrounding it, thus creating a bilenticular lens; and (iv) the 3-4 month old rabbit requires about 0.2 cc of the polysiloxane polymer material to fill the capsule bag.
In one embodiment of the polysiloxane polymers used in accordance with the present invention, the polysiloxane polymer has functional acryl groups that can be obtained from a polymer having the general formula:
In another embodiment R1 is methyl, that R2 is methyl, R4 is phenyl, that x is 2, either independently, or in combination.
According to these alternatives, in one embodiment R6 is methyl. According to another embodiment, the polysiloxane is a polymer of diphenyl or phenylalkyl siloxane and dialkyl siloxane with terminal acryl groups. According to further embodiments, the polysiloxane is a polymer of diphenyl or phenylalkyl siloxane and trifluoroalkyl(alkyl)siloxane, or a terpolymer or higher order polymer of diphenyl and/or phenylalkyl siloxane, dialkyl siloxane and trifluoroalkyl alkyl siloxane. According to another embodiment, polysiloxane is an acryl-terminated terpolymer of dimethyl siloxane, diphenyl siloxane or phenylmethyl siloxane and 3,3,3-trifluoropropylmethyl siloxane. In certain embodiments the polysiloxanes comprise at least about 4 mol % of trifluoropropylmethyl siloxane and about 1 to about 50 mol % of diphenylsiloxane and/or phenylmethylsiloxane. In other embodiments the polysiloxanes comprise about 4 to about 65 mol % trifluoropropylmethyl siloxane, and about 1 to about 50 mol % of diphenylsiloxaue and dimethylsiloxane monomer units. One suitable acryl-terminated polysiloxane composition comprises about 28 mol % trifluoropropyimethyl siloxane, about 4 mol % diphenyl siloxane and dimethyl siloxane monomer units.
The polysiloxane polymers used in accordance with the present invention are formed into an injectable lens material having a suitable viscosity to be injected through standard cannula with an 18 Gauge needle or finer. For this purpose the material has a viscosity lower than about 60 000 cSt or below about 8000 cSt for being readily injectable through a 21 Gauge needle. The injectable lens material includes at least one type of polysiloxanes according to any of the definitions above. The injectable lens material can also optionally comprise a photoinitiator and/or a crosslinking agent, which itself can be siloxane oligomer or polymer having functional acryl groups and further physiologically or ophthalmologically acceptable additives necessary for producing a lens.
A method of the in vivo production of an IOL, can comprise the steps of preparing an polysiloxane polymer having functional acryl groups; mixing the polymer and a photoinitiator, in one embodiment a medically acceptable blue light photoinitiator, into a composition; injecting the composition into the capsular bag of the eye; and initiating a polymerization reaction to create a lens in the capsular bag. Optionally, the elastomer can also comprise an UV absorbing compound or other conventional additives known to those skilled in the art. A special advantage of the materials used in accordance with the present invention is that the incorporation of a fluoroalkyl siloxane enables materials of high specific gravity to be produced
Examples of specific procedures for creating polysiloxane polymers useful in accordance with the present invention can be found in U.S. Pat. No. 6,737,496 which is incorporated by reference herein for all that it teaches regarding creating polysiloxane polymers.
Hyaluronic acid can also be administered in conjuction with the polysiloxane polymers used in accordance with the present invention. Administration of hyaluronic acid can be beneficial in wound healing. Further, fetal wounds that heal without scar formation have an extracellular matrix that is rich in hyaluronic acid. In one embodiment of the present invention, a viscoelastic substance such as hyaluronic acid may be used in conjunction with a polysiloxane polymer for capsule bag filling to enhance the regeneration of lenses following phacoemulsification and subsequent irrigation and aspiration of both the natural and cataractous lens and sealing of the anterior capsule. One skilled in the art will readily appreciate that a variety of high viscosity hyaluronic acid compositions, glycosaminoglycans (GAG's), and/or formulations thereof may be used in accordance with alternate embodiments of the present invention. For example, suitable hyaluronic compositions may include, but are not limited to the following: Restylane� OVD, Perlane� OVD, a variant formulation of Healon� OVD (AB Corp., Sweden), and/or compositions that include high viscosity hyaluronic acid forms such as those described in U.S. Pat. Nos.: 6,537,795; 6,090,596; 4,764,360; 6,086,597; 6,368,585; and 5,681,825; U.S. Patent Application Publication No. 2002/0018898 (Ser. No. 09/855,923), and in European Patent Application 0760863 B1, all of which are incorporated herein by reference in their entirety as if fully set forth. Any variant formulation or analogous composition of any of the aforementioned hyaluronic compounds and/or GAGs including, but not limited to hyaluronic acid forms with higher or lower molecular weights, hyaluronic acid forms at variant concentrations, chondroitin sulfate, a hyaluronic acid/chondroitin sulfate mixture, combinations of two or more of the abovementioned compositions, and/or combinations of any of the aforementioned compositions with other suitable agents may be used in accordance with alternate embodiments of the invention. Furthermore, inventive compositions may include a hyaluronic acid compound as well as any number of conventional carriers, additives, preservatives, antibiotics, therapeutic agents and the like that are generally formulated in pharmacological compositions of this nature, as will be readily appreciated by those of skill in the art. Such additional elements may, for example, promote the safety and/or efficacy of the inventive compound. Various quantities, molecular weights, concentrations, and/or forms of hyaluronic acid products may be used to improve the lens cell proliferation and differentiation. For example, a quantity between 0.01 to 3 cc of hyaluronic acid may be used to fill the lens capsule bag to improve the lens cell proliferation and differentiation.
In alternate embodiments, other media can be used individually or in combination to enhance the proliferation and differentiation of lens cells in accordance with the present invention; for instance, amniotic fluid, in vitro fertilization media, growth factors (e.g., BD MATRIGEL� Basement Membrane Matrix and BD MATRIGEL� Basement Membrane Matrix High Concentration; BD Biosciences, San Jose, Calif.), and/or other substances that can enhance or control the growth and proliferation of cells will be readily appreciated by one skilled in the art.
In another embodiment, lenticular tissue may be engineered using focal laser photophacocoagulation to remove excess viscoelastic substances and/or modify structure and clarity of the regenerated lens and/or bilenticular lens. As described in U.S. Pat. No. 6,322,556 and U.S. Patent Application Publication Nos. 2002/0103478 (Ser. No. 09/953,121) and 2006/0002981 (Ser. No. 10/881,426) which are all incorporated herein by reference as if fully set forth, laser photophacoablation (laser photoablation) has been used to partially remove ocular tissue (e.g., lens tissue) to correct vision deficiencies and to treat other vision-impairing ocular problems without causing substantial damage to the surrounding tissue regions. In the present invention, laser photophacoablation may be used to remove retained high viscosity or viscoelastic substances in the regenerated lens in combination with the inventive use of hyaluronic acid in combination with polysiloxane polymers.
Lens regeneration can also be enhanced in accordance with the present invention by sealing the anterior capsulotomy with one or more collagen patches. Insertion of a collagen patch may be effected during a procedure for treating ocular disease and/or correcting vision impairment, as for example, endocapsular lens extraction surgery. The lens capsule integrity is restored by inserting one or more collagen patches during endocapsular lens extraction surgery to seal the anterior capsulotomy and restore its continuity, which thereby improves the shape and structure of the regenerated lenses. It will be appreciated by those skilled in the art that a variety of collagen patches may be used and that the sealing of the capsulotomy may occur in various regions in connection with various embodiments of the present invention. For example, a collagen patch that is composed of bovine collagen type IV or a 12 hour collagen shield (Chiron Ophthalmics, Emeryville, Calif., U.S.A.) or a 24 or 72 hour PROSHIELD� Collagen Corneal Shield (Alcon Laboratories, Inc, Fort Worth, Tex.) may be used in accordance with an embodiment of the present invention. Additionally, a collagen patch may be used to seal any opening in the lens capsule bag, not just the anterior capsulotomy. Furthermore, in an alternate embodiment, injectable collagen may be used as a supplement to or a replacement for the inserted collagen patch to further enhance lens regeneration.
In an additional embodiment, collagen may be used as an internal scaffold for lens fiber cell proliferation and differentiation. A variety of collagen-based products may be used, as for example, 25% or 50% suspensions of purified bovine dermis in saline with 0.3% lidocaine (available under the trade name Zyderm I� and Zyderm II� from INAMED Corporation; Santa Barbara, Calif.), monomolecular bovine collagen suspended in solution at 3.5% and 6.5% concentrations (available under the trade name Resoplast� from Rofil Medical International; Breda, Holland), human collagen preparation comprised predominantly of intact collagen fibers as well as other matrix proteins suspended in a neutral pH buffer (available under the trade name Dermalogen� from Collagenesis Corporation; Beverly, Mass.), a cellular human dermal graft processed from tissue bank-derived skin (available under the trade name Alloderm� from LifeCell Corporation; Palo Alto, Calif.), GAG-based compound or polymer; and/or include collagen produced by amnion as described in U.S. Patent Application Publication No. 2004/0048796 (Ser. No. 10/397,867) which is incorporated by reference in its entirety as if fully set forth.
In those embodiments of the present invention directed to methods for treating ocular disease and/or correcting vision impairment, one can use these methods to treat any disease in which enhancing lens regeneration has a beneficial effect on a patient (e.g., ameliorating a disease, lessening the severity of its complications, preventing it from manifesting, preventing it from recurring, merely preventing it from worsening, or a therapeutic effort to effect any of the aforementioned, even if such therapeutic effort is ultimately unsuccessful). Methods of the present invention may be used to treat any diseases which are affected by lens tissue loss or damage, or ocular conditions or impairments which involve a medical procedure comprising the removal or alteration of lens tissue.
The present invention also includes kits. In one embodiment, the kits of the present invention comprise injectable lens materials including, in certain embodiments other materials to assist in the enhancement of lens regeneration. Kits of the present invention can contain one or more of the following in a package or container: (1) one or more injectable lens materials of the present invention; (2) one or more pharmaceutically acceptable adjuvants or excipients; (3) one or more vehicles for administration, such as one or more syringes; (4) one or more tools to use in a surgical procedure; (5) one or more additional bioactive agents for concurrent or sequential administration and/or (6) instructional information. Embodiments in which two or more of components (1)-(6) are found in the same container can also be used.
When a kit is supplied, the different components of the compositions included can be packaged in separate containers and admixed immediately before use. Such packaging of the components separately can permit long-term storage without losing the active components' functions. When more than one composition or active agent is included in a particular kit, the bioactive agents may be (1) packaged separately and admixed separately with appropriate (similar or different) vehicles immediately before use, (2) packaged together and admixed together immediately before use or (3) packaged separately and admixed together immediately before use. If the chosen compounds will remain stable after admixture, however, the admixture need not occur immediately before use but can occur at a time before use, including in one example, minutes, hours, days, months or years before use or in another embodiment at the time of manufacture.
The compositions included in particular kits of the present invention can be supplied in containers of any sort such that the life of the different components are preserved and are not adsorbed or altered by the materials of the container and/or so that other components are not damaged. For example, sealed glass ampules can contain lyophilized agents or variants or derivatives thereof or other bioactive agents, or buffers that have been packaged under a neutral, non-reacting gas, such as, without limitation, nitrogen. Ampules can consist of any suitable material, such as, without limitation, glass, organic polymers, such as, polycarbonate, polystyrene, etc., ceramic, metal or any other material typically employed to hold similar reagents. Other examples of suitable containers include, without limitation, simple bottles that may be fabricated from similar substances as ampules, and envelopes, that can comprise foil-lined interiors, such as aluminum or an alloy. Other containers include, without limitation, test tubes, vials, flasks, bottles, syringes, or the like. Containers can have one or more sterile access ports, such as a bottle having a stopper that can be pierced by a hypodermic injection needle. Other containers may have two compartments that are separated by a readily removable membrane that upon removal permits the components to be mixed. Removable membranes may be, without limitation, glass, plastic, rubber, etc.
As stated earlier, kits can also be supplied with instructional materials. Instructions may be printed on paper or other substrate, and/or may be supplied as an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, Zip disc, videotape, audiotape, flash memory device, etc. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.
As should be understood, the exact formulation, route of administration, and dosage should generally be determined by the attending physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide appropriate levels of nucleic acid molecules which are sufficient to maintain therapeutic effect.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term �about.� Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
The terms �a� and �an� and �the� and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. �such as�) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.
In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
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Saving Faith
By David Baldacci
(Grand Central Publishing, Hardcover, 9780446525770, 464pp.)
Publication Date: November 1999
Other Editions of This Title: Hardcover, Mass Market Paperback, Paperback, Compact Disc, Compact Disc
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In the field of popular fiction David Baldacci is far ahead of the competition. Continuing his string of New York Times bestsellers, Baldacci presents his most electrifying story to date-a novel of nonstop action, vividly etched characters, and an astounding vision of the inner sanctums of our government. Not far from Washington, D.C., in a wooded area of Northern Virginia, a small house at the end of a gravel road serves a secret purpose. With its sophisticated security apparatus and hidden miniaturized cameras, it is being used by the FBI to interview one of the most important witnesses the agency has ever had, a young woman with an incredible story to tell. But a few people know about the secret meeting. And for them, a violent drama is about to begin. One man-a local private investigator named Lee Adams-has come to the house on the orders of his client. Another man, a hired killer, stakes out the house on orders from his powerful paymasters. And the witness, Faith Lockhart, is coming to tell the FBI everything she knows about the powerful lobbyist with whom she has worked, a man who manipulates U.S. government policy and who, in the process, made some very dangerous enemies. Then, before Faith can tell her story, the hit man pulls the trigger and the wrong victim falls. Now Faith Lockhart is on the run-from the most dangerous people in America-with Lee Adams, a man she doesn't know, yet must trust. A relentless chase novel that unfolds as both the FBI and a killer search for Faith and Lee, this is also a searing and utterly suspenseful tale of power gone mad in Washington, and of one woman's desperate attempt to break out of a web of corruption and terror that reaches much further than even she can know. In the hands of master storyteller David Baldacci, Saving Faith elevates the thriller to a new level and poses stunning questions about the rules we live by, the rules we are governed by-and what happens when some people make rules of their own...
David Baldacci lives with his family in Virginia. He and his wife have founded the Wish You Well Foundation, a nonprofit organization dedicated to supporting literacy efforts across America. He invites you to visit him at www.davidbaldacci.com and his foundation at www.wishyouwellfoundation.org.

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#1319 of 1472
Maui, HI
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Expert Printing and Assembly
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Anuenue - Rainbow At The Ahinahina Ahu Haleakala Sunrise Maui Hawaii
Sharon Mau
Photograph - Photography
Elevation appx 10,000 feet above sea level. A beautiful morning anuenue (rainbow) at the Ahinahina Ahu - summit Kilakila O Haleakalā
- Ala hea ka la -
Haleakalā Sacred House of the Sun
Maui Hawaii
Summit - Haleakalā National Park is a United States national park located on the island of Maui in the state of Hawaii. The park covers an area of 33,265 acres, of which 19,270 acres is a wilderness area
Photo Copyright � Sharon Mau
This is a Rights-Managed Image protected by copyright.
My images do not belong to the public domain.
Images may not be reproduced, downloaded, distributed, transmitted, copied, reproduced in derivative works, displayed, published or broadcast by any means or in any form without prior written consent from the artist Sharon Mau - Mahalo
December 25th, 2010
Viewed 733 Times - Last Visitor from Frome, Somerset - United Kingdom on 02/25/2015 at 2:34 AM
Sales Sheet
atmospheric optics photographs
atmospheric optics canvas prints
atmospheric optics framed prints
atmospheric optics iphone cases
atmospheric optics throw pillows
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Brookline, MA - United States
Wow Sharon ~ amazing image! Cheers, Juergen
Pike Road, AL - United States
Fantastic image Sharon!
Binghamton, NY - United States
Gorgeous landscape, great capture, well done!
Maui, Ha - United States
. . ╰⊰✿ . �.�☆ ☆�.� Featured: :: Atmospheric Optics :: �.�☆ ☆�.� . ✿⊱╮ . . . . . http://fineartamerica.com/groups/atmospheric-optics.html
Wesley, ME - United States
Stunning image Sharon! v/f
Tekoa, WA - United States
Beautiful capture Sharon. Would love to have you join my new rainbow group on FAA. Here's the link: http://fineartamerica.com/groups/rainbow-colors-art-or-photos.html?tab=overview Love and Peace, Windy Mountain
Maui, Ha - United States
:: Aloha :: . . mahalo pumehana ia 'oe . thank you so much :))
Vancouver, WA - United States
Very good Sharon. It is breath taking.
Maui, Ha - United States
Aloha everyone .. thank you so much :)))
Peoria, AZ - United States
Congratulations on your sale Sharon!! Awesome work!
Jonesboro, GA - United States
Congratulations on your sale Sharon!
Cheshire - United Kingdom
Congrats on your well deserved sale!!
Toronto, ON - Canada
congrats Sharon :)
Saco, ME - United States
Beautiful piece Sharon congratulations
Colorado Springs, CO - United States
Congrats on your sale Sharon!!
Bushnell, Fl - United States
Fantastic image Sharon and congratulations on your sale.
Saint Regis Falls, NY - United States
Congrats on the sale! Beautiful scene...cold too :)).
Greensboro, NC - United States
This is an amazing photo, just beautiful. Congratulations on your sale.
Glenview, IL - United States
Congratulations on your sale Sharon - wonderful image!
Smithers, BC - Canada
What a wonderful photograph Sharon :-) Congratulations on you sale, this breathtakingly beautiful!
East Brunswick, NJ - United States
Beautiful! Congratulations, Sharon!
Littleton, CO - United States
Congratulations, congratulations, Sharon. Love your Hawaiian rainbow! -- Joe.
Sicklerville, NJ - United States
Congrats on your sale Sharon! Stunning capture!
Tampa, FL - United States
Congratulatons on your sale, Sharon. Beautiful!
Trencin, Sl - Slovak Republic
Congratulation Sharon, great shot....Aloha
Sharon Mau replied:
. thank you so much Shan :)
Whitewater, CO - United States
Your path is blessed and you portray it well!
Spokane Valley, WA - United States
Stunning, what an awesome capture....a rainbow above the couds...amazing!
Lehigh Acres , FL - United States
Beautiful capture. WOW
Sharon Mau replied:
::)) Aloha Joseph, thank you so much, it was truly an amazing morning. I was blessed and baptized by a rainbow, an experience I could never be able to adequately describe as this beautiful anuenue moved up the volcano and surrounded the ahu, embracing me in a cold mist of sparkling prismatic colours, a magical spiritual experience I will always remember.
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Having been written off and criticised all season, United look to have hit top form at the right time, having just beaten Tottenham Hotspur and Liverpool.
Phil Jones says he enjoys proving people wrong after they've had a dig at you.
We have proved people wrong up to now.
We have proved people wrong up to now.
Louis van Gaal gives latest Manchester United injury update - originally posted on Soccerlens.com
Manchester United manager Louis van Gaal has revealed that Luke Shaw missed today's clash against Sunderland because he was injured, while Phil Jones was suffering from illness.
The 20-times English champions managed a 2-0 victory over Sunderland at Old Trafford, courtesy to a brace from Wayne Rooney in the second half of the match.
Van Gaal confirms Robin van Persie and Phil Jones are fit to face Swansea - originally posted on Soccerlens.com
Louis van Gaal has confirmed his star striker Robin van Persie and centre-back Phil Jones are fit to face Swansea City.
The 20-times English champions make a trip to Wales as they take on the Swans in the Premier League clash scheduled between the two sides at the Liberty Stadium.
Ashley Young has spoken to the club's official website about what it's like being a part of the Manchester United dressing room.
On my left I've got Wazza and on my right I've got Angel [Di Maria]; Fletch also sits with us. Despite the language barrier with Angel we all have a laugh.
On my left I've got Wazza and on my right I've got Angel [Di Maria]; Fletch also sits with us. Despite the language barrier with Angel we all have a laugh.
Kevin Strootman transfer: Manchester United 'firmly expected to bid' for Dutchman - originally posted on Soccerlens.com
Strootman: A Louis van Gaal favourite
Manchester United to become the new Galactico! Well, that's the buzzword coming from UK press this morning.
According to highly respected journalist James Ducker of The Times, Manchester United manager Louis van Gaal is planning radical overhaul of the squad next summer, ready to take his total spending spree to around/over£350m in two years.
Manchester United have suffered from more injuries than any other club in the league this season, particularly in defence.
Jonny Evans has revealed they are unsure what to do about these "freak injuries".
Players don't get injured on purpose. There have been injuries with the odd hamstring or groin, there have been quite a few of those, but Rojo dislocated his shoulder and I had a fracture in my foot.
Players don't get injured on purpose. There have been injuries with the odd hamstring or groin, there have been quite a few of those, but Rojo dislocated his shoulder and I had a fracture in my foot.
Manchester United handed huge injury relief ahead of Arsenal clash - originally posted on Soccerlens.com
Louis van Gaal has been handed a massive boost when Manchester United face Arsenal at the Emirate on Sunday.
The Telegraph reports that star striker Radamel Falcao will be in contention, along with the central defending duo of Phil Jones and Jonny Evans.
United Captain To Miss The Manchester Derby Through Injury? - originally posted on Soccerlens.com
Wayne Rooney was expected to make his return this Sunday against Manchester City, after missing the last three games through suspension. The Red Devils' captain though, is now in danger of sitting out this one as well, after limping off with a foot injury on Monday.
West Brom vs Manchester United: Preview, Possible Lineups & Prediction - originally posted on Soccerlens.com
Victory tonight for Manchester United would move them back into the top four to end Premier League matchday 8.
West Brom will head into the match only one point above the relegation zone following Newcastle's win on Saturday.
Real Madrid defender Raphael Varane said he turned down a move to Manchester United because the club had just signed Phil Jones and the Frenchman feared that might limit his first team opportunities.
The French defender was one of European football's most promising prospect when he left Lens in the summer of 2011, with Real Madrid beating PSG and United in the race to the then 18-year-old.
Louis van Gaal confirms 10 absentees this weekend - originally posted on Soccerlens.com
Manchester United manager Louis van Gaal has confirmed that he is without 10 first-team players for Saturday's game at home to West Ham.
The Red Devils have been hit with a number of injuries to start their season as the Dutch manager has won only one of his first five Premier League games in charge of the world football giants.
Phil Jones out for a month
In today's press conference Louis Van Gaal revealed that Phil Jones is the latest to hand in his sick note, taking United's total number of injuries to nine.
"Fellaini is more than a month away, Jones maybe three weeks or a month," said Van Gaal.
"Carrick isn't ready but has run for the first time on grass.
It has been a summer of frustration at Old Trafford. After the early arrivals of Ander Herrera and Luke Shaw, it seemed there was about to be a much needed overhaul at United. But during the last two months, we have been forced to be patient as new boss Louis Van Gaal gave the current squad a chance to impress him.
Manchester United ended their US pre-season tour on a high note on Monday, as they came from behind to beat bitter rivals Liverpool 3-1 on Miami on Monday.
In the final of the International Champions Cup friendly tournament, Liverpool went ahead when Phil Jones brought down Raheem Sterling in the box, a clear penalty and Steven Gerrard scored.
Phil Jones has revealed Manchester United have already embraced Louis Van Gaal's tactical revolution and despite having been in charge for less than two weeks, the Dutchman has already won many admirers within the United squad, particularly thanks to his footballing philosophy.
Jones impressed in United's 7-0 mauling of Los Angeles Galaxy on Thursday and the 22-year-old has insisted he's happy to adapt to Van Gaal's new 3-5-2 system, if that means finally being handed an extended run is his preferred position, after spending his first three season at the club covering a variety of roles.
Manchester United has announced its 25-man squad for the 2014 US summer tour.
The squad will feature stars such as Wayne Rooney, Juan Mata, Danny Welbeck, David De Gea, Jonny Evans, Phil Jones and new signings Luke Shaw and Ander Herrera.
The club, who will fly to the United States today to begin its tour, will play a series of friendly matches across the United States:
• LA Galaxy vs Manchester United (Los Angeles) — July 23 • AS Roma vs Manchester United (Denver) — July 26 • Inter Milan vs Manchester United (Washington DC) — July 29 • Real Madrid vs Manchester United (Ann Arbor) — August 2
Manchester United may also play in Miami on August 4 if the club ends up being a group winner in the International Champions Cup.
A New England: After a woefully inadequate World Cup, how can England be resurrected? - originally posted on Soccerlens.com
ForRoy Hodgson, the Costa Rica game was the very beginning of themammoth task ofrebuilding his demoralized England team, and begin plans for a brighter future. It's almost unheard of to be using a World Cup game for such a purpose, but the disappointment of this campaign has been felt at every level, so sticking with the tried-and-failed plan made even less sense.
Player statsMost passes Antonio Valencia 69 (92%) Juan Mata 67 (92%) Mamadou Sakho 53 (90%) Ander Herrera 52 (87%) Joe Allen 48 (84%)
Attacking third passes Marouane Fellaini 17 (65%) Antonio Valencia 17 (90%) Juan Mata 16 (80%) Ander Herrera 13 (81%) Philippe Coutinho 11 (65%)
Ball recoveries Antonio Valencia 10 Philippe Coutinho 9 Michael Carrick 7 Phil Jones 7 Joe Allen 6
Tackles Ander Herrera 7/9 Daley Blind 6/7 Emre Can 4/6 Marouane Fellaini 4/5 Phil Jones 4/4
Aerial duels Marouane Fellaini 11/16 Martin Skrtel 4/8 Emre Can 4/7 Wayne Rooney 4/6 Jordan Henderson 3/6
Top passing combinations Valencia to Mata 35 Mata to Valencia 23 Blind to Fellaini 20 Herrera to Valencia 17 Valencia to Herrera 16 Mata to Herrera 16
Team stats Liverpool passes: 302/402 (75%) United passes: 460/562 (82%) Liverpool possession: 41.
Last season, United averaged 5.7 corners per game and this season it is 5.4. 15% of the corners we took last season lead to chances, and this year it is 13%. Just 1.4% of our corners last season resulted in goals and this year, so far, it is 2.5%.
In real terms, that means this season we've scored 3 times from 119 corners this season, which is pretty shocking.
Louis van Gaal has got good news on the injury front. After previously ruling out Wayne Rooney, the manager has confirmed that the captain will be available for Monday's game against Southampton and Angel di Maria isn't far behind him.
On Rooney: The news is very good, he shall play.
On Di Maria: It (his return) shall be quickly but not for Monday.
Roy Hodgson announced his England squad for the World Cup yesterday and Wayne Rooney, Danny Welbeck, Phil Jones and Chris Smalling were all selected. Tom Cleverley and Michael Carrick are on the standby list.
It's no surprise that Rooney is on the plane to Rio. Despite having rarely performed well for England, and having not done the business for the International team probably since Euro 2004, he will always be the player England fans rely on the most.
Phil Jones has sung the praises of his team mate, Marcos Rojo, after the Argentinean has settled in well after moving to the Premier League from Portugal.
Since Marcos has come he's played the right way and in the way we've wanted to play. It's difficult to come over to a different country and a different league and go straight into the team and hit your form, but he's done well.
Since Marcos has come he's played the right way and in the way we've wanted to play. It's difficult to come over to a different country and a different league and go straight into the team and hit your form, but he's done well.
Phil Jones has answered fans questions for United Review.
Who's the best defender you've played with? I've been lucky to have played with a lot of really good defenders already, so obviously the likes of Rio Ferdinand or Nemanja Vidic have to be up there. But even when I go back to my Blackburn days, I learned a lot from playing with Ryan Nelsen.
Transfer Talk: Who else should Arsenal sign this summer? is a post from: Just Football
by Carl Innes
Following the blockbuster signing of Alexis Sanchez, delighted supporters in North London have their eye on Arsenal transfer news as Arsene Wenger tries to complete more summer deals to get his side in contention for the Premier League title.
Phil Jones has spoken of his disappointment at not managing more than one point away to West Ham.
While both Manchester City and Liverpool have lost their this season, United knew that if they won, they would close the gap on 2nd place to just three points.
Now, they are right back in the thick of it again, fighting to stay in the top four.
Manchester United suffered the humiliation of being held to a goalless draw by League Two side Cambridge United on Friday night. The hosts, who sit in mid-table in the fourth tier of English football, earned a deserved replay after United failed to create enough chances throughout. Luckily for the Red Devils, the replay should not be an issue due to the absence of European football at Old Trafford this season.
Speaking with RoM for the World Cup preview, Martin Lipton and Dom Fifield have discussed the inclusion of Phil Jones and Chris Smalling in the England squad.
Martin Lipton, chief football writer for The Mirror
They are favourites of Roy Hodgson; and what might be hard for many United fans to get their heads around is that Hodgson regards these two from a very different perspective.
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Britain's Prince William might be perfectly poised now as he reaches his 30th birthday, but back when he was a child he was a right royal handful at times, this according to a new biography to be published this week in the U.K. by royal scribe Penny Junor.
Titled Prince William: Born to be King: An Intimate Portrait, Junor recalled one amusing incident during William's youth when he interrupted a meeting his father Prince Charles was having with Irish musician and humanitarian Bob Geldof. Wills was apparently none too pleased with the company his dad was keeping.
"Once, William barged into a meeting his father was having with the habitually disheveled musician Bob Geldof," Junor writes. (It's true that most days Geldof looks like he rolled out of bed and straight out the door.)
"'Why do you have to talk to that man?' (William) demanded. 'Because we have work to do,' said his father.
"'He's all dirty,' said William."
Geldof apparently lost his cool with the cheeky child.
"'Shut up, you horrible boy,' said Geldof," Junor wrote.
"'He's got scruffy hair and wet shoes,' said William, undeterred. 'Don't be rude,' said Charles, mortified."
Though Wills and Geldof have likely met since those childhood days, the Irish philanthropist is still friendly with Charles and his wife Camilla Parker Bowles.
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Hi Krystal, i'm following your twitter, too. Hope you will follow me back, too.
Hi Krystal, i am following your cute blog.
Hope you will follow me, too. http://ownhomeearning.blogspot.com/
Thanks a lot.
Hi Krystal! I'm following you. Please stop by. Would love your follow.


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There are no games scheduled for Friday, Feb 22.
Pennsylvania 88
(10-15, 5-3 Ivy)
Dartmouth 62
(8-15, 1-8 Ivy)
7:00 PM ET, February 22, 2008
Edward Leede Arena, Hanover, New Hampshire
Top Performers
Pennsylvania: B. Grandieri 15 Pts, 9 Reb, 3 Ast, 1 Stl
Dartmouth: E. Fitzgerald 12 Pts, 6 Reb, 2 Blk
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The Intro Tech Call
Yesterday at Happy Cog, Mark, Abby, and I had an intro call with a tech team for a client who will be implementing our templates into their CMS, which, in this case, is ExpressionEngine.
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The precision recipe of surprises, thrills, and fulfillment we provide. For clients.
We've written 18 blog posts about Client Relations. View all topics »
Yesterday at Happy Cog, Mark, Abby, and I had an intro call with a tech team for a client who will be implementing our templates into their CMS, which, in this case, is ExpressionEngine.
by Brenna Heaps
For my first driving lesson my father took me to the empty elementary school parking lot across the street from my house on a Saturday afternoon. He drove over, parked the car, switched seats with me, then instructed me to drive.
by Aura Seltzer
No matter the client, FAQs are often a topic of conversation during many site redesigns. Maybe they are legacy content and deemed a new requirement for the get-go. Maybe stakeholders raise them as a potential solution during the course of the engagement. Sometimes, they even creep up on us (unplanned) after launch.
We're bringing you this special edition of Cognition Roundtable, where Assistant PM Mica McPheeters speaks with our VP of Design Chris Cashdollar about the client's role in design projects. Spend the next half hour with Chris, as he pulls inspiration from his upcoming presentation at HOW Interactive Design Conference in Washington, DC—"Reevaluating the Role of Your Client in the Design Process." Specifically, he'll cover:
by Brenna Heaps
Leading up to the design phase of a project, we devote a lot of thinking to setting the project's core goals and requirements, as well as establishing a basic plan for how the project will flow. During this time, on my team, we ask as many questions as possible and learn as much as we can before we present a strategy to the client. In the end, everyone agrees on what the goals are, but how those goals will be realized is yet to be determined.
by Katie High
"What's in a name? that which we call a rose / By any other name would smell as sweet; / So Romeo would, were he not Romeo call'd" (Shakespeare, Romeo & Juliet, 2.2).
In the world of project management, naming conventions are often the source of miscommunication. You have to call your work something, but if you assume everyone interprets a name the way you intended, you're likely to stub your toe during the course of the project. As managers, minimizing risk and setting expectations is an everyday task, yet something as simple as a name or label can fly under our radar. We live and breathe our work, and we are passionate about it. It's a good practice to never assume labels are understood out of the gate. Here's a few tactics to help you make naming conventions work for you.
by Aura Seltzer
I am an overwriter.
I could stop this post right here, but you wouldn't believe me.
There is relief and guilt to overwriting—like you've just finished off a large bag of potato chips by yourself. You find comfort in there being no more chips to eat but also discomfort, because, well, you just ate an entire bag of chips.
Or, you've just written countless words to a client team explaining the intricacies of a deliverable. You exhale and cross the to-do off your list, but you secretly doubt whether the post overcomplicated the work or confused your client.
I once believed that great design was created inside of a secret creativity chamber. Armed with a knapsack full of snacks, I'd lock myself inside, and work long, hard, tedious hours until I emerged with a "masterpiece."
by Joe Rinaldi
Recently, I offered my suggestions regarding the RFP construction and management process, but I left my dear readers with a cliffhanger… Now that your RFP is complete and you're evaluating responses and pitches, how do you select the right proposal?
by Rawle Anders
At Happy Cog, we try to use the latest web technologies to bring our virtual teams (and families) together. But sometimes, a virtual meetup just won't do—most notably, the kickoff meeting to start a new client project. Few things can impact a project's success like the team building that takes place during the workshop sessions, lunches, and post-meeting drinks of a client on-site visit—after all, raising a virtual toast isn't nearly as satisfying as clinking two glasses together.
Warning, if you are reading this in a meeting STOP! Put down your mobile device or laptop and slowly lift your head and eyes upward until you see (and hear) the person speaking!
Years ago, I was presenting comps on a scheduled call to a key stakeholder of my then-agency's flagship account. It was my first call with him in months. He was unfortunately on vacation and without his laptop. That should have been the end of it.
Instead, he asked me to paint him a picture.
With my Pittsburgh roots comes a 30+ year fandom of the NHL hockey team the Pittsburgh Penguins. But one of my favorite Pens memories didn't happen during a game; it was actually a text message. A message sent by owner and legendary player, Mario Lemieux, to the team and coaches before decisive game 7 of the 2009 Stanley Cup finals.
by Joe Rinaldi
Industry creative folks I'm friends with personally and respect professionally have uttered the following to me on multiple occasions:
"I want to make cool shit."
I'll be honest, I just don't get it. To be fair, it's safe to say I don't get "cool" in general. I routinely dress like I'm headed to a corporate team-building ropes course, and I'm still waiting for Firefly to be picked up for season 2. So maybe it's no surprise that the quest for cool escapes me. I don't get the allure of making something cool for the sake of it being cool. Further, I don't understand how you sell that to clients, or more importantly, why they would pay for it.
by Rawle Anders
Every successful project needs an Awesome Blossom moment: when your relationship with a client enables the project to transcend deadlines and goals to more acutely capture the spirit of creating something great.
It all starts with finding the humanity in the project and sharing a sense of excitement with your client team members. As they have chosen your company to help build their web experience, the client has placed a great amount of trust in you. Your job, over the length of the engagement, is to solidify: a sound strategy based on the goals of the project; a transparent, trusted, and respectful working relationship with your client contacts; an agile, yet progressive, project process; and an open line of communication that can extend beyond the project.
by Kevin Sharon
Last week, Happy Cog was nominated for two Webby awards for our work with Zappos.com. I know some people don't like awards, but as someone who didn't grow up in an era when "everyone gets a trophy," I still think they're pretty rad. Seriously though, I think of a nomination like this as a recognition of doing great collaborative work with our clients. When I heard about the nominations, I was chatting with one of my coworkers who wondered, "can we really take the credit for this work?" As I typed the words, "shut your stupid face hole," and considered whether to press enter, I thought about his question for a moment and the life of our work after we hand it over to our clients.
by Robert Jolly
At Happy Cog, I am responsible for the bulk of our sales efforts along with ensuring that our ongoing client relationships are positive. The early days of the professional relationship are not unlike the very early stages of courtship and dating. If there's a connection to be made, its foundation is built on listening and sharing, which are sincere efforts for us to understand and help each other.
by Greg Storey
re: Not Red Dawn but Almost
All: It's 4:00 AM and I am both wide awake and completely exhausted at the same time.
First, I want to say that last week's Halo game was inspiring, informative, and productive.
Copyright 1995–2015 Happy Cog™


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Welcome to ringtones service Audiko.net, where you may search for the most popular ringtones for your cell. Today we have a ringtone of "Stay ft. Mikky Ekko" by Rihanna as well as 25051 other ringtones by Rihanna. You can listen to all 196 Rihanna – "Stay ft. Mikky Ekko" ringtone variations available here and download it for free right now. You can also browse other 17 albums produced by Rihanna for all time. "Stay ft. Mikky Ekko" is referred to Pop, and you can download a huge amount of Pop tracks absolutely for free. And finally, we have collected lyrics for this track and you can view it here as well. So feel free to browse, listen, download ringtones at Audiko.net. Make your phone sound cool!
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Date: 1886
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Urban Decay Eyeshadow Primer Potion - Original
5997 reviews
81% would repurchase
Package Quality: 3.1
Price: $$$
Package Quality: 3.1
Price: $$$
Not tested on animals
Urban Decay is a Cruelty-Free Subsidiary.
INGREDIENTSIsododecane, Talc, Cyclopentasiloxane, Disteardimonium Hectorite, Trihydroxystearin, Triethylhexanoin, Isopropyl Lanolate, Sorbitan Sesquioleate, VP/Eicosene Copolymer, Dimethicone, PEG-40 Stearate, Propylene Carbonate, Phenoxyethanol, Cera Alba (Synthetic Beeswax), Trimethylsiloxysilicate, Propylparaben, Methylparaben, Ethylparaben, Butylparaben, Methicone, Isobutylparaben
on 2/27/2009 9:12:00 PM
Age: 19-24
Skin: Very Oily, Medium, Warm
Hair: Brunette, Wavy, Fine
Eyes: Brown
I love this base! I put 3 dots of this stuff over my eye, and one underneath, and it takes care of everything. No smell, moderate price, but depending on how much you use shadow, it lasts a while. I love the packaging as well! Such a cute little bottle! =]
on 2/27/2009 4:20:00 PM
Age: 18 & Under
Skin: Acne-prone, Medium, Warm
Hair: Black, Kinky, Other
Eyes: Brown
I have very oily eyelids. around 30 minutes after applying any sort of eyeshadow, it starts to crease and becomes a gross oily mess. When I used this under my eyeshadow, I was amazed that after 8 hours, my eyeshadow was still in place, the colour was still vibrant and, it's just amazing.
on 2/27/2009 7:39:00 AM
Age: 25-29
Skin: Combination, Other, Not Sure
Hair: Black, Other, Other
Eyes: Brown
This is the first eye makeup base I use. I am very happy with the result: helps eye shadows stay longer, makes the colors more vibrant. It still creases after applying makeup for whole day in the summer. But overall this is an amazing product. The only complain is the packaging. It would be SO much better if it comes in a tube.
on 2/27/2009 1:17:00 AM
Age: 19-24
Skin: Acne-prone, Fair, Not Sure
Hair: Blond, Other, Other
Eyes: Hazel
When I heard the rave about this I had to buy it myself to try it. It was the first primer I had ever gotten, & i thought it would be my last. It wasn't bad- I actually loved it. No creasing, brighter eyeshadow, & longer lasting. HOWEVER, the product ran out quickly even after I cut it open! I now use macs paint, & it has lasted me twice as long so far, & i still have only used half of it because you only need a small amount, because it spreads from the oils of your fingers. Saying that, it is cheaper in the long run, A LOT cheaper! Plus I honestly like it just as good as UDPP. Sure, it isn't AS bright, but I can't even notice when I tried using UDPP on one eye & the paint on the other. it's much more worth it to buy the paint rather than UDPP IMO.
try macs paint if you're not sure, it will last a long time even if you don't like it as much, so it really is so much more worth it & less expensive.
on 2/27/2009 12:24:00 AM
Age: 25-29
Skin: Oily, Fair, Cool
Hair: Brunette, Curly, Fine
Eyes: Green
I have super oily eyelids and have tried other primers with little luck. I have always loved Urban Decay's makeup and I had never tried UDPP so when they had the 2 for $25 I scooped it up. It's creamy, silky and dries quickly. However, it just doesn't work for me. It dries my eyelids out, makes them irritated and itchy and doesn't keep my shadow on. I suppose my search will continue. I won't purchase this again.
on 2/27/2009 12:07:00 AM
Age: 19-24
Skin: Other, Fair-Medium, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
I received a deluxe sample of this primer potion and even though that packaging is slightly better than the normal sized primer packaging, you won't be able to get very much product out of the packaging without 'depotting it'--which basically means hacking it open! I do love the primer though--goes on well, and really keeps my eyeshadow on for hours and hours. I have terribly oily eyelids and this really works for at least 6 hours.
on 2/26/2009 4:34:00 PM
Age: 19-24
Skin: Very Oily, Olive, Warm
Hair: Brunette, Wavy, Medium
Eyes: Brown
For reference, you could fry potato chips on my eyelids they're so oily. That said, this stuff is a dream. I came in on Mardi Gras from a sweaty night of dancing and not a single smudge. The only places where it smudged was where water from my eyes got onto my eyelid, but that's no fault of the UDPP. This stuff is the truth, and if you've got oily lids like me and paint pots don't work, give this a try. I've never tried Shadow Insurance because this stuff is my HG eye base. It's just a smidge too light for my complexion, but once I start putting on eyeshadows, it doesn't matter.
I only took off 1 lippie because of the PACKAGING? What??? If I'm paying $17 for a product, you'd better believe that I expect to get my money's worth. Has anyone complained to Urban Decay yet? This actually makes me so mad that I'm going to go email them about it now (as if they haven't heard the complaints by now). I suggest you all do the same. Anyway, great product, HORRIBLE packaging and would only repurchase if packaging was modified.
on 2/26/2009 4:19:00 PM
Age: 36-43
Skin: Combination, Medium, Warm
Hair: Brown, Straight, Coarse
Eyes: Brown
I am Asian, med-fair skin w/yellow undertones and I really like this product. It goes on very smooth with a silky finish and my shadows go on with a richer color and stays on all day. It does not get crepy on my "older" skin.
As posters have suggested, I removed all the contents from it's cute little bottle. I could not believe how much of it was tucked inside the little tube! So if you do buy this product, do yourself a favor and get your money's worth and check out youtube for instructions on how to remove product from the tube! It was not difficult at all and I think it was worth the 5 minutes it took me!
Edited on 12/2009: I am still using the original product after 10 months! I found that adding just a drop or two of water softens this so a workable consistancy. Love this product and worth the money and effort of extracting it from it's original bottle!
on 2/26/2009 12:21:00 AM
Age: 36-43
Skin: Oily, Other, Not Sure
Hair: Brown, Other, Other
Eyes: Green
Not a horrible product but I was not a convert. I used the entire tube because I wanted to like UDPP as it has many fans. After I applied, let dry it was really hard for me to blend my shadows over. It seems that once I touched my eyeshadow brush to my eyelid, that was it - couldn't blend. Once the eyeshadow was applied it didn't budge and yes, this lasts ALL day and zero creasing but I really need the ability to blend colors so this didn't work for me.
on 2/25/2009 8:17:00 PM
Age: 19-24
Skin: Combination, Fair, Not Sure
Hair: Blond, Other, Other
Eyes: Blue
I know everyone has tried this product and if you haven't-it's at least worth a try. The product overall is very good. It does what it says it's going to. It primes your eyes for a flawless eyeshadow application. It blends in nicely, doesn't smell horrid, doesn't take forever to dry. All in all the product is great. The reason why I won't buy it again is because of the PACKAGING. COME ON, URBAN DECAY....can you get a better package for this stuff? If I'm spending the $16 on a tiny ass bottle, I at least want to be able to use the product in it's entirety. The product gets stuck and unreachable in the fat part at the top and the base of the bottle. A lot of girls are cutting them open and depoting the remainder, but it drys up quickly and there's A LOT of product stuck in those areas. What a waste of money!
Product good. Packaging bad.
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28th St SE & Patterson Ave SE
Kentwood, Michigan, 49546
Commute to Downtown Kentwood
Most errands require a car.
Score Details
28th St SE & Patterson Ave SE has a Walk Score of 36 out of 100. This location is a Car-Dependent neighborhood so most errands require a car.
This location is in Kentwood.
Explore how far you can travel by car, bus, bike and foot from 28th St SE & Patterson Ave SE.
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Popular apartment searches include pool, fitness and fireplace.
This location is in the city of Kentwood, MI. Kentwood has an average Walk Score of 22 and has 48,707 residents.Learn More About Kentwood