WO2013040310A1

WO2013040310A1 - Device and method for the controlled delivery of ophthalmic solution to the stroma of an eye

Info

Publication number: WO2013040310A1
Application number: PCT/US2012/055339
Authority: WO
Inventors: Bruce H. Dewoolfson; Mike Luttrell
Original assignee: Dewoolfson Bruce H; Mike Luttrell
Priority date: 2011-09-15
Filing date: 2012-09-14
Publication date: 2013-03-21

Abstract

The present disclosure is directed to an apparatus and method for delivering an ophthalmic solution to a portion of an eye, wherein the portion of the eye may be the stroma. The apparatus may be a syringe device including a syringe body and a plunger. The syringe body may further include a syringe body flange, a barrel, and a needle holding portion for holding a needle therein. The plunger may further include a plunger flange, an insertion portion, and a plunger stem. A tube insert having a substantially small diameter may be disposed within the syringe body for containing the ophthalmic solution therein. The barrel may include external indicator markings wherein the plunger stem aligns with the markings to indicate an amount of ophthalmic solution injected into the portion of the eye.

Description

DEVICE AND METHOD FOR THE CONTROLLED DELIVERY OF OPHTHALMIC SOLUTION TO THE STROMA OF AN EYE

Cross Reference to Related Applications

[001] This application claims the benefit of U.S. Provisional Application No. 61/534,966, filed on September 15, 201 1, and which is incorporated by reference in its entirety.

[002] The following patents and patent applications disclose subject matter related to the present disclosure and the contents thereof are incorporated herein by reference in their entirety.

[003] This application is related to:

[004] U.S. Patent Nos. 6,537,545, filed September 7, 2010, 6,946,440, filed September 15, 2000, and 7,402,562, filed June 7, 2005;

[005] U.S. Patent Application Publication No. 2009/0105127, filed October 10, 2008;

[006] U.S. Provisional Patent Application Nos. 61/241, 607, filed September 1 1, 2009; 61/266,705, filed December 4, 2009; 61/308,589, filed February 26, 2010; and 61/344,307 filed June 25, 2010;

[007] PCT International Publication Nos. WO 2009/114513, filed March 10, 2009, WO 2009/120549, filed March 18, 2009, and WO 2009/120550, filed March 18, 2009; and

[008] PCT Application Nos. PCT/US2007/008049, filed April 3, 2007; PCT/US2010/25036, filed February 23, 2010; and PCT/US201 1/041795, filed June 24, 201 1.

Technical Field

[009] The present disclosure is directed to an ophthalmic solution delivery device and method, and, more particularly, to a syringe device configured to deliver an ophthalmic solution to the stroma and method of delivering an ophthalmic solution to the stoma via the syringe device.

Background

[010] The cornea is the first and most powerful refracting surface of the optical system of the eye, The human cornea is a highly specialized tissue combining optical transparency with mechanical strength. It is made up of five layers, the outermost of which is the epithelium. The epithelium is only four to five cells thick, and renews itself continuously. Underneath the epithelium, the second layer is the acellular Bowman's membrane. It is composed of collagen fibrils and is normally transparent. Below Bowman's membrane, the third layer, and largest part of the cornea, is the stroma. The stroma makes up approximately 90% of the cornea's thickness, and is about 500 microns (μηι) thick.

[01 1 ] The stroma comprises a well organized matrix architecture composed of

approximately 200 parallel sheets of narrow-diameter collagen fibrils arranged orthogonal to neighboring fibril sheets. Corneal fibrils are primarily composed of type I collagen co- assembled with type V collagen. Small leucine-rich repeat proteoglycans (SLRPs), such as decorin, are critical for maintaining corneal transparency and corneal strength. The stroma is mostly water (-78%) and collagen (-16%), although other proteoglycans and glycoproteins are also present.

[012] When the cornea is misshapen or injured, vision impairment can result. In the case of a misshapen cornea, eyeglasses and contact lenses have traditionally been used to correct refractive errors, but refractive surgical techniques are now also routinely used. There are currently several different techniques in use.

[013] One such vision correction technique is radial keratotomy (RK). In RK, several deep incisions are made in a radial pattern around the cornea, so that the central portion of the cornea flattens. Although this can correct the patient's vision, it also weakens the cornea, which may continue to change shape following the surgery.

[014] Photorefractive keratectomy (PRK) is another vision correction technique. It uses an excimer laser to sculpt the surface of the cornea. In this procedure, the epithelial basement membrane is removed, and Bowman's membrane and the anterior stroma are photoablated.

However, some patients with initially good results may experience, in the months following the procedure, a change in their refraction caused by distortion of the cornea and/or other anomalies.

Collectively, these changes in refraction may be referred to as "regression." In addition, corneal haze can also occur following PRK, and the greater the correction attempted, the greater the incidence and severity of the haze.

[015] Laser in situ keratomileusis (LASIK) is yet another alternative. In this technique, an epithelial-stromal flap is cut with a microkeratome or a laser. The flap is flipped back on its hinge, and the underlying stroma is ablated with a laser. The flap is then reseated. There is a risk that the flap created will later dislodge, however. In addition, the CRS-USA LASIK Study noted that overall, 5.8% of LASIK patients experienced complications at the three-month follow up period that did not occur during the procedure itself. These complications included corneal edema (0.6%), corneal scarring (0.1%), persistent epithelial defect (0.5%), significant glare (0.2%), persistent discomfort or pain (0.5%), interface epithelium (0.6%), cap thinning (0.1%) and interface debris (3.2%).

[016] Most patients will have stable results after LASIK. That is, the one month to three month results will usually be permanent for most patients. However, some patients with initially good results may experience a change in their refraction (i.e., regression) over the first 3 to 6 months and possibly longer. LASIK can result in haze as well, although less frequently than with PRK, presumably because LASIK preserves the central corneal epithelium. [017] The chance of having regression following LASIK is related to the initial amount of refractive error. Patients with higher degrees of myopia (-8.00 to -14.00) are more likely to experience regression. For example, a -10.00 myope may initially be 20/20 after LASIK at the 2 week follow-up visit. However, over the course of the next 3 months, the refractive error may shift (regress) from -0.25 to -1.50, or even more. This could reduce the patient's visual acuity without glasses to less than 20/40, a point at which the patient would consider having an additional surgical procedure to correct the regression.

[018] All surgical procedures involve varying degrees of traumatic injury to the eye and a subsequent wound healing process. Netto et al., Cornea, Vol. 24, pp. 509-22 (2005). Regression occurs often as a result of a reduction of biomechanical structural integrity caused by the procedure. For example, one type of postoperative regression is keratectasia. Keratectasia is an abnormal bulging of the cornea. In keratectasia, the posterior stroma thins, possibly due to interruption of the crosslinks of collagen fibers and/or altered proteoglycans composition, reducing the stiffness of the cornea and permitting it to shift forward. Dupps, W.J., J. Refract. Surg., Vol. 21, pp. 186-90 (2005). The forward shift in the cornea causes a regression in the refractive correction obtained by the surgical procedure.

[019] In the past several years there has been increasing concern regarding the occurrence of keratectasia following LASIK. In LASIK, the cornea is structurally weakened by the laser ablation of the central stroma and by creation of the flap. While the exact mechanism of this phenomenon is not completely known, keratectasia can have profound negative effects on the refractive properties of the cornea. In some cases, the cornea thins and the resultant irregular astigmatism cannot be corrected, potentially requiring PRK to restore vision. The incidence of keratectasia following LASIK is estimated to be 0.66% (660 per 100,000 eyes) in eyes having greater than -8 diopters of myopia preoperatively. Pallikaris et al., J. Cataract Refract. Surg., Vol. 27, pp. 1796-1802 (2001). Although at present keratectasia is a rare complication of refractive surgery, the number of refractive surgical procedures performed each year continues to increase and, therefore, even this rare condition will impact many individuals. T. Seiler, J. Cataract Refract. Surg., Vol. 25, pp. 1307-08 (1999).

[020] In addition to corneal weakening resulting from surgical procedures, other conditions involve reduced structural integrity of the cornea. For example, keratoconus is a condition in which the rigidity of the cornea is decreased. Its frequency is estimated at 4-230 per 100,000. Clinically, one of the earliest signs of keratoconus is an increase in the corneal curvature, which presents as irregular astigmatism. The increase in curvature is thought to be due to stretching of the stromal layers. In advanced stages of keratoconus, a visible cone-shaped protrusion forms which is measurably thinner than surrounding areas of the cornea. [021] Keratoconus may involve a general weakening of the strength of the cornea, which eventually results in lesions in those areas of the cornea that are inherently less able to withstand the shear forces present within the cornea. Smolek et al., Invest. Ophthalmol. Vis. Sci. Vol. 38, pp. 1289-90 (1997). Andreassen et al., Exp. Eye Res., Vol. 31, pp. 435-41 (1980), compared the biomechanical properties of keratoconus and normal corneas and found a 50% decrease in the stress necessary for a defined strain in the keratoconus corneas.

[022] The alterations in the strength of the cornea in keratoconus appear to involve both the collagen fibrils and their surrounding proteoglycans. For example, Daxer et al., Invest.

Ophthalmol. & Vis. Sci., Vol. 38, pp. 121 -29 (1997), observed that in normal cornea, the collagen fibrils were oriented along horizontal and vertical directions that correspond to the insertion points of the four musculi recti oculi. In keratoconus corneas, however, that orientation of collagen fibrils was lost within the diseased areas. In addition, Fullwood et al., Biochem. Soc. Transactions, Vol. 18, pp. 961 -62 (1990), found that there is an abnormal arrangement of proteoglycans in the keratoconus cornea, leading them to suggest that the stresses within the stroma may cause slipping between adjacent collagen fibrils. The slippage may be associated with loss of cohesive forces and mechanical failure in affected regions. This may be related to abnormal insertion into Bowman's structure or to abnormalities in interactions between collagen fibrils and a number of stabilizing molecules such as type VI collagen or decorin. Many of the clinical features of keratoconus can be explained by loss of biomechanical properties potentially resulting from interlamellar and interfibrillar slippage of collagen within the stroma and increased proteolytic degradation of collagen fibrils, or entire lamellae.

[023] Because both keratoconus and postoperative keratectasia involve reduced corneal rigidity, relief from each condition could be provided by methods of increasing the rigidity of the cornea. For example, methods that increase the rigidity of the cornea can be used to treat postoperative keratectasia. The treatment can be administered to a patient who plans to undergo a refractive surgical procedure as a prophylactic therapy. In other cases, the treatment can be administered during the surgical procedure itself. In still other situations, the treatment may not be initiated until after the refractive surgical procedure. Of course, various combinations of treatment before, during, and after the surgery are also possible.

[024] It has also been suggested that a therapeutic increase in the stiffness of the cornea could delay or compensate for the softening of the cornea that occurs in keratoconus. Spoerl et al., Exp. Eye Res., Vo. 66, pp. 97- 103 (1998). While acknowledging that the basis for the differences in elasticity between normal and keratoconus corneas is unknown, those authors suggest that a reduction in collagen crosslinks and a reduction in the molecular bonds between neighboring stromal proteoglycans could play a role. [025] There are several treatments for increasing corneal rigidity and compensating for corneal softness. Some of these treatments suffer from drawbacks that include development of corneal haze and scarring, as well as the risk of endothelial cell damage. While some of these drawbacks are associated with the particular agents used, some of these drawbacks are associated with the techniques used to administer the agents. In addition, other such treatments, while practiced with some degree of success, could benefit from enhanced delivery of the agents to the cornea. The need exists, therefore, for system that provides improved delivery of agents to the cornea.

[026] Riboflavin has been shown to reduce the progression of keratectasia in patients with keratoconus. Aldehydes have also been used to crosslink collagen fibers and, thereby improve the structural integrity of the cornea. For example, U.S. Patent No. 6,537,545 describes the application of various aldehydes to a cornea in combination with a reshaping contact lens. The contact lens is used to induce the desired shape following either enzyme orthokeratology or refractive surgery, and the aldehyde is used to crosslink collagens and proteoglycans in the cornea. However, application of such agents can be problematic.

[027] In addition, small leucine-rich repeat proteoglycans (SLRPs), such as decorin; fibril- associated collagens with interrupted triple helices (FACITs); or the enzyme transglutaminase, can be used to retard relaxation of corneal tissue back to the original curvature when used as an adjunct to an orthokerotological procedure. See U.S. Patent No. 6,946,440. However, while there have been devices developed to contain solutions in an area on the surface of the cornea (see e.g., PCT International Publication No. WO 2009/120550), there has not been a delivery device that facilitates introduction of such agents directly into the subsurface portions of the stroma.

[028] Although orthokeratology and surgical techniques such as LASIK seek to improve visual acuity using radically different approaches, the success of both orthokeratology and surgical techniques may be improved by increasing structural integrity of the cornea. Despite the fact that surgery disrupts the cornea and removes corneal tissue, methods of stabilizing collagen fibrils using proteins that crosslink the collagen fibrils, such as decorin or the enzyme transglutaminase, have been shown to improve the outcome following a surgical procedure to improve visual acuity. Those results also provide a basis for treating diseases of the cornea, such as keratectasia from other causes, such as keratoconus.

[029] In addition to agents that increase the structural integrity of the cornea, there may be a desire to deliver other types of ophthalmic solutions, such as antibiotics and/or other agents, to the cornea. [030] For a number of different ophthalmic agents, it may be advantageous to deliver such agents directly to subsurface portions of the stroma. Although certain agents may be applied topically, in order to achieve penetration to a desired depth within the cornea, it is sometimes necessary to pretreat the cornea with agents that enhance penetration, such as agents that dissociate epithelial cell junctures. Further, even with penetration-enhancing agents, satisfactory penetration of agents to the desired depth of the cornea may not always be achievable.

[031 ] The present disclosure is directed to improvements in delivery of ophthalmic solutions to the cornea.

Brief Summary

[032] In one aspect, a syringe device is disclosed. The syringe device may comprise a syringe body including a needle disposed therein and a plunger configured to be removably connected to the syringe body. The plunger may comprise a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the syringe body. In one embodiment, the tube insert may be configured to receive ophthalmic solution to be delivered to a portion of an eye. Furthermore, the plunger insertion portion may be configured to be inserted within the tube insert to deliver the ophthalmic solution.

[033] In another aspect, a syringe device is disclosed. The syringe device may comprise a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body. The needle holding portion may include a needle disposed therein. The syringe device may also include a plunger configured to be removably connected to the syringe body, wherein the plunger further comprises a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the barrel of the syringe body. In one embodiment, the tube insert may be fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye.

[034] In yet another aspect, a syringe device is disclosed, wherein the syringe device may comprise a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body. The needle holding portion may include a needle disposed therein. The syringe device may also include a plunger configured to be removably connected to the syringe body, wherein the plunger further comprises a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the barrel of the syringe body. In one embodiment, the tube insert may be fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye, and the plunger insertion portion may be configured to be inserted within the tube insert to deliver the ophthalmic solution.

[035] In another aspect, a method of injecting ophthalmic solution into a portion of an eye is described. In one embodiment, the method may include providing a syringe device having a syringe body with a needle disposed therein, a plunger configured to be inserted into the syringe body, and a tube insert disposed within the syringe body. The method may further comprise filling the tube insert of the syringe body with an ophthalmic solution, inserting the plunger into the tube insert, inserting the needle into the portion of the eye, and injecting into the portion of the eye a specific amount of the ophthalmic solution.

[036] Additional objects and advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the various described embodiments. The objects and advantages of the exemplary embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[037] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

Brief Description of the Drawings

[038] Fig. 1 illustrates an exemplary embodiment of the disclosed syringe device with the plunger in a retracted position;

[039] Fig. 2 illustrates an exemplary embodiment of the disclosed syringe device with the plunger in a depressed position;

[040] Fig. 3 illustrates another view of an exemplary embodiment of the disclosed syringe device;

[041] Fig. 4A illustrates a cross-sectional view of an embodiment of the disclosed syringe device;

[042] Fig. 4B illustrates a detailed view of Fig. 4A of a needle holding portion of a syringe body with the plunger in a depressed position;

[043] Fig. 5A illustrates another cross-sectional view of an embodiment of the disclosed syringe device;

[044] Fig. 5B illustrates a detailed view of Fig. 5A of a needle holding portion of a syringe body;

[045] Fig. 6A illustrates a side view of an embodiment of a syringe body of the syringe device;

[046] Fig. 6B illustrates a detailed view of a needle protruding from the syringe body of Fig. 6A; [047] Fig. 7 shows the effects of decorin drops on corneal historesis for an individual patient;

[048] Fig. 8 shows the effects of decorin drops on corneal historesis for multiple patients; and

[049] Fig. 9 shows the effects of decorin injections on corneal historesis for multiple patients.

Detailed Description

[050] In order that the present disclosure may be more readily understood, certain terms are first defined. Other definitions are set forth throughout the description of the embodiments.

Definitions

[051] A "refractive surgical procedure" includes, but is not limited to, Radial Keratotomy (RK), Photorefractive Keratoplasty (PRK), LASIK (Laser-Assisted In Situ Keratomileusis), Epi- LASIK, IntraLASIK, Laser Thermal Keratoplasty (LTK), and Conductive Keratoplasty.

[052] "Stabilizing" includes increasing the rigidity, as measured by the Corneal Response Analyzer manufactured by Reichert Ophthalmic Institute. This instrument gives a quantitative measure of corneal rigidity called the Corneal Resistance Factor (CFR) and also a quantitative measure of corneal historesis (CH). "Stabilizing" can also mean decreasing the ability of one collagen fibril to move relative to another collagen fibril by virtue of increased intermolecular interactions.

[053] "Crosslinks" includes the formation of both direct and indirect bonds between two or more collagen fibrils. Direct bonds include covalent bond formation between an amino acid in one collagen fibril and an amino acid in another fibril. For example, the transglutaminase family of enzymes catalyze the formation of a covalent bond between a free amine group (e.g., on a lysine) and the gamma-carboxamide group of glutamine. Transglutaminase thus is not itself part of the bond. Indirect bonds include those in which one or more proteins serve as an intermediary link between or among the collagen fibrils. For example, decorin is a horse-shoe shaped proteoglycan that binds to collagen fibrils in human cornea forming a bidentate ligand attached to two neighboring collagen molecules in the fibril or in adjacent fibrils, helping to stabilize fibrils and orient fibrillogenesis. Scott, JE, Biochemistry, Vol. 35, pages 8795 (1996).

[054] A "protein that crosslinks collagen fibrils" includes proteins that form direct or indirect crosslinks between two or more collagen fibrils. Examples include decorin and transglutaminase. In certain embodiments, a protein that crosslinks collagen fibers is not a hydroxylase, such as lysyl oxidase or prolyl oxidase.

[055] "Transglutaminase" includes any of the individual transferase enzymes having the enzyme commission (EC) number EC 2.3.2.13. Examples of human transglutaminase proteins include those identified by the following REFSEQ numbers: NP_000350; NP_004604;

NP_003236; NP__003232; NP_004236; NP_945345; and NP_443187. Besides human transglutaminase, transglutaminase prepared from non-human sources is included within the practice of the exemplary embodiments disclosed herein. Examples of non-human sources include, but are not limited to, primates, cows, pigs, sheep, guinea pigs, mice, and rats. Thus, in one embodiment, the transglutaminase is a transglutaminase solution prepared from an animal source (e.g., Sigma Catalogue No. T-5398, guinea pig liver). In other embodiments, however, the transglutaminase is from a recombinant source, and can be, for example, a human transglutaminase (e.g., the transglutaminase available from Axxora, 6181 Cornerstone Court East, Suite 103, San Diego, CA 92121 or from Research Diagnostics, Inc., a Division of Fitzgerald Industries Intl, 34 Junction Square Drive, Concord MA 01742-3049 USA).

[056] "Decorin" includes any of the proteins known to the skilled artisan by that name, so long as the decorin functions as a bidentate ligand attached to two neighboring collagen molecules in a fibril or in adjacent fibrils. Thus, "decorin" includes the core decorin protein. In particular, decorin proteins include those proteins encoded by any of the various alternatively spliced transcripts of the human decorin gene described by REFSEQ number NM_001920.3. In general, the human decorin protein is 359 amino acids in size, and its amino acid sequence is set forth in REFSEQ number NP_00191 1. Various mutations and their effect on the interaction of decorin with collagen have been described, for example by Nareyeck et al., Eur. J. Biochem., Vo. 271, pages 3389-98 (2004), and those mutants that bind collagen are also within the scope of the term "decorin," as is the decorin variant known as the 179 allelic variant {see De Cosmo et al., Nephron, Vol. 92, pages 72-76 (2002)). Decorin, for use in the disclosed methods, may be from various animal sources, and it may be produced recombinantly or by purification from tissue. Thus, not only human decorin, but decorin from other species, including, but not limited to, primates, cows, pigs, sheep, guinea pigs, mice, and rats, may also be used in the disclosed methods. An example of human decorin that can be used in the disclosed methods is the recombinant human decorin that is available commercially from Gala Biotech (now Catalant). Glycosylated or unglycosylated forms of decorin can be used.

[057] As used herein, the terms "treatment," "treating," and the like, refer to efforts to obtain a desired pharmacologic and/or physiologic effect. A treatment can administer a composition or product to a patient already known to have a condition. A treatment can also administer a composition or product to a patient as part of a prophylactic strategy to inhibit the development of a disease or condition known to be associated with a primary treatment. In the context of a surgical procedure, prophylactic treatment is any treatment administered to a patient scheduled to undergo a surgical procedure for the purpose of improving the outcome of that surgical procedure or otherwise reducing undesirable secondary effects associated with the surgical procedure. An example of a prophylactic treatment is the administration of an

immunosuppressive agent to a patient prior to the transplantation of an organ or tissue.

"Treatment," as used herein, covers any treatment of a condition or disease in a mammal, particularly in a human, and includes: (a) inhibiting the condition or disease, such as, arresting its development; and (b) relieving, alleviating or ameliorating the condition or disease, such as, for example, causing regression of the condition or disease.

[058] The terms "individual," "subject," "host," and "patient," used interchangeably herein, refer to a mammal, including, but not limited to, murines, simians, humans, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.

Injector Device

[059] The present disclosure is directed to a device for delivering an ophthalmic solution to the stroma of an eye. The device 1, which may be referred to as an injector device, a syringe device, or the like, may include a syringe body 2, a plunger 3, and a needle 4.

[060] Figs. 1 and 2 show one exemplary embodiment in which the syringe body 2 may include a syringe body flange 5, a barrel 6, and a needle holding portion 7. The syringe body flange 5 may be integral to the barrel 6 and disposed atop the barrel 6. The syringe body flange 5 allows a practitioner to grip and hold the syringe body 2 for steady and accurate placement of the syringe device 1 around the eye and accurate injection of ophthalmic fluid into the stroma of the eye. The syringe body flange 5 may further include an opening 8 (Fig. 5A) for insertion of the plunger 3. In one embodiment, the opening 8 may taper, shown by the tapered portion 22 (Fig. 5A) at a specified angle towards the barrel 6 and the needle holding portion 7, to be described in more detail later. In one exemplary embodiment, the angle at which the opening 8 tapers is about 30°. This opening 8 may be advantageous for allowing a practitioner to more easily fill the syringe body 2 with ophthalmic fluid, and/or to allow a practitioner to more easily insert the plunger 3 into the syringe body 2 for delivery of the ophthalmic fluid during treatment. The syringe body flange 5 may also include a notch 9 to receive a plunger stem 10 and to allow the plunger stem 10 to slide through the notch 9 during a treatment, as described in more detail below. In one exemplary embodiment, the syringe body flange 5 may have a length of about 1 inch and a width of less than about 0.5 inches.

[061] As described above, in some embodiments, the barrel 6 of the syringe body 2 may be made integrally with the syringe body flange 5. The barrel 6 may be arranged in a substantially cylindrical shape, and the barrel 6 may include a hollow interior portion 1 1 (Fig. 5A), or reservoir, which allows ophthalmic solution to be stored therein. The hollow interior portion 1 1 may be in fluid communication with the tapered portion 22 extending from the opening 8 through the syringe body flange 5 and a portion of the barrel 6 (Fig. 5A). The hollow interior portion 1 1 may also be in fluid communication with the needle 4. As described in more detail below, the hollow interior portion 11 of the barrel 6 also allows for insertion of the plunger 3 into the barrel 6 to deliver ophthalmic solution to the stroma of the eye. In some embodiments, the barrel 6 may have an outer diameter of about 0.25 inches, and an inner diameter of less than about 0.1 inches, although a barrel having various diameters could be used. Due to the manufacturing process of forming the barrel 6, to be described in more detail below, the barrel 6 may further include two holes 12a, 12b (Figs. 4B, 5A), near the needle holding portion 7 of the syringe body 2. The two holes 12a, 12b can be formed due to stabilizing pins provided during the molding procedure in order to stabilize a tube insert 13 to ensure that the tube insert 13 is centered along a core of the barrel 6. When the stabilizing pins are removed, the two holes 12a, 12b may remain in the barrel 6 near the needle holding portion 7. In some embodiments, the two holes 12a, 12b remain in the barrel 6 when the syringe device 1 is in its finished form, i.e., the two holes 12a, 12b may not be filled with material before using the syringe device 1 during a procedure,

[062] The syringe body 2 may also include the needle holding portion 7. The needle holding portion 7 may be formed integrally with the barrel 6 of the syringe body 2, and like the barrel 6, the needle holding portion 7 may be arranged in a substantially cylindrical shape. In one exemplary embodiment, the needle holding portion 7 includes a space for the needle 4 to be disposed therein. The space may be arranged along a central axis of the needle holding portion 7. As shown in Figs. 1-6A, the needle holding portion 7 may have a smaller diameter than the diameter of the barrel 6.

[063] The syringe device 1 may further include a plunger 3, which may include an insertion portion 14 to be inserted into the hollow interior portion 1 1 of the barrel 6, and a plunger stem 10 to be disposed on an exterior of the barrel 6. The plunger 3 may also include a flange 15 connected to both the insertion portion 14 and the plunger stem 10 to guide the insertion portion 14 and the plunger stem 10. As shown in FIG. 3, the plunger flange 15 may further include ridges 16 formed on a flat portion of the plunger flange 15 where a practitioner could place a thumb when injecting ophthalmic solution into a portion of the eye. The ridges 16 may help to ensure that the practitioner's thumb does not slip from the plunger flange 15 so that the ophthalmic solution can be delivered accurately and reliably to the stroma of the eye. In some embodiments, the plunger flange 15 may have a circular configuration, although other configurations are possible. [064] The insertion portion 14 of the plunger 3 may be configured to have a cylindrical shape to correspond to the hollow interior portion 1 1 of the barrel 6 of the tube insert 13 disposed within the syringe body 2, as described in more detail below. The diameter of the insertion portion 14 may be smaller than the inner diameter of the tube insert 13 so that the insertion portion 14 may be slidably disposed within the tube insert 13. In some embodiments, the insertion portion 14 of the plunger 3 may include a circumferential notch 17 at a distal end of the insertion portion 14, as shown in Fig. 4B. This notch 17 may be provided with a sealing mechanism 18, for example an o-ring, which may be a miniature o-ring, to provide a reliable seal between the plunger insertion portion 14 and the tube insert 13 containing ophthalmic solution.

[065] As mentioned above, the plunger stem 10 may be included as an indication to a practitioner of the amount of ophthalmic solution delivered during a treatment. The plunger stem 10 extends from the plunger flange 15. In some embodiments, the plunger stem 10 extends from the plunger flange 15 in a tapered manner. In at least some embodiments, the plunger insertion portion 14 extends further from the plunger flange 15 than the plunger stem 10. The plunger stem 10 terminates at a distal end of the plunger stem 10, which includes a flat portion 19 to reliably indicate the amount of ophthalmic solution delivered during a treatment.

Additionally, the plunger stem 10 may be configured to include a flat side 20 to face the barrel 6 of the syringe body 2 when the plunger 3 is disposed within the hollow interior portion 11 of the syringe body 2.

[066] The syringe may further include at least one needle 4. The needle 4 may be fixedly molded in the needle holding portion 7, as shown at least in Figs. 4A and 4B. As mentioned above, the needle 4 may be in fluid communication with the hollow interior portion 11 of the barrel 6 to allow the ophthalmic solution to be delivered from the syringe device 1 into a portion of an eye, wherein the portion of the eye may be the stroma. In at least some embodiments, the needle 4 extends the length of the needle holding portion 7, and protrudes from the end of the needle holding portion 7 by a predetermined length.

[067] Because the needle 4 is fixed within the needle holding portion 7 of the syringe device

1 , the length at which the needle 4 protrudes from the needle holding portion 7 may be precise and sufficient so as to allow the needle 4 to puncture at least to the stroma of an eye of a patient receiving treatment, and to prevent the needle 4 from puncturing past the stroma. In some embodiments, the needle 4 protrudes by a length of between about 200 and 300 μηι. In some instances, the needle 4 may protrude from the needle holding portion 7 by a length of less than about 250 μιη, e.g., about 225 μιη. Providing a needle in this manner may promote accurate delivery of ophthalmic solution during treatment, allowing a practitioner to inject the solution at an appropriate depth in the eye tissue. Additionally, the needle 4 may include an aperture 26 at the tip of the needle 4 in fluid communication with the ophthalmic solution via a needle passage 24 extending through an interior of the needle 4 (Figs. 6A and 6B). During treatment, the ophthalmic solution may exit through the aperture 26 to be injected into a portion of the eye. In some instances, the aperture 26 may be provided on a side of the needle 4 rather than at the tip, which may allow delivery of the ophthalmic solution to the eye tissue while maintaining sharpness of the needle tip to facilitate puncturing a portion of the eye during treatment.

[068] As described above, the plunger stem 10 may be provided to indicate to a practitioner the amount of ophthalmic solution delivered during treatment. In order to accomplish this, in one embodiment the barrel 6 of the syringe body 2 may be provided with markings 21 during or after the syringe body is formed. The markings 21, which may be provided on an outside of the barrel 6, may be dashed lines with numbers corresponding to the amount of ophthalmic solution contained within the tube insert 13, which may be made from a metal such as stainless steel, molded within the barrel 6. The markings 21 may indicate the amount of ophthalmic solution in microliters, although other units may be indicated on the barrel 6 of the syringe body 2. In one embodiment, when the insertion portion 14 of the plunger 3 is inserted within hollow interior portion 11 of the barrel 6, the plunger stem 10 is disposed over the markings 21 provided on the exterior of the barrel 6. Thus, a practitioner can easily identify the amount of ophthalmic solution delivered during a treatment without having to rely on visually inspecting the amount of ophthalmic solution contained within a syringe body based on the position of a plunger portion disposed within the syringe body. The plunger stem 10 and markings 21 provide a means for a practitioner to easily identify the amount of ophthalmic solution delivered to a portion of an eye, for example the stroma, during a treatment.

[069] As noted above, the barrel 6 of the syringe body 2 may further include the tube insert 13 provided in the hollow interior portion 1 1 to define a hollow space into which the ophthalmic solution may be stored before, during, and/or after a treatment, as illustrated in Figs. 4A and 4B. In one embodiment, the tube insert 13 may be a made from a metal, such as stainless steel. The tube insert 13 may be provided at the core of the barrel 6, and the plunger insertion portion 14 is configured to be slidably disposed within the tube insert 13 during injection of the ophthalmic solution. The interior of the tube insert 13 may be in fluid communication with the needle 4. By disposing the plunger insertion portion 14 within the tube insert 13, a practitioner is able to depress the plunger 3 in order to inject ophthalmic solution to a portion of the eye, such as the stroma. In one embodiment, the tube insert 13 has an outer diameter of less than about 0.1 inches, a inner diameter of less than about 0.08 inches, and a wall thickness of less than about

0.02 inches. Additionally, the tube insert 13 may have a length of less than about 1.2 inches, which may be less than the length of the barrel 6 of the syringe body 2. Also, in some embodiments, the tube insert 13 may be constructed of hypodermic needle tubing, for example, ETW 13 304 stainless steel.

[070] Providing a stainless steel tube as the tube insert 13 may advantageously allow for a tube having a smaller diameter that that of a plastic molded tube, in which to hold ophthalmic solution to be injected during a treatment. It may be problematic to mold a plastic tube having such a small diameter while having a length sufficient to extend within a portion of the barrel in order to hold ophthalmic solution. Forming the tube insert 13 of stainless steel and providing the tube insert 13 along the core of the barrel 6 may solve this problem. Additionally, because a tube insert 13 provided as a stainless steel tube may be opaque, a practitioner would not likely be able to visually inspect the amount of ophthalmic fluid delivered or remaining in the stainless steel tube. Therefore, the plunger 3 having the plunger stem 10 and the barrel 6 having markings 21 as described above may provide a reliable external indication means for a practitioner to accurately determine the amount of ophthalmic solution injected and/or remaining in the syringe body 2 without having to see the fluid within the tube insert 13 when the tube insert 13 is constructed from an opaque material, such as stainless steel.

[071] The syringe body 2 may be made from a number of plastic materials. In one embodiment, the syringe body 2 may be made from transparent polycarbonate radiation stabilized, medical grade, Bayer Makrolon® 2558, or an engineering approved equivalent.

[072] As described above, typical plastic syringes may be incapable of having an inner diameter for holding ophthalmic fluid molded to a diameter small enough to allow a practitioner to accurately deliver small doses of the fluid to a portion of a patient's eye. Moreover, typical syringes may rely on the practitioner to visually inspect the position of a plunger within a barrel of the syringe or the level of the fluid held within the syringe to determine the amount of fluid injected and/or remaining in the syringe. The tube insert 13 of the instant syringe device 1, however, may be capable of having a substantially small inner diameter to store precise amounts of ophthalmic fluid, to be delivered to a portion of a patient's eye during a treatment.

Furthermore, the plunger 3 having a plunger stem 10 disposed on an exterior of the barrel 6 of the syringe body 2, along with markings 21, may reliably indicate to a practitioner the amount of ophthalmic fluid injected and/or remaining in the tube insert 13 of the syringe body 2.

[073] One exemplary embodiment of the use or operation of the syringe device 1 will now be described. The syringe device 1 may either be provided to a practitioner pre-filled with ophthalmic fluid, or the syringe device 1 may be provided to a practitioner in an empty state to be filled by the practitioner prior to treatment. If the syringe device 1 is provided in an empty state, the practitioner may remove the plunger 3 from the syringe body 2, and fill the syringe body 2 with ophthalmic fluid from a separate sealed package. The syringe body 2 may be filled through the opening 8 in the syringe body flange 5. It should be noted that filling the syringe body 2 with ophthalmic fluid involves filling the tube insert 13 with the ophthalmic fluid.

Typically, a practitioner may insert a syringe device into a fluid, then draw the plunger back in order to fill a barrel of the syringe with treatment fluid. While a practitioner may fill the instant syringe device 1 in this manner, because of the small diameter of the tube insert 13, which, as discussed herein, may be provided as a stainless steel tube, into which the ophthalmic fluid is received, either providing the syringe device 1 prefilled or filling the device 1 from the back end may be advantageous.

[074] Next, a practitioner may begin to administer dosages of the ophthalmic fluid freehand to a portion of the eye. The practitioner may be capable of administering dosages directly where the treatment is needed, for example directly at a diseased location on a portion of the eye. The practitioner may manually insert the needle 4, which, as illustrated in Fig. 5B, protrudes from the needle holding portion 7 of the syringe body 2, into the portion of the eye to be treated to a predetermined depth. The insertion of the needle 4 may be assisted by providing a needle 4 having a sharp tip, as described above. The depth of needle insertion may be limited by the length of the needle 4 and the location where the needle 4 contacts the needle holding portion 7, as illustrated, e.g., in Fig. 5B. Furthermore, the length of the needle 4 may be predetermined to inject ophthalmic fluid into a portion of the eye to be treated, for example the stroma. Once the practitioner inserts the needle 4, she or he may begin to depress the plunger 3 to inject fluid contained within the tube insert 13 of the barrel 2 into the portion of the eye to be treated.

During the injection, the practitioner may monitor the location of the plunger stem 10 relative to the markings 21 provided on the side of the barrel 2 in order to determine the amount of ophthalmic solution injected into the portion of the eye. Because of the plunger stem 10 and the markings 21 included on the barrel 2, the practitioner may need not rely on visualizing the fluid actually contained within the tube insert 13 to ascertain the amount of fluid remaining therein. Once the practitioner has administered the appropriate dosage of ophthalmic fluid for a particular treatment, she or he may withdraw the needle 4 and syringe device 1 from the portion of the treated portion of the eye.

[075] The syringe device 1 may be disposable so that a practitioner can dispose of the entire device 1 after treatment of a patient. Thus, the syringe device 1 may be provided as a single-use device, which may be used to inject ophthalmic fluid into a plurality of injection sites of a portion of a patient's eye or eyes during a single treatment.

[076] The methods of strengthening the cornea in association with a surgical procedure may be initiated at any of a variety of points in time after the patient has been informed that surgery is needed, or informed that surgery is an option for that patient. For example, a patient considering LASIK may receive the strengthening treatment at the time of his or her LASIK prescree ing examination. Alternatively, the strengthening treatment may be administered at a time between the prescreening exam and the surgery. In general, the strengthening treatment will take place within the month preceding the surgery, although, in some cases the time period may be more than a month before the surgery. For example, it is possible that the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before. Usually, however, the

strengthening treatment will be administered about one to two weeks before the corneal surgery. Often, when it is administered before surgery, the strengthening treatment will be administered about 10 days before the surgery, although it may be administered about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 days before the corneal surgery. It is also possible to treat the cornea on the same day as the corneal surgery.

[077] In other embodiments, the strengthening treatment takes place during the surgical procedure. These embodiments do not exclude treatments at other times, such as before and/or after the surgical procedure. Varying the amount of ophthalmic solution used when the strengthening treatment takes place during the surgical procedure is within the scope of the disclosed embodiments. The amount of solution administered may depend at least in part upon the concentration of the agent in the solution used, as well as the potency of the particular agent, and the severity of the condition being treated. The amount administered may also depend on whether multiple injections will be given, either over time, or at different locations of the cornea. The selection of the amount of solution to be administered may be left to the discretion of the practitioner during individual procedures. One exemplary dosage of agents is between 7μί and 15μί per injection site, although dosages less than 7μΙ_^ or more than 15μΙ_^ per injection site could be administered.

Example: Study of Stromal. Distribution of Fluorescent Solution Following Injection into Human Donor Cornea

[078] The objective of this study was to evaluate the stromal distribution of different volumes of a fluorescent solution following injection into human donor cornea using the syringe device 1 described herein. For this study, Oregon Green 488 was used as the fluorescent solution. Two sets of human donor cornea were procured, and prior to injection, the donor corneas were gently rinsed with sterile phosphate buffered saline. Three different volumes of

Oregon Green 488 were loaded into the injector device and injected into the central region of human donor cornea. Cornea #1 received 20μΙ_^ of Oregon Green 488 solution, cornea #2 received

of Oregon Green 488 solution, and cornea #3 received 30μί of Oregon Green 488 solution. The distribution, depth, and uniformity of distribution were evaluated using confocal microscopy to examine the central cornea and each quadrant of the peripheral cornea. Results for the 20 Ι_^ injection volume showed strong central cornea fluorescence at a depth of approximately 225 um, but weak distribution in peripheral quadrants surrounding the central cornea, and fluorescent intensity diminished beyond the 250μπι depth. Results for the 25μΙ, and 30μΙ, injection volumes showed strong central cornea and peripheral cornea fluorescence at a depth of approximately 225 nL, and fluorescence intensity only slightly diminished in the peripheral cornea quadrants. In sum, the syringe device 1 successfully delivered fluorescent solution to human donor cornea to a depth of approximately 225μιη, and injection volumes of 25μΙ, and 30μΙ, provided uniform distribution of fluorescence across the entire corneal stroma to a depth of approximately 225μηι.

[079] One exemplary embodiment of the method of making the syringe body 2 of the syringe device 1 will now be described. In order to stabilize the tube insert 13, the tube insert 13 may be loaded onto stabilizing pins (not shown) for stabilization. The tube insert 13 may be stabilized in order to ensure that the tube insert 13 is disposed centrally with respect to a longitudinal axis of the barrel 6 of the syringe body 2. Once the tube insert 13 is stabilized, plastic forming the syringe body 2 may then be molded around the tube insert 13. Additionally, the needle 4 may be molded into the plastic forming the syringe body 2. In one embodiment, the needle 4 may be molded into the need holding portion 7 of the syringe body 2. Additionally, the plastic may be injection molded around the tube insert 13. Additionally, the plastic forming the syringe body 2 may be transparent polycarbonate radiation stabilized, medical grade, Bayer Makrolon® 2558, or an engineering approved equivalent. Molding the plastic around the tube insert 13 in this manner confines the tube insert 13 to a core of the syringe body 2. Once the syringe body 2 is removed from the stabilizing pins, two holes 12a, 12b may remain in a lower portion of the barrel 6 where the stabilizing pins were located during the molding process. In some embodiments, the two holes 12a, 12b may be filled or, alternatively, left as open holes in the syringe device 1 and not filled before a practitioner operates the syringe device 1 during a treatment. After the molding process, the markings 21 for indicating an amount of ophthalmic solution may be applied to the exterior of the barrel 6 of the syringe body 2. In some exemplary embodiments, the mold may have a surface finishing, such as an SPI B-l finish or better.

[080] Forming at least the syringe body 2 in this manner avoids the limits imposed by using plastic molding to form the entire syringe body 2. By forming the plastic syringe body 2 around the tube insert 13, the syringe device 1 may be made economically with minimal labor, while allowing for the injection of very small volumes of ophthalmic solution into a portion of an eye during a treatment. This may be due to the small diameter of the tube insert 13, which, in some instances, may be made from a metal such as stainless steel. Furthermore, applying the markings 21 on the barrel 6 of the syringe body 2 after the molding process provides an indicating means for a practitioner to easily determine the amount of ophthalmic solution injected and/or remaining in the syringe device tube insert 13 during a procedure.

[081 ] Other advantages may include providing a cost-effective syringe device 1 which is commercially viable for large-scale operations. As described above, the syringe device 1 may require one needle 4 rather than a plurality of needles before being disposed of after treatment. Furthermore, operating the syringe device 1 may be intuitive and thus simple for a trained practitioner such as a doctor. Thus, using this syringe device 1 during a procedure a practitioner can easily and accurately deliver a desired dosage of ophthalmic solution to a portion of an eye, where the portion of the eye may be the stroma.

[082] The disclosed devices and methods have been described generally. Where a range of values is provided, it is understood that each intervening value may be encompassed within the exemplary embodiments described herein. The upper and lower limits of various ranges may independently be included in the ranges, subject to any specifically excluded limit in the stated range.

Industrial Applicability

[083] The disclosed syringe device 1 may be applicable for administering an ophthalmic solution to the eye of a patient. In particular, the syringe device 1 may be configured to deliver ophthalmic solutions to the front (i.e. anterior) of the eye.

[084] The disclosed syringe device 1 can be used to inject ophthalmic solutions to a subsurface region of the stroma. Exemplary uses for such injections may include treatments for, and/or prevention of, "front-of-the-eye" conditions, such as myopia, hyperopia, astigmatism, keratectasia, and keratoconus, by administering agents that improve the structural integrity of the cornea, e.g., by increasing its rigidity. Such uses may include stabilizing the cornea, correcting refractive error, and improving unaided visual acuity. For example, exemplary treatments may be administered in conjunction with refractive surgery procedures, such as LASIK, PRK, RK, and other surgical refractive procedures. In addition, exemplary treatments may include, or may be associated with, non-surgical refractive procedures, such as orthokeratology and corneal rehabilitation.

[085] In addition, the disclosed device 1 may be utilized to administer agents to the cornea for the purpose of rendering the cornea more malleable and/or pliable (e.g., corneal acylation). This procedure may be performed prior to a stabilization procedure not associated with a surgical treatment.

[086] Possible agents shown to increase structural rigidity of the cornea include

compositions with proteins that crosslink collagen fibrils. Exemplary compositions may include such proteins along with a pharmaceutically acceptable carrier. For example, decorin crosslinks the collagen fibrils by binding to each of two different fibrils to form a bridge therebetween. Another such protein is transglutaminase, which crosslinks collagen fibrils by catalyzing the formation of a covalent bond between an amino acid in one collagen fibril and an amino acid in a second collagen fibril. The disclosed syringe device may be utilized to inject compositions including decorin or transglutaminase.

[087] In one exemplary embodiment, such agents may be administered by the disclosed syringe device to the cornea subject to a refractive surgical procedure. The treatment may be initiated before, during, and/or after the surgery. Exemplary refractive surgical procedures may include, but are not limited to, Radial Keratotomy (RK), Photorefractive Keratoplasty (PRK), LASIK (Laser-Assisted In Situ Keratomileusis), Epi-LASIK, IntraLASIK, Laser Thermal Keratoplasty (LTK), and Conductive Keratoplasty.

[088] The disclosed syringe device may be employed in methods of treating keratectasia, comprising administering to the stroma a composition comprising a protein that crosslinks collagen fibrils and a pharmaceutically acceptable carrier. The treatment can be prophylactic, contemporaneous with a surgical procedure, postoperative, or can involve multiple

administrations during one or more of those time points. Although the keratectasia may develop following a refractive surgical procedure, such as LASIK, it may also develop in an eye that has not had a surgical procedure.

[089] The disclosed syringe device may be employed in methods of treating keratoconus, comprising administering to the eye of a patient who has keratoconus a composition comprising a protein that crosslinks collagen fibrils and a pharmaceutically acceptable carrier.

Example: Comparison of Corneal Hysteresis in LASIK Patients: Superficial Decorin Eve Drops vs. Needle-injected Decorin [090] Testing has shown that needle injection of decorin to subsurface regions of the stroma produce greater improvements than merely administering drops containing decorin to the stromal bed. The following data illustrates the benefit of subsurface injections as compared to superficial drops.

[091 ] The effects of decorin application on the biomechanical properties of the post-LAS!K cornea were measured in five human myopic LASIK patients in a pilot study performed by

Gabriel Carpio, MD at the Hospital Angeles, Mexico. Two drops of decorin solution were applied to the stromal bed during the LASIK procedure and one drop to the back of the surgical flap. In each patient, both eyes were subjected to LASIK, but only one eye received the decorin treatment (the treated eye). The other eye did not receive the decorin treatment and served as a control (the untreated eye). The biomechanical integrity of the cornea was measured using the Reichert Ocular Response Analyzer (ORA). Figures 7 and 8 show the difference in corneal hysteresis (CH) between the treated eyes and the untreated eyes from the time of treatment through a five-month follow-up period. Figure 7 shows the effects of decorin drops on corneal historesis for an individual patient. Figure 7 presents the data for an individual patient who had an OD of -6.25 and an OS of -6.00. The x-axis shows the time periods at which measurements were taken, i.e., at baseline and at various time points post surgery. The Y-axis shows the results as a percentage of baseline corneal historesis.

[092] In the patient whose results are shown in Figure 7, the corneal hysteresis of the treated eye exceeded that of the untreated eye at each time point post-LAS!K procedure.

[093] Figure 8 shows the effects of decorin drops on corneal historesis for multiple patients. Figure 8 groups the data for all five myopic patients in the study.

[094] The grouped data in Figure 8 shows improvement, at all time points, in corneal hysteresis in the treated eyes as compared to the untreated eyes. While these improvements are significant, even better results could be realized with an alternative delivery method.

[095] In a preliminary clinical study, the decorin ophthalmic solution was administered, via injection, to LASIK patients during the surgical procedure. The contralateral treated eye served as the control. Figure 9 shows the effects of decorin injections on corneal historesis for multiple patients. Results in Figure 9 below show an increase in corneal hysteresis in LASIK eyes receiving injections of decorin into the stroma (rather than merely drops deposited on the surface of the stroma and on the underside of the flap).

[096] For the patients shown in Fig. 9, decorin injections provided substantial strengthening of corneal structure following LASIK surgery and may reduce regression and the incidence of ectasia. It is also noteworthy that, on average, the corneal historesis is actually higher in the treated eyes two months after surgery than it was pre-surgery (i.e., at "baseline"). While there was hope that improvements in corneal historesis would be realized with decorin injection, as compared to those observed in patients receiving decorin drops, it was unexpected that corneal historesis would improve to a level that exceeded baseline.

[097] Since the integrity/rigidity of the cornea can apparently be improved to a point higher than that naturally occurring in the patient, there are possibilities for using decorin injections beyond restoration of degraded corneal strength. For example, distortion of vision may occur with significant physical loads on the body, such as during sports and other activities that place high physical demands on the body, but still require a high level of visual acuity, e.g., playing high impact sports, flying fighter jets, or driving a race car. [098] A football player, such as a receiver, or a baseball player, such as an outfielder, must be able to see the ball even as his head bounces while running after the ball. It may be possible to improve a player's vision under these circumstances by injecting decorin to improve corneal rigidity, which may result in less temporary distortion of the corneal shape under loads experienced while running, jumping, and landing. Similarly, fighter pilots and race car drivers are subjected to high gravitational forces (G-forces), as well as bouncing/shaking forces due to turbulence or rough road surfaces. Such forces can result in temporary distortion of the corneal shape and, therefore, degraded vision. Thus, improvement of corneal rigidity with decorin injections may increase visual acuity under high activity-related loading.

[099] In addition, in some embodiments, the disclosed syringe device may be used to inject other types of agents, such as antibiotics, anti-inflammatory agents, anti-allergy agents, antihistamines, or any other ophthalmic solution that is desired to be delivered to subsurface regions of the stroma.

[0100] Although embodiments herein are shown and discussed as being configured for applications involving injection of solutions to the eye, embodiments are envisioned that may be configured for injection anywhere in or on the body. For example, features of the disclosed apparatus, such as needle insertion depth regulating means, various handle configurations and features, plunger actuating configurations, etc., may be adaptable for syringes used elsewhere in the body besides the eye. Similarly, various support structure or locator member configurations may be implemented according to the target area of injection. Exemplary non-ophthalmic uses may include, but are not limited to, insulin injections, antibiotic injections, anti-inflammatory injections for skin inflammation, anti-allergy injections, injection of anti-viral agents, etc.

Additional possible uses may include surgical and non-surgical skin alterations (e.g., plastic/cosmetic surgery), for example, collagen, epithelial injections, Botox, etc. The volume of the hollow cavity, size of the needle, depth of injection, and other various parameters of the disclosed syringe device may be selected appropriately for the area of the body being treated, and the type of agent injected.

[0101 ] Also, the disclosed devices may be utilized to aspirate liquids from the eye or other parts of the body. Possible uses may include specimen collection for various uses. For example, the disclosed devices may be utilized to take tissue samples, blood samples for various testing, (e.g., glucose testing), and other fluid samples, etc. Needle sizes may be determined according to the desired application. For example, embodiments configured for collecting tissue samples may have a needle with a larger inner diameter than embodiments utilized solely for fluid collection. [0102] As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a subject polypeptide" includes a plurality of such polypeptides and reference to "the agent" includes reference to one or more agents and equivalents thereof known to those skilled in the art, and so forth.

[0103] Unless defined otherwise, all technical and scientific terms used herein may have the same meaning as commonly understood by one of ordinary skill in the art to which the exemplary embodiments belong. Any publications mentioned herein, including patents, patent applications, and publications are incorporated herein by reference in their entireties to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0104] Any publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior invention.

Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0105] While the exemplary embodiments disclosed herein have been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the trae spirit and scope of the various exemplary embodiments. In addition, modifications may be made to adapt a particular situation, material, composition of matter, process, process step, or steps to the objective, spirit, and scope of the present description. Other embodiments will be apparent to those skilled in the art from consideration of the specification and practice of the exemplary embodiments disclosed herein, and it is intended that the specification and examples be considered as exemplary only.

Claims

WHAT IS CLAIMED IS:

1 . A syringe device comprising:

a syringe body including a needle disposed therein;

a tube insert disposed within the syringe body, the tube insert configured to receive ophthalmic solution to be delivered to a portion of an eye; and

a plunger configured to be removably connected to the syringe body, the plunger further comprising a plunger flange connected to an insertion portion, the insertion portion being configured to be disposed within the tube insert to deliver the ophthalmic solution.

¹

2. The syringe device according to claim 1 , the plunger further comprising a plunger stem connected to the plunger flange, the plunger stem configured to be disposed outside of the syringe body when the insertion portion is disposed within the tube insert.

3. The syringe device according to claim 2, the syringe body further comprising a syringe body flange having a notch therein, the notch being configured to receive at least a portion of the plunger stem.

4. The syringe device according to claim 2, wherein the insertion portion and the plunger stem extend in the same direction linearly from the plunger flange.

5. The syringe device according to claim 1 , further comprising a notch formed in the insertion portion at a distal end of the insertion portion, the notch configured to receive a sealing mechanism to provide a seal between the insertion portion and the tube insert.

6. A syringe device comprising:

a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body;

a needle disposed within the needle holding portion;

a plunger configured to be removably connected to the syringe body, the plunger including a plunger flange connected to both an insertion portion and a plunger stem; and

a tube insert disposed within the barrel of the syringe body, the tube insert fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye.

7. The syringe device according to claim 6, wherein the tube insert comprises a stainless steel tube insert.

8. The syringe device according to claim 6, wherein all of the ophthalmic solution to be injected through the needle is stored within the tube insert.

9. The syringe device according to claim 6, further comprising a plurality of markings on an outer side of the barrel, wherein the plunger stem is configured to be aligned with at least one of the plurality of markings during an injection to indicate the amount of the ophthalmic solution injected into the portion of the eye.

10. The syringe device according to claim 9, further comprising a notch formed in the syringe body flange, the notch being configured to receive at least a portion of the plunger stem to align the plunger stem with the at least one of the plurality of markings during the injection.

1 1 . The syringe device according to claim 6, wherein the needle holding portion is configured to limit a depth of insertion of the needle into the portion of the eye.

12. A syringe device comprising:

a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body, wherein the needle holding portion includes a needle disposed therein;

a tube insert disposed within the barrel of the syringe body, the tube insert fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye, wherein the plunger insertion portion is configured to be inserted within the tube insert to deliver the ophthalmic solution.

13. The syringe device according to claim 12, further comprising a notch formed in the syringe body flange, the notch being configured to receive at least a portion of the plunger stem.

14. The syringe device according to claim 12, wherein the plunger stem is configured to be disposed outside of the syringe body when the insertion portion is disposed within the tube insert.

15. The syringe device according to claim 12, wherein the tube insert comprises a stainless steel tube insert.

16. The syringe device according to claim 15, wherein all of the ophthalmic solution to be injected through the needle is stored within the tube insert.

17. The syringe device according to claim 12, further comprising a plurality of markings on an outer side of the barrel, wherein the plunger stem is configured to be aligned with at least one of the plurality of markings during an injection to indicate the amount of the ophthalmic solution injected into the portion of the eye.

18. A method of injecting ophthalmic solution into a portion of an eye, the method comprising: filling at least a portion of a syringe body of a syringe device with an ophthalmic solution, wherein a tube insert disposed within a barrel of the syringe body is filled with the ophthalmic solution;

inserting a plunger of the syringe device into the tube insert;

inserting a needle of the syringe device into the portion of the eye; and

injecting into the portion of the eye a specific amount of the ophthalmic solution.

19. The method according to claim 18, wherein during the injecting, a plunger stem of the plunger moves linearly along an outside of the syringe body.

20. The method according to claim 19, wherein during the injecting, the plunger stem aligns with markings provided on the outside of the syringe body to indicate an amount of ophthalmic solution injected into the portion of the eye.