Injectable cross-linked hydrogel composition for permanent vitreous replacement

Abstract

ABSTRACT INJECTABLE CROSS-LINKED HYDROGEL COMPOSITION FOR PERMANENT VITREOUS REPLACEMENT An artificial vitreous implant composition for permanent vitreous replacement is disclosed. The composition comprises a first component including multi-arm polyethylene glycol functionalized with maleimide groups at 2-4% w / v and a second component including thiolated hyaluronic acid at 0.5-1.5% w / v, both in physiologic buffer. The components undergo crosslinking via Michael addition when mixed to form an in-situ hydrogel within 2-4 minutes at body temperature. The hydrogel exhibits refractive index of 1.336-1.340, optical transmission exceeding 95%, neutral buoyancy with density 0.99-1.02 g / mL, and storage modulus of 0.05-0.5 Pa matching natural vitreous. A sterile dual-syringe delivery system with static mixing element and 23-27 gauge injection cannula enables surgical administration. The composition provides permanent transparent vitreous replacement without requiring removal or postoperative positioning, addressing limitations of silicone oil and gas tamponades used in vitreoretinal surgery. [To be published with Figure 1]

Description

FIELD OF THE INVENTION

[001] The present invention relates to medical devices and biomaterials for ophthalmological applications. More particularly, it pertains to synthetic, biocompatible implant compositions for replacing the natural vitreous body of the human eye. Specifically, the invention concerns injectable hydrogel compositions that form in situ within the vitreous cavity to provide long-term vitreous replacement following vitrectomy or traumatic vitreous loss.BACKGROUND OF THE INVENTION

[002] The following description of related art is intended to provide background information pertaining to the field of the invention. This section may include certain aspects of the art that may be related to various features of the present invention. However, it should be appreciated that this section be used only to enhance the understanding of the reader with respect to the present invention, and not as admissions of prior art.

[003] The natural vitreous body is a transparent, viscoelastic gel comprising approximately 99% water along with hyaluronic acid and collagen networks that maintain ocular shape, provide structural support to the retina, and maintain optical clarity. In vitreoretinal surgery, the vitreous is frequently removed through pars plana vitrectomy to treat conditions such as retinal detachment, proliferative vitreoretinopathy, macular holes, and traumatic vitreous loss. Following vitrectomy, the vitreous cavity must be filled with a substitute material to provide temporary or long-term tamponade. Conventional vitreous substitutes include silicone oils (with viscosities ranging from 1,000 to 5,000 centistokes), heavy silicone oils (specific gravity 1.02-1.06), expansile gases (sulfur hexafluoride, perfluoropropane), and more recently, foldable capsular vitreous bodies. These materials are introduced into the vitreous cavity through surgical incisions using specialized injection cannulas, typically ranging from 20 to 25 gauge. Silicone oils function by creating a physical barrier due to their immiscibility with aqueous humor and their higher specific gravity or lower density relative to water.

[004] However, existing vitreous substitutes face significant technical limitations that compromise their clinical utility and patient outcomes. Silicone oils, while providing effective tamponade, require a second surgical procedure for removal, typically 3-6 months post-implantation, as permanent retention leads to complications including cataract formation in over 90% of phakic eyes, secondary glaucoma with intraocular pressure elevations exceeding 21 mmHg in approximately 20-40% of cases, corneal endothelial cell loss at rates of 8-12% per year, and oil emulsification with globule sizes ranging from 10-50 micrometers that can migrate into the anterior chamber. Heavy silicone oils, designed for treating inferior retinal pathologies, exhibit similar complications with additional challenges of subretinal migration through retinal breaks. Expansile gases provide temporary tamponade lasting 2-8 weeks depending on the gas type, but require strict postoperative head positioning for 1-2 weeks to maintain the gas bubble in contact with the target retinal area, limiting patient mobility and compliance. Gas tamponades also carry risks of intraocular pressure spikes exceeding 30 mmHg during the expansion phase. Foldable capsular bodies require larger surgical incisions (typically 3.5-4.0 mm) for insertion, involve complex implantation procedures with potential for capsule malposition, and cost significantly more than fluid tamponades. Importantly, none of these substitutes adequately replicate the optical properties of natural vitreous, with refractive indices varying from 1.40 (silicone oil) to 1.00 (gas), compared to the native vitreous refractive index of 1.336-1.340. The mechanical properties also differ substantially, with silicone oils exhibiting viscosities 100-1000 times higher than natural vitreous, affecting intraocular fluid dynamics and potentially causing retinal traction.

[005] Therefore, there exists a technical need for an injectable vitreous substitute composition that forms a stable, transparent hydrogel in situ within the vitreous cavity without requiring subsequent removal. There is a further need for a hydrogel composition with optical properties matching natural vitreous, including refractive index in the range of 1.336-1.340 and optical transmission exceeding 95% across visible wavelengths. Additionally, there is a need for a formulation with rapid gelation kinetics (2-4 minutes) compatible with surgical timeframes, neutral buoyancy to eliminate postoperative positioning requirements, and long-term stability within the intraocular environment. Such a composition should be formed from fully synthetic, biocompatible components to ensure reproducibility, eliminate immunogenicity concerns, and provide optional reversibility for elective removal if required.OBJECTS OF THE INVENTION

[006] Some of the objects of the present invention, which at least one embodiment herein satisfies, are as listed herein below.

[007] An object of the present invention is to provide an artificial vitreous implant composition that forms a transparent, biocompatible hydrogel in situ within the vitreous cavity following injection.

[008] An object of the present invention is to provide a hydrogel composition with optical properties matching natural vitreous, including a refractive index of 1.336-1.340 and optical transmission of at least 95% across visible wavelengths.

[009] An object of the present invention is to provide a two-component injectable system that undergoes rapid crosslinking via Michael addition reaction to form a stable hydrogel within 2-4 minutes at physiologic temperature.

[0010] An object of the present invention is to provide a vitreous replacement composition with neutral buoyancy and physiologic osmolarity to eliminate postoperative positioning requirements and ensure biocompatibility.

[0011] An object of the present invention is to provide a permanent vitreous substitute with optional reversibility through enzymatic or light-induced degradation for controlled removal if clinically necessary.

[0012] An object of the present invention is to provide a sterile delivery system enabling precise co-injection of hydrogel components through standard vitrectomy cannulas during surgical procedures.SUMMARY OF THE INVENTION

[0013] In an exemplary embodiment, an artificial vitreous implant composition is described. The composition comprises a first component comprising a multi-arm polyethylene glycol functionalized with maleimide groups having a molecular weight of 20-40 kDa at a concentration of 2-4% w / v in a physiologic buffer solution having a pH of 7.2-7.4. The composition further comprises a second component comprising thiolated hyaluronic acid having a molecular weight of 200-1500 kDa with a degree of thiolation of 10-30% at a concentration of 0.5-1.5% w / v in said physiologic buffer solution. The first component and the second component, when combined, undergo a crosslinking reaction via Michael addition to form an in-situ cross-linked hydrogel. The in-situ cross-linked hydrogel has a refractive index of 1.336-1.340, a pH of 7.0-7.4, an osmolarity of 280-310 mOsm, an optical transmission of at least 95% across 400-800 nm wavelength range, and a density of 0.99-1.02 g / mL.

[0014] In another embodiment, the multi-arm polyethylene glycol is a four-arm polyethylene glycol. According to an embodiment, the physiologic buffer solution is a HEPES-balanced salt solution. In a further embodiment, the crosslinking reaction forms the in-situ cross-linked hydrogel within 2-4 minutes at a temperature of 37°C. The in-situ cross-linked hydrogel exhibits a storage modulus of 0.05-0.5 Pa at 37°C and swelling of less than or equal to 5% in physiologic saline at 37°C over 7 days. According to an embodiment, the composition further comprises at least one additive selected from the group consisting of antioxidants, nutrients, and therapeutic agents for sustained intraocular delivery. In an embodiment, the in-situ cross-linked hydrogel comprises reversible linkages that permit enzymatic degradation or light-induced dissolution for controlled removal. The first component and the second component are pharmaceutically pure and free of human or animal plasma derivatives.

[0015] In an exemplary embodiment, a sterile delivery system for administering the composition is described. The delivery system comprises a dual-syringe assembly comprising a first syringe containing the first component and a second syringe containing the second component. The delivery system includes a static mixing element fluidly connected to the first syringe and the second syringe. The static mixing element combines the first component and the second component to form a mixed solution. The delivery system further comprises an injection cannula having a gauge size of 23-27 gauge fluidly connected to the static mixing element. The injection cannula delivers the mixed solution into a vitreous cavity of an eye. The dual-syringe assembly, the static mixing element, and the injection cannula are configured for single-use application.

[0016] In an exemplary embodiment, a method of preparing an artificial vitreous implant in situ is described. The method comprises providing a first sterile component comprising a multi-arm polyethylene glycol functionalized with maleimide groups having a molecular weight of 20-40 kDa at a concentration of 2-4% w / v in a physiologic buffer solution having a pH of 7.2-7.4. The method includes providing a second sterile component comprising thiolated hyaluronic acid having a molecular weight of 200-1500 kDa with a degree of thiolation of 10-30% at a concentration of 0.5-1.5% w / v in said physiologic buffer solution. The method comprises performing a pars plana vitrectomy on an eye of a patient to create a vitreous cavity. The method includes simultaneously delivering the first sterile component and the second sterile component through a static mixing element to combine the first sterile component and the second sterile component into a mixed solution. The method comprises injecting the mixed solution through a 23-27 gauge cannula into the vitreous cavity to fill approximately 90-95% of the vitreous cavity. The method includes allowing the mixed solution to undergo crosslinking via Michael addition within 2-4 minutes at body temperature to form an in-situ cross-linked hydrogel. The in-situ cross-linked hydrogel has a refractive index of 1.336-1.340, a pH of 7.0-7.4, an osmolarity of 280-310 mOsm, optical transmission of at least 95%, and a density of 0.99-1.02 g / mL. The in-situ cross-linked hydrogel provides long-term tamponade without requiring postoperative positioning or subsequent removal.

[0017] The foregoing general description of the illustrative embodiments and the following detailed description thereof are merely exemplary aspects of the teachings of this invention, and are not restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The invention will now be described with reference to the accompanying drawings, which illustrate embodiments by way of example only. The same numbers are used throughout the drawings to refer to features and components.

[0019] Figure 1 is a flowchart illustrating a method of preparing an artificial vitreous implant in situ, in accordance with an embodiment of the present invention.

[0020] The foregoing shall be more apparent from the following more detailed description of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention describes compositions, delivery systems, and methods for providing permanent vitreous replacement in ophthalmological applications. Exemplary embodiments will now be described with reference to the accompanying drawing. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

[0022] The following description provides exemplary embodiments for illustrative purposes and is not intended to limit the scope or applicability of the invention. Various specific details are provided to enable thorough understanding, but embodiments may be practiced without these details. Well-known chemical components, materials, and techniques may be shown without unnecessary detail to avoid obscuring the embodiments.

[0023] The terms "exemplary" or "demonstrative" mean serving as an example and are not necessarily preferred or advantageous over other designs. References to "one embodiment" or "an embodiment" throughout this specification do not necessarily refer to the same embodiment, and particular features may be combined in any suitable manner. As used herein, singular forms include plural forms unless the context indicates otherwise, and "comprises" or "comprising" specify the presence of stated elements but do not preclude additional elements.

[0024] The aspects of the present invention are directed to an artificial vitreous implant composition comprising two reactive components that undergo in-situ crosslinking to form a biocompatible hydrogel, a sterile delivery system for precise administration during vitrectomy, and a method for preparing the implant directly within the vitreous cavity. The invention addresses the technical limitations of existing vitreous substitutes, including the need for removal surgery, postoperative positioning requirements, optical incompatibility, and lack of permanent stability, by providing a transparent, biocompatible hydrogel that matches the optical and physical properties of natural vitreous through a two-component crosslinking system based on thiol-maleimide Michael addition chemistry.

[0025] The artificial vitreous implant composition comprises a first component that serves as the electrophilic crosslinking partner in the hydrogel formation reaction. The first component comprises a multi-arm polyethylene glycol functionalized with maleimide groups as the reactive functional groups. The multi-arm polyethylene glycol provides a water-soluble, biocompatible polymer backbone that forms the structural network of the resulting hydrogel. The maleimide functional groups are electrophilic moieties that react selectively with thiol groups through Michael addition chemistry, enabling controlled crosslinking without the need for external initiators, catalysts, or ultraviolet radiation.

[0026] The multi-arm polyethylene glycol has a molecular weight in the range of 20 to 40 kilodaltons (kDa). This molecular weight range provides an optimal balance between solution viscosity, crosslinking density, and final hydrogel mechanical properties. In some embodiments, the multi-arm polyethylene glycol has a molecular weight of approximately 20 kDa, which provides higher crosslinking density and increased mechanical strength. In other embodiments, the multi-arm polyethylene glycol has a molecular weight of approximately 30 kDa, providing moderate crosslinking density suitable for most applications. In further embodiments, the multi-arm polyethylene glycol has a molecular weight of approximately 40 kDa, yielding lower crosslinking density with increased water content and softer gel characteristics.

[0027] In some embodiments, the multi-arm polyethylene glycol comprises a four-arm polyethylene glycol structure. The four-arm configuration provides four reactive sites per polymer molecule, enabling efficient network formation with controlled crosslinking density. Each arm of the four-arm polyethylene glycol terminates in a maleimide functional group. The four-arm architecture provides geometric symmetry that promotes uniform crosslinking throughout the hydrogel network. Alternative embodiments may employ six-arm or eight-arm polyethylene glycol structures to modify the crosslinking density and mechanical properties of the resulting hydrogel.

[0028] The maleimide functional groups are covalently attached to the terminal ends of each polyethylene glycol arm. In some embodiments, the maleimide groups are linked to the polyethylene glycol through an ester linkage, ether linkage, or urethane linkage formed during the synthesis of the functionalized polymer. The maleimide group comprises a five-membered heterocyclic ring structure containing a nitrogen atom and two carbonyl groups in a 1,3-relationship. The carbon-carbon double bond in the maleimide ring is electron-deficient due to the adjacent carbonyl groups, making it highly reactive toward nucleophilic thiol groups through Michael addition.

[0029] The first component is formulated at a concentration of 2 to 4 percent weight per volume (% w / v) in a physiologic buffer solution. This concentration range provides sufficient reactive groups for complete gelation while maintaining solution viscosity low enough for injection through small-gauge cannulas. In some embodiments, the first component is formulated at approximately 2% w / v, providing lower solution viscosity for easier injection through 27-gauge cannulas. In other embodiments, the concentration is approximately 3% w / v, providing balanced reactivity and handling characteristics. In further embodiments, the concentration is approximately 4% w / v, yielding faster gelation times and higher final gel strength.

[0030] The first component is dissolved in a physiologic buffer solution having a pH in the range of 7.2 to 7.4. This pH range is slightly alkaline and matches the pH of aqueous humor and vitreous humor in the human eye. The physiologic pH ensures biocompatibility and prevents irritation or inflammatory response upon injection into the vitreous cavity. The buffer system maintains stable pH throughout storage and during the gelation reaction. In some embodiments, the physiologic buffer solution comprises a HEPES-balanced salt solution. HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) is a zwitterionic organic chemical buffering agent that maintains pH stability in the physiological range of 7.2 to 7.4.

[0031] The physiologic buffer solution comprises ionic components that match the osmolarity and ionic composition of intraocular fluids. In some embodiments, the buffer solution comprises sodium chloride at a concentration of approximately 0.64% w / v, potassium chloride at approximately 0.075% w / v, calcium chloride dihydrate at approximately 0.048% w / v, and magnesium chloride hexahydrate at approximately 0.03% w / v. These electrolytes provide physiologic ionic strength and contribute to the osmolarity of the solution. The buffer solution may also comprise sodium acetate trihydrate at approximately 0.39% w / v and sodium citrate dihydrate at approximately 0.17% w / v to provide additional buffering capacity and maintain pH stability.

[0032] The artificial vitreous implant composition further comprises a second component that serves as the nucleophilic crosslinking partner. The second component comprises thiolated hyaluronic acid, which is hyaluronic acid that has been chemically modified to incorporate thiol functional groups. Hyaluronic acid is a naturally-occurring glycosaminoglycan consisting of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. Hyaluronic acid is a major component of natural vitreous humor, contributing to its viscoelastic properties and biocompatibility. The thiolation of hyaluronic acid introduces reactive thiol groups (also known as sulfhydryl groups, -SH) that can participate in Michael addition reactions with the maleimide groups of the first component.

[0033] The thiolated hyaluronic acid has a molecular weight in the range of 200 to 1500 kilodaltons (kDa). This high molecular weight provides the necessary viscosity and chain entanglement to support gel formation and maintain mechanical integrity of the hydrogel network. In some embodiments, the thiolated hyaluronic acid has a molecular weight of approximately 200 kDa, which provides lower solution viscosity and faster diffusion for rapid crosslinking. In other embodiments, the molecular weight is approximately 500 to 800 kDa, providing moderate viscosity suitable for most applications. In further embodiments, the molecular weight is approximately 1000 to 1500 kDa, yielding higher viscosity and increased chain entanglement for enhanced gel strength.

[0034] The degree of thiolation of the hyaluronic acid is in the range of 10 to 30 percent. The degree of thiolation refers to the percentage of disaccharide repeat units that have been modified to incorporate a thiol functional group. This degree of modification provides sufficient reactive sites for crosslinking while maintaining the biocompatibility and hydrophilicity of the hyaluronic acid backbone. In some embodiments, the degree of thiolation is approximately 10%, providing lower crosslinking density and softer gel characteristics. In other embodiments, the degree of thiolation is approximately 20%, offering balanced reactivity and mechanical properties. In further embodiments, the degree of thiolation is approximately 30%, yielding higher crosslinking density and increased gel strength.

[0035] The thiol functional groups are covalently attached to the hyaluronic acid backbone through modification of the hydroxyl groups or carboxyl groups present in the repeating disaccharide units. In some embodiments, the thiol groups are introduced by reaction of hyaluronic acid with a thiolating reagent such as cysteine, homocysteine, thioglycolic acid, or dithiothreitol in the presence of a carbodiimide coupling agent. The thiol groups may be attached via ester linkages to the carboxyl groups of glucuronic acid residues, or via ether or thioether linkages to the hydroxyl groups. The thiol groups remain in the reduced state (-SH) and are protected from oxidation during storage by maintaining the solution under inert atmosphere or by adding reducing agents.

[0036] The second component is formulated at a concentration of 0.5 to 1.5 percent weight per volume (% w / v) in said physiologic buffer solution. This concentration provides sufficient polymer chain density for gel network formation while maintaining injectability. In some embodiments, the second component is formulated at approximately 0.5% w / v, providing lower viscosity for injection through smaller cannulas. In other embodiments, the concentration is approximately 1.0% w / v, offering balanced handling characteristics. In further embodiments, the concentration is approximately 1.5% w / v, yielding faster gelation and higher final gel density.

[0037] The second component is dissolved in the same physiologic buffer solution composition as the first component, with pH maintained at 7.2 to 7.4. The buffer composition ensures compatibility when the two components are mixed, preventing pH shifts or ionic imbalances that could compromise gelation or biocompatibility. The osmolarity of the second component solution is matched to the first component to ensure the final mixed composition maintains physiologic osmolarity.

[0038] When the first component and the second component are combined, they undergo a crosslinking reaction via Michael addition. Michael addition is a chemical reaction in which a nucleophile (the thiol group) adds to an α,β-unsaturated carbonyl compound (the maleimide group). In this reaction, the thiol groups of the thiolated hyaluronic acid attack the electron-deficient carbon-carbon double bond of the maleimide groups, forming a stable carbon-sulfur (C-S) bond. This reaction proceeds spontaneously at physiologic pH and temperature without requiring external catalysts, initiators, or energy input such as heat or ultraviolet light.

[0039] The Michael addition reaction between thiols and maleimides is highly selective and proceeds with excellent conversion efficiency. The reaction creates permanent covalent crosslinks between the multi-arm polyethylene glycol molecules and the hyaluronic acid chains, forming a three-dimensional polymer network that entraps water to create a hydrogel. The crosslinking density is controlled by the molecular weights, concentrations, and degrees of functionalization of the two components. The reaction proceeds at physiologic pH (7.0 to 7.4) and physiologic temperature (approximately 37°C), making it ideal for in-situ formation within the vitreous cavity.

[0040] The resulting in-situ cross-linked hydrogel exhibits properties that closely match those of natural vitreous humor. The hydrogel has a refractive index in the range of 1.336 to 1.340 at a wavelength of 589 nanometers (sodium D-line) at 25°C. This refractive index range is essentially identical to that of natural vitreous humor (approximately 1.336 to 1.340) and aqueous humor (approximately 1.336), ensuring that the implant does not cause optical distortions or interfere with vision. The refractive index is primarily determined by the water content and polymer composition of the hydrogel.

[0041] The in-situ cross-linked hydrogel has a pH in the range of 7.0 to 7.4, which is physiologic and compatible with ocular tissues. The pH is maintained by the buffer system incorporated in both components. In some embodiments, the pH of the fully formed hydrogel is approximately 7.2, closely matching the pH of natural vitreous. The physiologic pH prevents irritation, inflammation, or damage to the retina, lens, or other intraocular structures.

[0042] The in-situ cross-linked hydrogel has an osmolarity in the range of 280 to 310 milliosmoles per kilogram (mOsm / kg). This osmolarity range is isotonic with ocular fluids, preventing osmotic stress on surrounding tissues. Natural vitreous humor has an osmolarity of approximately 300 to 310 mOsm / kg. In some embodiments, the hydrogel osmolarity is approximately 300 mOsm / kg, matching the natural vitreous. The osmolarity is determined by the concentrations of dissolved salts and the polymer components in the buffer solution.

[0043] The in-situ cross-linked hydrogel exhibits optical transmission of at least 95 percent across the visible wavelength range of 400 to 800 nanometers. This high optical transmission ensures that the hydrogel is transparent and does not interfere with the passage of light through the eye to the retina. In some embodiments, the optical transmission is at least 96%, at least 97%, or at least 98% across the visible spectrum. The high transmission is achieved by using fully water-soluble, non-scattering polymer components and ensuring complete dissolution without particulates or aggregates. Natural vitreous humor exhibits optical transmission greater than 98% in the visible range.

[0044] The in-situ cross-linked hydrogel has a density in the range of 0.99 to 1.02 grams per milliliter (g / mL) at 37°C. This density range provides neutral buoyancy, meaning the hydrogel has essentially the same density as the aqueous humor and surrounding ocular fluids. Natural vitreous humor has a density of approximately 1.0053 g / mL. In some embodiments, the hydrogel density is approximately 1.00 g / mL, matching water density. In other embodiments, the density is approximately 1.005 g / mL, closely matching natural vitreous. The neutral buoyancy eliminates the need for postoperative head positioning that is required with silicone oil or gas tamponades, which have significantly different densities than aqueous humor.

[0045] In some embodiments, the crosslinking reaction forms the in-situ cross-linked hydrogel within a time period of 2 to 4 minutes at a temperature of 37°C. This rapid gelation time is clinically advantageous, allowing the surgeon to complete the injection before significant gelation occurs in the delivery cannula, while ensuring the hydrogel solidifies promptly after injection into the vitreous cavity. In some embodiments, the gelation time is approximately 2 minutes, providing rapid stabilization. In other embodiments, the gelation time is approximately 3 minutes, offering more working time for complete injection. In further embodiments, the gelation time is approximately 4 minutes, allowing for larger volume injections or slower injection rates.

[0046] The gelation time is influenced by several factors including the concentrations of the two components, the degrees of functionalization (maleimide substitution and thiol substitution), the molecular weights of the polymers, the pH and temperature of the environment, and the mixing efficiency. The gelation time can be adjusted by modifying these parameters. For instance, higher concentrations or higher degrees of functionalization lead to faster gelation, while lower concentrations or functionalization degrees slow the gelation rate.

[0047] In some embodiments, the in-situ cross-linked hydrogel exhibits a storage modulus in the range of 0.05 to 0.5 Pascals (Pa) at 37°C when measured by oscillatory rheometry. The storage modulus (G') is a measure of the elastic component of the hydrogel's viscoelastic properties and indicates the gel strength. Natural vitreous humor has a storage modulus of approximately 0.1 to 0.3 Pa. In some embodiments, the hydrogel storage modulus is approximately 0.05 Pa, providing a very soft gel similar to aged vitreous. In other embodiments, the storage modulus is approximately 0.2 Pa, closely matching young, healthy vitreous. In further embodiments, the storage modulus is approximately 0.5 Pa, providing increased mechanical support. The storage modulus is controlled by adjusting the crosslinking density through the component concentrations and functionalization degrees.

[0048] In some embodiments, the in-situ cross-linked hydrogel exhibits swelling of less than or equal to 5 percent in physiologic saline at 37°C over a period of 7 days. The swelling ratio is defined as the change in hydrogel volume or weight when immersed in saline solution relative to the initial volume or weight immediately after gelation. Minimal swelling is important to maintain stable volume within the fixed space of the vitreous cavity and to prevent increases in intraocular pressure. In some embodiments, the swelling is less than 3%, ensuring dimensional stability. The low swelling is achieved by appropriate crosslinking density and by using hydrophilic polymers that are already near equilibrium hydration at the time of gelation.

[0049] In some embodiments, the composition further comprises at least one additive selected from the group consisting of antioxidants, nutrients, and therapeutic agents for sustained intraocular delivery. Antioxidants may include compounds such as ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione, or synthetic antioxidants that protect retinal tissues from oxidative stress. Nutrients may include amino acids, glucose, or vitamins that support the metabolic needs of retinal cells. Therapeutic agents may include anti-VEGF (vascular endothelial growth factor) drugs such as ranibizumab, bevacizumab, or aflibercept for treating neovascular age-related macular degeneration or diabetic retinopathy; corticosteroids such as triamcinolone acetonide or dexamethasone for reducing inflammation; antibiotics for preventing or treating endophthalmitis; or neuroprotective agents for preserving retinal ganglion cells.

[0050] When additives are incorporated, they may be dissolved in either the first component, the second component, or both components prior to mixing. In some embodiments, therapeutic agents are dispersed as microparticles or nanoparticles within one or both components to provide controlled release over extended periods of weeks to months. The hydrogel network acts as a drug delivery depot, slowly releasing the therapeutic agent into the vitreous cavity through diffusion and / or hydrogel degradation mechanisms.

[0051] In some embodiments, the in-situ cross-linked hydrogel comprises reversible linkages that permit enzymatic degradation or light-induced dissolution for controlled removal. While the hydrogel is designed for permanent implantation, clinical situations may arise where elective removal is desired. The reversible linkages provide a mechanism for controlled degradation of the hydrogel network. In some embodiments, the reversible linkages comprise ester bonds within the polymer structure that can be hydrolyzed by esterase enzymes. The introduction of an esterase enzyme solution into the vitreous cavity would gradually degrade the crosslinks, converting the solid hydrogel into soluble polymer fragments that can be cleared by natural aqueous turnover.

[0052] In other embodiments, the reversible linkages comprise photodegradable groups that cleave upon exposure to specific wavelengths of light. For example, ortho-nitrobenzyl ester groups incorporated into the crosslinks undergo photochemical cleavage when exposed to ultraviolet or near-ultraviolet light at wavelengths of approximately 365 to 405 nanometers. By directing a focused light source into the vitreous cavity, the surgeon could selectively degrade the hydrogel network to facilitate removal. The photodegradable approach provides spatial and temporal control over the degradation process.

[0053] In some embodiments, both the first component and the second component are pharmaceutically pure and free of human or animal plasma derivatives. Pharmaceutical purity ensures the absence of contaminants, endotoxins, or impurities that could cause adverse reactions. The polyethylene glycol is typically synthesized through chemical polymerization of ethylene oxide, yielding a purely synthetic polymer. The hyaluronic acid may be derived from bacterial fermentation (using Streptococcus species) rather than from animal sources such as rooster combs or bovine vitreous, eliminating concerns about immunogenicity, prion contamination, or variability in source material. The absence of human or animal plasma derivatives makes the composition suitable for patients with religious or ethical objections to animal-derived materials and eliminates the theoretical risk of disease transmission.

[0054] A sterile delivery system is provided for administering the artificial vitreous implant composition into the vitreous cavity during ophthalmic surgery. The delivery system enables precise, controlled mixing and injection of the two reactive components. The delivery system comprises several interconnected elements that work cooperatively to deliver the mixed hydrogel precursor solution into the eye before gelation occurs.

[0055] The delivery system comprises a dual-syringe assembly. The dual-syringe assembly comprises a first syringe and a second syringe that are held in a common housing or frame. The first syringe contains the first component (the multi-arm polyethylene glycol functionalized with maleimide groups dissolved in physiologic buffer), and the second syringe contains the second component (the thiolated hyaluronic acid dissolved in physiologic buffer). The two syringes are positioned parallel to each other and are configured for simultaneous actuation.

[0056] In some embodiments, the first syringe and the second syringe are prefilled and hermetically sealed during manufacturing under aseptic conditions. The prefilled configuration eliminates the need for the surgeon to draw up and mix components at the time of surgery, reducing the risk of contamination and simplifying the surgical workflow. The syringes are packaged in sterile blister packs or trays and are gamma-irradiated or subjected to ethylene oxide sterilization to ensure sterility.

[0057] Each syringe comprises a barrel, a plunger, and a tip. The barrel is a cylindrical chamber that holds the liquid component. The barrel is fabricated from a transparent material such as glass or medical-grade plastic (for example, polypropylene or cyclic olefin copolymer) to allow visual inspection of the contents. The plunger comprises a rubber or elastomeric stopper that seals the barrel and a rod that extends from the stopper for manual actuation. The tip of each syringe comprises a luer-lock or luer-slip fitting that enables connection to other components of the delivery system.

[0058] The dual-syringe assembly includes a mechanical coupling mechanism that synchronizes the actuation of the two plungers. In some embodiments, the coupling mechanism comprises a common actuator block or yoke that engages both plunger rods simultaneously. When the surgeon applies force to the actuator block, both plungers advance at the same rate, ensuring equal volumes of the first component and the second component are delivered. In some embodiments, the coupling mechanism includes a mechanical linkage or gear system that maintains a fixed volumetric ratio between the two syringes, which may be 1:1 or another ratio if different concentrations are used.

[0059] The delivery system further comprises a static mixing element. The static mixing element is a device that combines and mixes the two liquid components as they flow through it, without requiring moving parts or external energy input. The static mixing element is fluidly connected to the first syringe and the second syringe. Specifically, the outlet tips of both syringes are connected to the inlet ports of the static mixing element via tubing or direct luer-lock connections.

[0060] The static mixing element comprises an internal structure designed to induce turbulent flow and intimate mixing of the two component streams. In some embodiments, the static mixing element comprises a series of helical baffles or blades arranged within a cylindrical housing. As the two liquid streams enter the mixing element, they are split, rotated, and recombined multiple times as they pass through the helical elements, resulting in thorough mixing. In other embodiments, the static mixing element comprises a tortuous path with alternating chambers and constrictions that divide and recombine the fluid streams.

[0061] The length and internal geometry of the static mixing element are designed to achieve complete homogenization of the two components within the residence time required for the fluids to flow through the element. In some embodiments, the static mixing element has a length of approximately 20 to 50 millimeters and an internal diameter of approximately 1 to 3 millimeters. The number of mixing elements (helical sections) may range from approximately 6 to 20 elements, depending on the viscosities of the components and the desired mixing efficiency.

[0062] The static mixing element is fabricated from biocompatible, medical-grade materials such as polypropylene, polycarbonate, or stainless steel. The internal surfaces are smooth to minimize dead volumes and prevent fouling or clogging. The static mixing element is designed to provide complete mixing while introducing minimal pressure drop, allowing the surgeon to inject the mixed solution with reasonable manual force.

[0063] The delivery system further comprises an injection cannula. The injection cannula is a hollow needle or tube through which the mixed solution is delivered into the vitreous cavity. The injection cannula is fluidly connected to the static mixing element. Specifically, the outlet of the static mixing element is connected to the proximal end (hub) of the injection cannula via a luer-lock connection or integrated molded junction.

[0064] The injection cannula has a gauge size of 23 to 27 gauge. Gauge size refers to the outer diameter of the cannula, with higher gauge numbers indicating smaller diameters. A 23-gauge cannula has an outer diameter of approximately 0.64 millimeters, a 25-gauge cannula has an outer diameter of approximately 0.51 millimeters, and a 27-gauge cannula has an outer diameter of approximately 0.41 millimeters. These small-gauge sizes enable minimally invasive injection through self-sealing sclerotomy incisions that do not require suturing.

[0065] In some embodiments, the injection cannula is a 23-gauge cannula, providing sufficient internal diameter for low-resistance flow of the mixed solution while requiring only a small incision. In other embodiments, a 25-gauge cannula is used, offering a balance between flow characteristics and incision size. In further embodiments, a 27-gauge cannula is used for maximum minimally-invasive access, though requiring slightly higher injection pressure due to the smaller internal diameter.

[0066] The injection cannula has a length sufficient to reach from the external eye surface through the sclera and pars plana region into the vitreous cavity. In some embodiments, the cannula length is approximately 15 to 25 millimeters. The distal tip of the cannula (the end that enters the eye) may be beveled at an angle, such as approximately 45 degrees, to facilitate penetration through the sclera. Alternatively, the cannula may be inserted through a pre-placed trocar or valved cannula system commonly used in vitreoretinal surgery.

[0067] The injection cannula is fabricated from medical-grade stainless steel, titanium alloy, or rigid polymer materials. The internal lumen is smooth-bored to minimize flow resistance and prevent clogging. The cannula is designed to maintain patency throughout the injection process, which typically lasts approximately 30 seconds to 2 minutes depending on the volume being injected (typically 3 to 5 milliliters for an adult human vitreous cavity).

[0068] The dual-syringe assembly, the static mixing element, and the injection cannula are configured for single-use application. Single-use design ensures sterility, prevents cross-contamination between patients, and eliminates the need for reprocessing or sterilization. After the injection procedure is completed, the entire delivery system is discarded as medical waste. The single-use configuration simplifies inventory management and reduces the risk of device malfunction due to repeated use or inadequate cleaning.

[0069] In some embodiments, the entire delivery system is provided as an integrated assembly in which the syringes, static mixing element, and injection cannula are permanently connected or molded as a single unit. This integrated design eliminates the need for assembly by the surgeon and reduces the risk of connection failures or leakage during injection. The integrated assembly is packaged in a sterile tray or pouch and is ready for immediate use upon opening.

[0070] In alternative embodiments, the delivery system components are provided as separate sterile items that are assembled by the surgeon or surgical staff immediately prior to use. For example, the prefilled syringes may be connected to the static mixing element, and the injection cannula may be attached to the mixing element outlet, using sterile technique. This modular approach provides flexibility in selecting different cannula sizes based on the specific surgical approach.

[0071] The spatial arrangement of the delivery system components ensures efficient fluid flow and mixing. The first syringe and the second syringe are positioned parallel to each other, with their longitudinal axes aligned and their tips oriented in the same direction. The static mixing element is positioned at the distal end of the dual-syringe assembly, receiving input flows from both syringes at its proximal end. The injection cannula extends distally from the static mixing element, providing a linear flow path from the mixing element outlet to the intraocular target site.

[0072] The flow path through the delivery system is continuous and unobstructed. Fluid flows from the syringe barrels, through the syringe tips, into the static mixing element inlets, through the mixing element internal geometry, out the mixing element outlet, through the cannula lumen, and out the cannula tip into the vitreous cavity. The total internal volume of the flow path (excluding the syringe barrels) is minimized to reduce waste of the reactive components and to ensure that the mixed solution exits the cannula before significant gelation occurs.

[0073] In alternative embodiments, the delivery system may incorporate additional features for enhanced control or safety. For example, a pressure gauge or force indicator may be integrated into the actuator mechanism to provide feedback to the surgeon about the injection pressure. Excessive pressure could indicate cannula occlusion or highly viscous mixed solution, alerting the surgeon to potential problems.

[0074] In some embodiments, the delivery system includes a flow control mechanism such as a valve or adjustable restrictor that allows the surgeon to modulate the injection rate. Slower injection rates provide more time for the mixed solution to flow into all regions of the vitreous cavity before gelation begins, while faster injection rates reduce the overall procedure time.

[0075] In further embodiments, the delivery system may include volumetric indicators or graduations on the syringe barrels to allow the surgeon to monitor the amount of material injected. Typical fill volumes for vitreous replacement range from approximately 3 to 5 milliliters for adult human eyes, representing approximately 90 to 95 percent of the vitreous cavity volume. Partial filling strategies may be employed for specific clinical situations, and volumetric monitoring enables precise control.

[0076] Referring now to Figure 1, a flowchart illustrating a method (100) for preparing an artificial vitreous implant in situ is shown, in accordance with embodiments of the present invention. The method (100) describes the operational sequence performed by an ophthalmic surgeon during vitreoretinal surgery to replace the natural vitreous with the artificial hydrogel implant.

[0077] At step (102), the method (100) includes providing a first sterile component comprising a multi-arm polyethylene glycol functionalized with maleimide groups having a molecular weight of 20-40 kDa at a concentration of 2-4% w / v in a physiologic buffer solution having a pH of 7.2-7.4. This step involves obtaining the first component in sterile, ready-to-use form. In some embodiments, the first component is provided in a prefilled syringe that has been manufactured under aseptic conditions and sterilized. The surgeon removes the prefilled syringe from its sterile packaging and inspects it for any defects, particulates, or discoloration. The syringe is brought to ambient temperature or warmed slightly to approximately 25 to 37°C to ensure optimal viscosity for injection.

[0078] At step (104), the method (100) includes providing a second sterile component comprising thiolated hyaluronic acid having a molecular weight of 200-1500 kDa with a degree of thiolation of 10-30% at a concentration of 0.5-1.5% w / v in said physiologic buffer solution. Similar to step (102), this step involves obtaining the second component in sterile, prefilled form. The second component syringe is removed from sterile packaging, inspected, and prepared for use. Both components are maintained separate until the moment of injection to prevent premature mixing and gelation.

[0079] In some embodiments, the first sterile component and the second sterile component are provided as part of the integrated dual-syringe delivery system described previously. In this case, steps (102) and (104) are combined, as both components are present in the same sterile package as a ready-to-use device. The surgeon removes the entire delivery system from its packaging, inspects it, and proceeds to the next steps.

[0080] At step (106), the method (100) includes performing a pars plana vitrectomy on an eye of a patient to create a vitreous cavity. Pars plana vitrectomy is a standard vitreoretinal surgical procedure in which the natural vitreous humor is removed from the eye. The procedure is typically performed using a three-port approach, with small-gauge (23, 25, or 27 gauge) trocars inserted through the pars plana region, which is the flat portion of the ciliary body located approximately 3 to 4 millimeters posterior to the limbus (the junction between cornea and sclera).

[0081] During vitrectomy, a vitreous cutter instrument is inserted through one trocar port. The vitreous cutter comprises a guillotine-type cutting mechanism that aspirates and simultaneously cuts the vitreous gel into small fragments that are removed from the eye. The surgeon systematically removes the vitreous from all regions of the vitreous cavity, including the central vitreous, peripheral vitreous, and vitreous base. Infusion of balanced salt solution through another port maintains intraocular pressure and replaces the volume of vitreous removed. Any remaining vitreous attachments to the retina or other structures are carefully dissected to achieve complete vitreous removal.

[0082] Following complete vitrectomy, the vitreous cavity is a fluid-filled space bounded anteriorly by the lens (in phakic eyes) or the posterior capsule (in pseudophakic eyes after cataract surgery), and posteriorly by the retina. The cavity volume in an adult human eye is typically approximately 4 to 5 milliliters. The cavity is filled with balanced salt solution at this stage. Any additional surgical procedures required for the underlying pathology, such as membrane peeling, laser photocoagulation, or treatment of retinal breaks, are completed during this step before proceeding to hydrogel injection.

[0083] At step (108), the method (100) includes simultaneously delivering said first sterile component and said second sterile component through a static mixing element to combine said first sterile component and said second sterile component into a mixed solution. This step represents the initiation of hydrogel formation. The surgeon connects the injection cannula of the delivery system to one of the vitrectomy ports or inserts it through a separate sclerotomy incision into the vitreous cavity. The distal tip of the injection cannula is positioned within the vitreous cavity, directed toward a central or posterior location to allow filling from the back of the eye forward.

[0084] The surgeon then actuates the dual-syringe assembly by applying steady, continuous pressure to the plunger mechanism. As pressure is applied, equal volumes of the first component from the first syringe and the second component from the second syringe are expelled and flow into the static mixing element. Within the static mixing element, the two component streams are intimately mixed through the turbulent flow patterns created by the internal mixing geometry. The thiol groups of the thiolated hyaluronic acid begin reacting with the maleimide groups of the multi-arm polyethylene glycol via Michael addition chemistry, initiating crosslink formation.

[0085] The mixed solution exits the static mixing element and flows through the injection cannula lumen. At this stage, the mixed solution is still a viscous liquid, as only initial crosslinking has occurred. The gelation time of 2 to 4 minutes provides a working window during which the solution remains injectable. The surgeon continues steady injection while observing the fill of the vitreous cavity through the surgical microscope.

[0086] At step (110), the method (100) includes injecting said mixed solution through a 23-27 gauge cannula into said vitreous cavity to fill approximately 90-95% of said vitreous cavity. This step involves controlled delivery of a predetermined volume of the mixed solution into the eye. The surgeon continues the injection initiated in step (108), filling the vitreous cavity from posterior to anterior. As the mixed solution enters the cavity, it displaces the balanced salt solution that was present after vitrectomy. The balanced salt solution is allowed to exit through one of the vitrectomy ports or is actively aspirated to prevent overfilling and elevation of intraocular pressure.

[0087] The target fill volume is approximately 90 to 95 percent of the total vitreous cavity volume. Complete 100% filling is not performed to avoid excessive pressure on the lens or retina. In an adult human eye with a typical vitreous cavity volume of approximately 4.5 milliliters, the surgeon injects approximately 4.0 to 4.3 milliliters of the mixed solution. The remaining 5 to 10 percent of the cavity volume accommodates the expansion or contraction of the hydrogel during gelation and accounts for slight variations in cavity volume between patients.

[0088] The injection rate is controlled by the force applied to the syringe plungers and by the internal diameter and length of the injection cannula. Typical injection rates range from approximately 0.5 to 2.0 milliliters per minute, with total injection time for a full vitreous cavity fill ranging from approximately 2 to 8 minutes. The surgeon monitors the filling progress visually and adjusts the injection rate as needed.

[0089] In some embodiments, the injection is performed with the cannula tip initially positioned posteriorly near the optic nerve head or macula, and the cannula is gradually withdrawn toward the anterior cavity as injection proceeds. This technique ensures complete filling of the posterior cavity, which is the most critical region for retinal support. In other embodiments, the injection is performed with the cannula tip held at a fixed central location, allowing the solution to flow naturally to all regions of the cavity.

[0090] Upon completion of the desired fill volume, the surgeon stops applying pressure to the syringe plungers and carefully withdraws the injection cannula from the eye. The sclerotomy incision through which the cannula was inserted is typically self-sealing due to the small gauge size (23-27 gauge). If necessary, the incision may be secured with a single suture or with light cautery. The vitrectomy port trocars are removed and the sclerotomy sites are inspected to ensure they are sealed. The conjunctiva is repositioned over the sclerotomy sites.

[0091] At step (112), the method (100) includes allowing said mixed solution to undergo crosslinking via Michael addition within 2-4 minutes at body temperature to form an in-situ cross-linked hydrogel having a refractive index of 1.336-1.340, a pH of 7.0-7.4, an osmolarity of 280-310 mOsm, optical transmission of at least 95%, and a density of 0.99-1.02 g / mL. This step occurs spontaneously after injection and does not require any action by the surgeon beyond waiting for the gelation to complete.

[0092] The crosslinking reaction via Michael addition between the thiol groups and the maleimide groups continues at an accelerated rate after injection, as the high surface area mixing and body temperature (approximately 37°C) optimize the reaction kinetics. The surgeon can observe the gelation process through the surgical microscope as the mixed solution transitions from a mobile liquid to a stable gel. The gel becomes progressively more viscous and eventually solidifies into a non-flowing hydrogel that maintains its shape and position within the vitreous cavity.

[0093] The gelation time of 2 to 4 minutes is measured from the moment of mixing (step 108) to the point at which the material no longer flows under gravity. In some embodiments, the gel point (defined as the time when storage modulus G' equals loss modulus G'' in rheological measurements) occurs at approximately 1 to 2 minutes, with full gelation and stabilization complete by 2 to 4 minutes. By the time the surgeon has withdrawn the cannula and closed the incisions (steps following injection), the hydrogel has typically reached sufficient gel strength to provide retinal support.

[0094] The in-situ cross-linked hydrogel formed through this process exhibits all the properties specified in the composition claims. The hydrogel has a refractive index of 1.336 to 1.340, ensuring it is optically compatible with the ocular media and does not cause visual distortion or aberrations. The pH of 7.0 to 7.4 prevents any chemical irritation or alteration of the intraocular environment. The osmolarity of 280 to 310 mOsm prevents osmotic stress on retinal cells or other tissues. The optical transmission of at least 95% across the visible spectrum (400 to 800 nm) ensures the hydrogel is transparent and allows clear visualization of the retina during subsequent examinations and does not interfere with the patient's vision.

[0095] The density of 0.99 to 1.02 g / mL provides neutral buoyancy, meaning the hydrogel neither floats anteriorly toward the lens (as low-density materials like gas or silicone oil do) nor sinks posteriorly (as heavy silicone oils do). The neutral buoyancy eliminates the need for postoperative head positioning requirements that are mandatory with other vitreous substitutes. The patient can assume any head position immediately after surgery without concern that the tamponade material will shift away from the target tissue.

[0096] The method (100) achieves the objective stated in the method claim preamble: preparing an artificial vitreous implant in situ. The resulting hydrogel provides long-term tamponade without requiring postoperative positioning or subsequent removal. The hydrogel remains in place indefinitely, providing continuous support to the retina and maintaining the structural integrity of the globe. Unlike temporary tamponades such as silicone oil or gas, which must be removed or which dissipate over time, the crosslinked hydrogel is stable for years to decades within the intraocular environment.

[0097] In alternative method embodiments, the injection technique may be modified to accommodate specific clinical scenarios. For example, in cases of inferior retinal detachment, the injection may be performed with the patient's head tilted to position the inferior retina in a dependent location, ensuring that the mixed solution flows to the area of pathology. In cases of macular holes, the injection may be performed to create a slight overfill in the posterior pole region, providing enhanced tamponade pressure on the macular region.

[0098] In some embodiments, the method includes a pause step between vitrectomy (step 106) and injection (steps 108-110), during which additional surgical manipulations are performed. For example, if the retina has a tear or hole, the surgeon may apply endolaser photocoagulation around the break to create a chorioretinal adhesion before injecting the hydrogel. Similarly, if proliferative membranes or epiretinal membranes are present, these may be peeled or excised before hydrogel injection.

[0099] In further embodiments, the method may include injection of a therapeutic agent either before or after the hydrogel injection. For instance, an intravitreal injection of an anti-VEGF drug may be performed at the conclusion of the surgery to address neovascularization. Alternatively, the therapeutic agent may be incorporated directly into the hydrogel components as described previously, eliminating the need for a separate injection.

[00100] The present invention provides technical advancement in the field of ophthalmic surgical materials and vitreous substitutes. The disclosed composition addresses limitations of existing vitreous replacement materials, which typically require removal surgery (silicone oils), impose strict postoperative positioning requirements (gas tamponades), or have complex implantation procedures with limited availability (foldable capsular bodies). Existing vitreous substitutes also fail to adequately match the optical properties of natural vitreous, with refractive indices ranging from 1.40 for silicone oil to 1.00 for gas, compared to the native vitreous refractive index of approximately 1.336 to 1.340.

[00101] In particular, the present invention provides a two-component injectable hydrogel system based on thiol-maleimide crosslinking chemistry, which offers improvements in optical clarity, refractive index matching, neutral buoyancy, biocompatibility, and long-term stability. By implementing a crosslinking reaction that proceeds via Michael addition at physiologic pH and temperature without external initiators or catalysts, the disclosed composition enables in-situ gelation within the vitreous cavity with precise control over gelation kinetics.

[00102] The technical contribution lies in the specific combination of multi-arm polyethylene glycol functionalized with maleimide groups and thiolated hyaluronic acid at defined molecular weight ranges, concentrations, and degrees of functionalization. Unlike conventional approaches that employ single-component hydrogels, collagen-based materials subject to enzymatic degradation, or synthetic polymers with inappropriate optical or mechanical properties, the present invention achieves permanent vitreous replacement through a covalently crosslinked network that matches all critical parameters of natural vitreous.

[00103] For example, in some embodiments, the hydrogel exhibits a refractive index of 1.336 to 1.340, optical transmission exceeding 95%, storage modulus of 0.05 to 0.5 Pa, and neutral buoyancy with density of 0.99 to 1.02 g / mL, all of which closely match natural vitreous properties. This represents a technical advancement in vitreoretinal surgery with applications in treating retinal detachment, proliferative vitreoretinopathy, macular holes, and traumatic vitreous loss. Additionally, the rapid gelation time of 2 to 4 minutes with controlled initiation only upon mixing provides surgical handling characteristics superior to materials that gel too quickly (making injection difficult) or too slowly (allowing material migration before stabilization).

[00104] The use of fully synthetic, non-animal-derived materials (synthetic polyethylene glycol and bacterially-derived hyaluronic acid) ensures batch-to-batch reproducibility, eliminates immunogenicity concerns, and removes the risk of prion or viral contamination associated with animal-derived collagens or other biological materials. The optional incorporation of reversible linkages provides a safety mechanism for elective removal if clinically necessary, while the default configuration provides permanent support without degradation.

[00105] The foregoing description presents exemplary embodiments for purposes of illustration and enablement. The invention is not limited to the precise forms disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention, and may be made without departing from the scope of the appended claims. The embodiments were selected to explain principles and practical applications, enabling others skilled in the art to utilize the invention in various embodiments and with various modifications as suited to the particular use contemplated. The scope of the invention is defined by the appended claims and their equivalents.

Claims

1. An artificial vitreous implant composition comprising: a first component comprising a multi-arm polyethylene glycol functionalized with maleimide groups having a molecular weight of 20-40 kDa at a concentration of 2-4% w / v in a physiologic buffer solution having a pH of 7.2-7.4; and a second component comprising thiolated hyaluronic acid having a molecular weight of 200-1500 kDa with a degree of thiolation of 10-30% at a concentration of 0.5-1.5% w / v in said physiologic buffer solution; wherein said first component and said second component, when combined, undergo a crosslinking reaction via Michael addition to form an in-situ cross-linked hydrogel having a refractive index of 1.336-1.340, a pH of 7.0-7.4, an osmolarity of 280-310 mOsm, an optical transmission of at least 95% across 400-800 nm wavelength range, and a density of 0.99-1.02 g / mL.

2. The composition of claim 1, wherein said multi-arm polyethylene glycol is a four-arm polyethylene glycol.

3. The composition of claim 1, wherein said physiologic buffer solution is a HEPES-balanced salt solution.

4. The composition of claim 1, wherein said crosslinking reaction forms said in-situ cross-linked hydrogel within 2-4 minutes at a temperature of 37°C.

5. The composition of claim 1, wherein said in-situ cross-linked hydrogel exhibits a storage modulus of 0.05-0.5 Pa at 37°C and swelling of less than or equal to 5% in physiologic saline at 37°C over 7 days.

6. The composition of claim 1, further comprising at least one additive selected from the group consisting of antioxidants, nutrients, and therapeutic agents for sustained intraocular delivery.

7. The composition of claim 1, wherein said in-situ cross-linked hydrogel comprises reversible linkages that permit enzymatic degradation or light-induced dissolution for controlled removal.

8. The composition of claim 1, wherein said first component and said second component are pharmaceutically pure and free of human or animal plasma derivatives.

9. A sterile delivery system for administering the composition of claim 1, said delivery system comprising: a dual-syringe assembly comprising a first syringe containing said first component and a second syringe containing said second component; a static mixing element fluidly connected to said first syringe and said second syringe, wherein said static mixing element combines said first component and said second component to form a mixed solution; and an injection cannula having a gauge size of 23-27 gauge fluidly connected to said static mixing element, wherein said injection cannula delivers said mixed solution into a vitreous cavity of an eye; wherein said dual-syringe assembly, said static mixing element, and said injection cannula are configured for single-use application.

10. A method (100) of preparing an artificial vitreous implant in situ, the method comprising: providing (102) a first sterile component comprising a multi-arm polyethylene glycol functionalized with maleimide groups having a molecular weight of 20-40 kDa at a concentration of 2-4% w / v in a physiologic buffer solution having a pH of 7.2-7.4; providing (104) a second sterile component comprising thiolated hyaluronic acid having a molecular weight of 200-1500 kDa with a degree of thiolation of 10-30% at a concentration of 0.5-1.5% w / v in said physiologic buffer solution; performing (106) a pars plana vitrectomy on an eye of a patient to create a vitreous cavity; simultaneously delivering (108) said first sterile component and said second sterile component through a static mixing element to combine said first sterile component and said second sterile component into a mixed solution; injecting (110) said mixed solution through a 23-27 gauge cannula into said vitreous cavity to fill approximately 90-95% of said vitreous cavity; and allowing (112) said mixed solution to undergo crosslinking via Michael addition within 2-4 minutes at body temperature to form an in-situ cross-linked hydrogel having a refractive index of 1.336-1.340, a pH of 7.0-7.4, an osmolarity of 280-310 mOsm, optical transmission of at least 95%, and a density of 0.99-1.02 g / mL; wherein said in-situ cross-linked hydrogel provides long-term tamponade without requiring postoperative positioning or subsequent removal.