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WO2006031358A2 - Polymeres dendritiques, gels reticules, et leurs utilisations comme agents de scellement et lentilles ophtalmiques - Google Patents

Polymeres dendritiques, gels reticules, et leurs utilisations comme agents de scellement et lentilles ophtalmiques Download PDF

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Publication number
WO2006031358A2
WO2006031358A2 PCT/US2005/029097 US2005029097W WO2006031358A2 WO 2006031358 A2 WO2006031358 A2 WO 2006031358A2 US 2005029097 W US2005029097 W US 2005029097W WO 2006031358 A2 WO2006031358 A2 WO 2006031358A2
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WO2006031358A3 (fr
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Mark W. Grinstaff
Michael A. Carnahan
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Hyperbranch Medical Technology, Inc.
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Publication of WO2006031358A2 publication Critical patent/WO2006031358A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J189/00—Adhesives based on proteins; Adhesives based on derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J201/00—Adhesives based on unspecified macromolecular compounds
    • C09J201/005—Dendritic macromolecules

Definitions

  • Dendritic Polymers Crosslinked Gels, and Their Uses as Ophthalmic Sealants and Lenses
  • Ophthalmic sealants and adhesives play an important role in helping patients recover from eye surgery or eye trauma.
  • Ophthalmic sealants and adhesives are useful in treating patients suffering from a variety of ophthalmic conditions, including corneal lacerations, retinal tears, corneal transplants, and cataract procedures. These dendritic polymers and crosslinked gels are also useful as a lens replacement material, a lens substitute material, and an intaocular lens. A discussion of each of these conditions is presented below.
  • Corneal perforations are produced by a variety of medical conditions (e.g., infection, inflammation, xerosis, neurotrophication, and degeneration) and traumas (chemical, thermal, surgical, and penetrating).
  • corneal perforations often lead to loss of vision and a decrease in an individual's quality of life.
  • different treatments are currently available from suturing the wound to a cornea graft.
  • the surgical procedures are difficult given the delicate composition of the cornea and the severity of the wound which increase the likelihood for leakage and severe astigmatism after surgery.
  • tissue adhesives glues
  • the criteria for an adhesive are to: 1) bind to the tissue (necrosed or not, very often wet) with an adequate adhesion force; 2) be non-toxic; 3) be biodegradable or resorbable; 4) be sterilizable; and 5) not interfere with the healing process.
  • alkyl-cyanoacrylates are available for the repair of small perforations.
  • these "super glues” present major inconveniences.
  • Their monomers, in particular those with short alkyl chains, can be toxic with formation of formaldehyde. They also polymerize too quickly leading to applications that might be difficult and, once polymerized, the surface of the glue is rough and hard which leads to patient discomfort and a need to wear contact lens.
  • cyanoacrylate is tolerated as a corneal sealant, a number of complications have been reported including cataract formation, corneal infiltration, glaucoma, giant papillary conjunctivitis, and symblepharon formation.
  • Adhesive hemostats based on fibrin, are usually constituted of fibrinogen, thrombin and factor XIII. Systems with fibrinogen and photosensitizers activated with light are also being tested. If adhesive hemostats have intrinsic properties which meet the requirements for a tissue adhesive, autologous products (time consuming in an emergency) or severe treatments before clinical use are needed to avoid any contamination to the patient.
  • An ideal sealant for corneal perforations should 1) not impair normal vision, 2) quickly restore the intraocular pressure, IOP, 3) maintain the structural integrity of the eye, 4) promote healing, 5) adhere to moist tissue surfaces, 6) possess solute diffusion properties which are molecular weight dependent and favorable for normal cornea function, 7) possess rheological properties that allow for controlled placement of the polymer on the wound, and 8) polymerize under mild conditions.
  • sutures have limitations and drawbacks.
  • suture placement itself inflicts trauma to corneal tissues, especially when multiple passes are needed.
  • sutures such as 10-0 nylon (which is the suture of choice in the cornea as well as other in vivo area) can act as a nidus for infection and incite corneal inflammation and vascularization. With persistent inflammation and vascularization, the propensity for corneal scarring increases.
  • corneal suturing often yields uneven healing and resultant regular and irregular astigmatism. Postoperatively, sutures are also prone to becoming loose and/or broken and require additional attention for prompt removal.
  • effective suturing necessitates an acquired technical skill that can vary widely from surgeon to surgeon and can also involve prolonged operative time.
  • a corneal transplant or penetrating keratoplasty surgery the diseased cornea is removed with a special round cutting tool called a trephine.
  • the donor cornea is cut to a matching size. Then, the donor cornea is placed upon the eye and secured in place with approximately 16 sutures around the transplant to secure the new cornea in place.
  • a sutureless procedure would therefore be highly desirable and would offer the following advantages: (1) sutures provide a site for infection, (2) the sutured cornea takes 3 months to heal before the sutures need to be removed, and (3) the strain applied to the new cornea tissue from the sutures can distort the cornea.
  • An ocular adhesive may also serve as an adjuvant to sutures and/or reduce the necessary number of sutures.
  • phacoemulsification Clear corneal incisions in the temporal cornea offer several advantages with phacoemulsification.
  • the major advantage associated with phacoemulsification is the reduction in size of the entrance wound. Smaller wounds require fewer sutures or even no sutures at all, minimizing induction of astigmatism, decreasing bleeding and subconjunctival hemorrhage, and speeding the recovery of visual acuity. See Agapitos, P. J. Curr. Opin. Ophthalmol. 1993, 4, 39-43 and LyIe, W. A.; Jin, G. J. J. Cataract Refract. Surg. 1996, 22, 1456-1460.
  • OCT optical coherence tomography
  • Laser-assisted in situ keratomileusis is the popular refractive surgical procedure where a thin, hinged corneal flap is created by a microkeratome blade. This flap is then moved aside to allow an excimer laser beam to ablate the corneal stromal tissue with extreme precision for the correction of myopia (near-sightedness) and astigmatism. At the conclusion of the procedure, the flap is then repositioned and allowed to heal. However, with trauma, this flap can become dislocated prior to healing, resulting in flap striae (folds) and severe visual loss. When this complication occurs, treatment involves prompt replacement of the flap and flap suturing.
  • sutures has limitations and drawbacks as discussed above. These novel adhesives could also play a useful role in the treatment of LASIK flap dislocations and striae (folds). These visually debilitating flap complications are seen not uncommonly following the popular procedure LASIK, and are currently treated by flap repositioning and suturing (which require considerable operative time and technical skill). A tissue adhesive could provide a more effective means to secure the flap. Refractive surgery - Lens Replacement
  • Cataracts or other diseases or injuires that lead to poorly functioning or damaged lens require the natural lens to be replaced.
  • the optical properties of the normal eye lens are the consequence of a high concentration of proteins called "crystallins" forming a natural hydrogel.
  • crystallins proteins that form a natural hydrogel.
  • the anatomical basis of accommodation includes the lens substance, lens capsule, zonular fibers, ciliary muscle and the elastic part of the choroid. Accommodation occurs through accurately controlled adjustments in the shape and thickness of the lens.
  • the capsular bag is essential in transmitting the various extralenticular forces to the lens substance.
  • Modern cataract surgery can be done through a small incision (usually 2.5-3.5 mm). Once the incision is made, the anterior chamber is filled with a viscoelastic and the capsular bag is pricked with a needle. From this incision, a small continuous circular capsulorhexis (CCC) approximately 1.5 mm in diameter is performed using capsulorhexis forceps. Next endocapsular phacoemulsification is performed and the lens epithelial cells are removed by aspiration. http://deiJts.washington.edu/ophthweb/foldedIOLpic.htmlThe nornial function of the lens is to focus light onto the retina.
  • CCC circular capsulorhexis
  • intraocular lens Since removing the cataract leaves the eye without a lens to focus light, an artificial (intraocular) lens is commonly placed inside the eye. Most intraocular lenses are made of plastic, silicone, or acrylic compounds; have no moving parts; and last for the remainder of a person's life. These intraocular lens implants are held in place by the posterior capsule are not able to provide ocular accommodation. http ://depts.washington.edu/ophth web/unfolded IOLpichtmlhttp ://depts. Washington .e du/ophthweb/capsulotpk.htmlRefilling the lens capsule with in situ crosslinking materials described herein offers the potential to produce a synthetic hydrogel with mechanical properties similar to the lens of a twenty year old.
  • the invention describes materials that reproduce the properties of the natural lens and these synthetic hydro gels maintain the integrity of the capsule to gain partial or full accommodation and restore vision to the patient.
  • the dendritic polymers of said invention are incorporated in current IOL materials such as PMMA to alter hydrophilicity, water transport, refractive index, mechanical properties or biological response. Retina - Retinal Holes
  • the polymerization can be slowed down by adding iophendylate to the monomers but still the reaction occurs in two to three seconds. Risks of retinal tear at the edge of the treated hole can also be observed because of the hardness of cyanoacrylate once polymerized.
  • the vitreous is a normally clear, gel-like substance that fills the center of the eye. It makes up approximately 2/3 of the eye's volume, giving it form and shape before birth. Certain problems affecting the back of the eye may require a vitrectomy, or surgical removal of the vitreous.
  • a vitrectomy the surgeon creates small incisions/punctures in the eye (sclerotomies) for separate instruments. These incisions are placed in the pars plana of the eye, which is located just behind the iris but in front of the retina.
  • the instruments which pass through these incisions include a light pipe, an infusion port, and the vitrectomy cutting device.
  • each sclerotomy site is closed with a single interrupted suture of 8-0 silk or 7-0 polyglycolic acid suture.
  • the eye is filled with fluid until the vitreous is replaced as the eye secretes aqueous and nutritive fluids.
  • Glaucoma - Leaking Bleb Some of the most common eye conditions that require vitrectomy include 1) complications from diabetic retinopathy such as retinal detachment or bleeding, 2) macular hole 3) retinal detachment, 4) pre-retinal membrane fibrosis, 5) bleeding inside the eye (vitreous hemorrhage), 6) injury or infection, or 7) certain problems related to previous eye surgery. Glaucoma - Leaking Bleb
  • Leaking filtering blebs after glaucoma surgery are difficult to manage and can lead to serious, vision-threatening complications. Leaking blebs can result in hypotony and shallowing of the anterior chamber, choroidal effusion, maculopathy, retinal, and choroidal folds, suprachoroidal hemorrhage, corneal decompensation, peripheral anterior synechiae, and cataract formation. A leaking bleb can also lead to the loss of bleb function and to the severe complications of endophthalmaitis. The incidence of bleb leaks increases with the use of antimetabolites. Bleb leaks in eyes treated with 5-fluorouracil or mitomycin C may occur in as many as 20 to 40% of patients.
  • Bleb leaks in eyes treated with antimetabolities may be difficult to heal because of thin avascular tissue and because of abnormal fibrovascular response. If the leak persists despite the use of conservative management, a 9-0 to 10-0 nylon or absorbable suture on a tapered vascular needle can be used to close the conjunctival wound. In a thin-walled or avascular bleb, a suture may not be advisable because it could tear the tissue and cause a larger leak.
  • Fibrin adhesives have been used to close bleb leaks. The adhesive is applied to conjunctival wound simultaneously with thrombin to form a fibrin clot at the application site. The operative field must be dry during the application because fibrin will not adhere to wet tissue.
  • Cyanoacrylate glue may be used to close a conjuctival opening.
  • the surrounding tissue must be dried and a single drop of the cyanoacrylate is placed.
  • the operative must be careful not to seal the applicator to the tissue or to seal surrounding tissue with glue given its quick reaction.
  • a soft contact lens is then applied over the glue to decrease patient discomfort.
  • this procedure can actually worsen the problem if the cyanoacrylate tears from the bleb and causes a larger wound.
  • Blepharoplasty is an operation to remove excess skin, fat and muscle from around the eyes to correct droopy eyelids and bagginess under the eyes. It can be performed on the upper lids and lower lids, at the same time or separately. The operation may be done using either conventional or laser techniques. For surgery on the upper eyelids, cuts are made into the natural lines and creases in the lid, and into the laughter lines at the corner of the eye. For surgery on the lower eyelids, a cut is usually made just below the eyelashes. This means the scars run along the eye's natural folds, concealing them as much as possible. Excess fat, muscle and loose skin are removed, and the cut is closed using sutures . If only fat is being removed, sometimes the cut is made on the inside of the lower eyelid, leaving no visible scar. A tissue adhesive could provide a more effective means to secure the cuts made during surgery.
  • the present invention generally relates to methods of sealing a wound or creating a lens.
  • the wound is an ophthalmic wound
  • the compositions used to seal the wound comprise a dendrimer.
  • the dendritic polymers have an acrylate group attached at the periphery of the dendrimer. Treatment of the acrylate-capped dendritic polymers with ultraviolet radiation causes the dendritic polymers to polymerize forming a seal.
  • the dendritic polymers have a lysine, cysteine, isocysteine residue or other nucleophilic group attached to the periphery of the dendrimer.
  • compositions used to seal the wound comprise a compound that has a polylysine core to which cysteine, isocysteine, or other nucleophilic groups are attached.
  • Addition of a compound containing two or more electrophilic groups such as aldehydes, activated esters, or acrylates to the cysteine- or isocysteine-capped polylysine compounds produces a polymeric compound that can form a seal.
  • the dendritic polymer may be functionalized with electrophilic groups, and then treated with a compound comprising nucleophilics groups in order to form a sealant.
  • a synthetic lens made using the dendritic polymers of the invention.
  • a synthetic lens is formed and used in an ophthalmic procedure.
  • the compositions used to form the lens comprise a dendrimer for replacement or substitution of a natural lens.
  • the dendrimer has an acrylate group attached at the periphery of the dendrimer. Treatment of the acrylated-capped dendrimers with ultraviolet radiation causes the dendrimers to polymerize forming a hydrogel lens material.
  • the dendritic polymers have a lysine, cysteine, or isocysteine residue or other nucleophilic group attached to the periphery of the dendrimer.
  • compositions used to form the lens comprise a compound that has a polylysine core to which cysteine or isocysteine groups or other nucleophilic groups are attached.
  • Addition of a compound containing an electrophilic group such as an aldehyde, activated ester, or acrylate to the cysteine- or isocysteinecapped polylysine compounds produces a hydrogel lens material.
  • the dendritic polymer may be functionalized with electrophuic groups, and then treated with a compound comprising nucleophilics groups in order to form a lens.
  • Another aspect of the invention relates to pharmaceutical compositions comprising the dendritic macromolecules of the invention.
  • the pharmaceutical compositions comprise a dendritic macromolecule containing a polylysine core.
  • Another aspect of the invention relates to a method of treating disease using the pharmaceutical compositions of the invention.
  • Another aspect of the invention relates to kits for sealing a wound or preparing a lens.
  • Other aspects of the invention relate to delivery devices and methods for controlling the polymerization of a hydrogel system.
  • Figure 1 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 2 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 3 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 4 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 5 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 6 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 7 depicts various monomers that can be used to prepare dendrimers used in the invention.
  • Figure 8 depicts a dendrimer terminated with nucleoside groups amenable to the invention.
  • Figure 9 depicts dendrimers and compounds useful for making dendrimers amenable to the present invention.
  • Figure 10 depicts a double-acting, single-barrel syringe.
  • Figure 11 depicts a double-barrel syringe.
  • One aspect of the present invention relates to clinical treatments, such as sealing or repairing ophthalimic wounds or incisions created during an ophthalmic surgery.
  • the present invention is specifically embodied in the use of novel crosslinkable polymers, such as dendritic macromolecules and their in vitro, in vivo, and in situ uses.
  • novel crosslinkable polymers such as dendritic macromolecules and their in vitro, in vivo, and in situ uses.
  • These biomaterials/polymers are likely to be an effective sealant/glue for other surgical procedures where the site of the wound is not easily accessible or when sutureless surgery is desirable.
  • These biomaterials/polymers are also likely to be an effective synthetic lens material for restoration of vision after a cataract procedure.
  • the polymers, after being crosslinked, can be seeded with cells and then used to repair the damaged ophthalmic tissue.
  • the polymers and cells can be mixed and then injected into the in vivo site and crosslinked in situ for tissue repair or replacement.
  • the crosslinked polymers provide a three dimensional templates for new cell growth.
  • Crosslinking such as with a methacrylated functionalized denditic polymer, can be achieved using light or a chemical reaction.
  • An embodiment of this invention is the preparation of crosslinkable biodendritic macromolecules that can undergo a covalent or non-covalent crosslinking reaction to form a three-deminsional crosslinked gel or network, wherein the crosslinking reaction does not involve a single or multi-photon process (i.e., light).
  • the dendritic polymer can be used for the encapsulation of or the covalent attachment of pharmaceutical agents/drugs such as bioactive peptides (e.g., growth factors), antibacterial compositions, antimicrobial compositions, and antinflammatory compounds to aid/enhance the closure and repair of the wound.
  • pharmaceutical agents/drugs such as bioactive peptides (e.g., growth factors), antibacterial compositions, antimicrobial compositions, and antinflammatory compounds to aid/enhance the closure and repair of the wound.
  • Another aspect of the invention is the use of the dendritic polymer to form a synthetic hydro gel lens or lens material.
  • the crosslinkable formulation is injected via a small openinging into an empty lens capsule bag. Subsequent crosslinking by a photochemical or chemical reaction affords a hydrogel lens.
  • these dendritic polymers can be combined with conventional IOL materials such as acrylates and used in a cataract or other lens removal and replacment procedure.
  • An additional embodiment is the use of the branched structures to increase the refractive index or the incorporation of aromatic amino acids or other aromatic or heterocycles into the dendritic structure to increase the refractive index.
  • additives may be small or large molecule carbohydrates, amino acids, peptides, or other water soluble polymers (linear or branched), small molecules (e.g., phenol, phe, trp,), natural polymers (e.g., albumin, hyaluronic acid, collagen, alginate, polyglutamic acid, polyamino acids), and/or synthetic polymers (e.g., polymethylmethacrylate, polyacrylic acid, sulfonated-polystyrene, silicone, polyvinyl alcohol).
  • small molecules e.g., phenol, phe, trp,
  • natural polymers e.g., albumin, hyaluronic acid, collagen, alginate, polyglutamic acid, polyamino acids
  • synthetic polymers e.g., polymethylmethacrylate, polyacrylic acid, sulfonated-polystyrene, silicone, polyvinyl alcohol.
  • Synthetic aromatic or heterocyclic polymers and polymers having an amide, urea, thiourea, or the like linkages are preferred embodiments.
  • Polymers and small molecules which possess a high refractive index (above 1.10) are specific examples of the additives which may be used in this optical system.
  • Dendritic polymers are globular monodispersed polymers composed of repeated branching units emitting from a central core.
  • dendrimers are highly ordered, possess high surface area to volume ratios, and exhibit numerous end groups for functionalization. Consequently, dendrimers display several favorable physical properties for both industrial and biomedical applications including: small polydispersity indexes (PDI), low viscosities, high solubility and miscibility, and excellent adhesive properties.
  • PDI polydispersity indexes
  • Biodendrimers are a novel class of dendritic macromolecules composed entirely of building blocks known to be biocompatible or degradable to natural metabolites in vivo.
  • biodendrimers or biodendritic macromolecules composed of such biocompatible or natural metabolite monomers such as but not limited to glycerol, lactic acid, glycolic acid, succinic acid, ribose, adipic acid, malic acid, glucose, citric acid, glycine, lysine, cysteine, alanine, etc.
  • a further embodiment of the invention is a dendritic structure that possess glycerol and one or more of lactic acid, glycolic acid, succinic acid, ribose, adipic acid, malic acid, glucose, citric acid, glycine, lysine, cysteine, alanine, etc. as a building block, m certain instances, the dendrimer is terminated with a photoreactive group or nucleophilic group. In certain instances, the terminus of the dendrimer contains a nucleoside.
  • An additional embodiment of the invention is a dendritic structure that is composed of all lysine resides such that it is a generation one or higher or a lysine dendritic macromolecule terminated with cystene residues such that it is a generation one or higher.
  • the present invention is generally in the area of the synthesis and fabrication of dendritic polymers and copolymers of polyesters, polyethers, polyether-esters, and polyamino acids or combinations thereof.
  • linear poly(glycolic acid), poly(lactic acid), and their copolymers are synthetic polyesters that have been approved by the FDA for certain uses, and have been used successfully as sutures, drug delivery carriers, and tissue engineering scaffold for organ failure or tissue loss (Gilding and Reed, Polymer, 20:1459 (1979); Mooney et al., Cell Transpl., 2:203 (1994); and Lewis, D. H. in
  • Biodegradable Polymers as Drug Delivery Systems, Chasin, M., and Langer, R., Eds., Marcel Dekker, New York, 1990).
  • tissue engineering applications isolated cells or cell clusters are attached onto or embedded in a synthetic biodegradable polymer scaffold and this polymer-cell scaffold is next implanted into recipients (Langer and Vacanti, Science, 260:920 (1993).
  • a large number of cell types have been used including cartilage cells ( Freed et al., Bio/Technology, 12:689 (1994)).
  • the advantages include their degradability in the physiological environment to yield naturally occurring metabolic products and the ability to control their rate of degradation by varying the ratio of lactic acid. In the dendritic structures the degradation can be controlled by both the type of monomer used and the generation number.
  • a further embodiment of this invention is to attach biological recognition units for cell recognition to the end groups or within the dendrimer structure.
  • the tripeptide arginine-glycine-aspartic (RGD) can be added to the structure for cell binding.
  • RGD tripeptide arginine-glycine-aspartic
  • Barrera et al. described the synthesis of a poly(lactic acid) (pLAL) containing a low concentration of N-epsilon.-carbobenzoxy-L-lysine units.
  • the polymers were chemically modified through reaction of the lysine units to introduce arginine-glycine-aspartic acid peptide sequences or other growth factors to improve polymer-cell interactions (Barrera et al., J. Am. Chem.
  • the advantages of a dendritic polymer include multiple end groups for functionalization, crosslinked gels with high crosslinking densities at low polymer concentration, globular structure, low viscosities, and well-defined composition.
  • Gels Another aspect of the present invention relates to using dendritic polymeric gels, gel-cell, gel-drug compositions for ophthalmic surgeries, drug delivery, and tissue engineering.
  • Gels are 3D polymeric materials which exhibit the ability to swell in water and to retain a fraction of water within the structure without dissolving.
  • the physical properties exhibited by gels such as water content, sensitivity to environmental conditions (e.g., pH, temperature, solvent, stress), soft, adhesivity, and rubbery consistency are favorable for biomedical and biotechnological applications.
  • gels may be used as coatings (e.g. biosensors, catheters, and sutures), as "homogeneous" materials (e.g.
  • gel matrices for the entrapment of cells, including stem cells, as artificial organs/tissues have been explored for more than fifteen years in some applications, and encapsulation is a promising approach for a number of disease states including Parkinson's disease (L-dopamine cells), liver disease (hepatocyte cells), and diabetes (islets of Langerhans).
  • islets of Langerhans the insulin producing cells of the pancreas
  • islets of Langerhans have embedded encapsulated in an ionically crosslinked alginate (a natural hydrogel) microcapsule with a poly-L-lysine coating, and successfully reduced blood sugar levels in diabetic mice following transplantation.
  • the entrapment of cells in the gel to create a artificial cornea to replace or aid in the repair of a damaged cornea.
  • Another aspect of the present invention relates to a method and means for designing, constructing, and utilizing artificial dendritic matrices as temporary scaffolding for cellular growth and implantation.
  • a further embodiment of the invention to provide biodegradable, non-toxic matrices which can be utilized for cell growth, both in vitro, in vivo, and in situ.
  • the cell scaffold/matrix/gel can be formed in vitro or in situ by crosslinking.
  • It is yet another object of the invention to provide matrices in different configurations so that cell behavior and interaction with other cells, cell substrates, and molecular signals can be studied in vitro.
  • the dendritic macromolecules of the present invention are usefully employed as a general tissue sealant or adhesive.
  • a further embodiment of this invention is the composition and use of these polymers as an ophthalmic sealant or adhesive for corneal lacerations, retinal tears, corneal transplants, and catatact procedures. This is by no means a complete list of examples, but is only to show some representative examples where this material can be used and those skilled in the art will reconginze that the sealant/adhesive has wide-spread application in ophthalmic and general surgeries.
  • a further embodiment of this invention is to use biodendritic crosslinkable polymers for sealing corneal perforations.
  • a further embodiment of this invention is to use biodendritic crosslinkable polymer for sealing retinal holes.
  • a further embodiment of this invention is to use biodendritic crosslinkable polymers for sealing leaking blebs.
  • a further embodiment of this invention is to use biodendritic crosslinkable polymers for sealing a corneal transplant. Besides ophthalmological applications these crosslinkable polymers have additional surgical uses when the site of the wound is not easily accessible or when sutureless surgery is desired.
  • These crosslinkable sealants/glues may be of potential use for cardiovascular surgery (aortic dissection, anastomotic bleeding), urinary tract surgery (nephrotomy closure, urethral repair, hypospadia repair), pulmonary surgery (sealing parenchymal & bronchial leaks, bronchopleural fistula repair, persistent air leak repairs), G.I.
  • biologically active agents may be incorporated in the dendritic gel.
  • Active agents amenable for use in the compositions of the present invention include growth factors, such as transforming growth factors (TGFs), fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue ctivated peptides (CTAPs), osteogenic factors, and biologically active analogs, fragments, and derivatives of such growth factors.
  • TGFs transforming growth factors
  • FGFs fibroblast growth factors
  • PDGFs platelet derived growth factors
  • EGFs epidermal growth factors
  • CAPs connective tissue ctivated peptides
  • osteogenic factors and biologically active analogs, fragments, and derivatives of such growth factors.
  • TGF transforming growth factor
  • TGF transforming growth factor
  • FGFs fibroblast growth factors
  • PDGFs platelet derived growth factors
  • EGFs epidermal growth factors
  • CAPs connective tissue
  • TGF supergene family include the beta transforming growth factors (for example, TGF- ⁇ l, TGF- ⁇ 2, TGF- ⁇ 3); bone morphogenetic proteins (for example, BMP-I , BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin-binding growth factors (for example, fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)); Inhibins (for example, Inhibin A, Inhibin B); growth differentiating factors (for example, GDF- 1); and Activins (for example, Activin A, Activin B, Activin AB).
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • PDGF platelet-derived growth factor
  • IGF insulin-like growth factor
  • Inhibins for example, Inhibin A, Inhibin B
  • growth differentiating factors for
  • these biomaterials are also of use as a wound dressing.
  • the treatment used for wound closure is the classical suture technique.
  • tissue adhesives e.g., glues, sealants, patches, films and the like
  • the general criteria for an adhesive are to bind to the tissue (necrosed or not, sometimes wet) with an adequate adhesion force, to be non-toxic, biodegradable or resorbable, sterilizable, selectively permeable to gases, impermeable to bacteria and able to control evaporative water loss.
  • the two main properties of the adhesive are to protect the wound and to enhance the healing process, or at least not prevent it. Numerous sealants have been investigated and used for different clinical applications.
  • Adhesive hemostats based on fibrin, are the most common products of biological origin. These sealants are usually constituted of fibrinogen, thrombin and factor XIII, as well as fibrinogen/photosensitizers systems. If their intrinsic properties meet the requirements for a tissue adhesive, autologous products (which are time consuming in emergency) or severe treatments before clinical use are needed to avoid any contamination to the patient.
  • Synthetic materials mainly polymers and hydrogels in particular have been developed for wound closure.
  • Alkyl-cyanoacrylates are available for the repair of cornea perforations.
  • One investigator has observed no difference in healed skin incisions that were treated by suture or by ethyl-2-cyanoacrylate-"Mediglue” application.
  • these "super glues” present major inconveniences.
  • Their monomers, in particular those with short alkyl chains, are or might be toxic and they polymerize too quickly leading to difficulty in treating the wound. Once polymerized, the surface of the glue is rough and hard. This might involve discomfort to the patient and, for example, in case of cornea perforation treatment, a contact lens needs to be worn.
  • dendrimers or dendritic polymers are crosslinked using either light or a chemical crosslinking reaction-non light activated.
  • the crosslinking reaction may be an acyrylate polymerization initiated by light, reaction of a dihydrazide with a diketone to make a stablized imine, a siloxane crosslinking reaction, or a nucleophilic attack onto an electrophilic site such as reaction of a thiol or amine with an activated ester, aldol condensation, and the like.
  • a further embodiment of this invention is the crosslinking between dendritic polymers and dendritic polymers and linear polymers or any combination thereof to form a crosslinked gel or network.
  • the gels can be highly hydrated and hydrophilic and thus called hydrogels.
  • the polymers are functionalized to contain groups that will react with each other to form the gel.
  • the dendritic polymers have been chemically modified to have more than two functional groups such nucleophilic groups, such as primary amino (-NH 2 ) groups or thiol (-SH) groups, which can react with electrophilic groups such as an acrylate, succmimidyl ester, maleimide, or aldehyde.
  • Each functional group on a multifunctionally dendritic polymer is capable of covalently binding with another polymer, thereby effecting crosslinking between the polymers and formation of the network.
  • covalently crosslinked networks can be formed by reacting an activated ester (such as a succinimidyl ester) with an amine or thiol (such as a terminal primary or secondary amine, lys, cys, etc.) Thiol or cysteine terminated dendritic structure that forms a disulfide crosslinked network with another thiol or cysteine terminated dendritic(s) or linear polymer(s) will also form a gel. Alternatively, a gel is formed during the reaction of an aldehyde functionalized small molecule or polymer and an amine or cysteine functionalized polymer.
  • an activated ester such as a succinimidyl ester
  • an amine or thiol such as a terminal primary or secondary amine, lys, cys, etc.
  • Thiol or cysteine terminated dendritic structure that forms a disulfide crosslinked network with another thiol or cysteine terminated dendritic(
  • An additional method is to have a maleimide or vinylsulfone functionalized dendritic polymer react with a thiol functionalized dendritic, linear, comb, or other polymer to form the gel.
  • An acrylate functionalized polymer reacts with an amine or thiol functionalized polymer to form the crosslinked gel.
  • a further embodiment of this invention is the use of a chemical peptide ligation reaction to create a crosslinked gel involving a dendritic polymer. In this reaction an aldehyde or aldehyde-acid reacts with a cysteine functionalized polymer to form a gel or crosslinked network.
  • Biodendrimers based on a core unit and branches which is composed of glycerol and lactic acid, glycerol and glycolic acid, glycerol and succinic acid, glycerol and adipic acid, and glycerol, succinic acid, and PEG represent examples of this class of polymers according to the present invention.
  • polymers such as PEG and PLA can be attached to the core unit or to a branch to make large starburst or dendritic polymers.
  • the gels of the invention can be formed by applying a dendrimeric compound to a wound of a patient, and then exposing the dendrimeric compound to a polymerization agent.
  • a dendrimeric compound having acrylate groups attached to the periphery of the dendrimer is applied to a wound of a patient, and then the dendrimeric compound is exposed to ultraviolet radiation.
  • a dendrimeric compound having a nucleophilic group attached to the periphery of the dendrimer is applied to a wound of a patient, and then the dendrimeric compound is exposed to a compound having electrophilic groups.
  • a polymerization agent is applied to a wound of a patient, and then the polyermization agent is exposed to a dendrinieric compound.
  • PEG(NHS) 2 is applied to a wound of a patient, and then PEG(NHS) 2 is exposed to a dendrimeric compound having a nucleophilic group attached to the periphery of the dendrimer.
  • the polymerization agent may a copolymer containing either nucleophilic or electrophilic endgroups.
  • a large number of copolymers are known the art and are amendable to the present invention.
  • the copolymer comprises hydrophobic and hydrophilic domains.
  • the polymerization agent is a copolymer of polyethylene glycol and polypropylene glycol, wherein the copolymer has either nucleophilic or electrophilic endgroups attached to the ends of the copolymer.
  • One aspect of the present invention relates to a method for preparing and administrating in situ a biocompatible gel ex vivo, in vitro, or in vivo, comprising: (a) forming a reactive composition by admixing a biocompatible crosslinking polymer having two different nucleophilic groups such as sulfhydryl and amine groups where there is at least one amine or sulfhydryl group on the polymer with a biocompatible crosslinking polymer B having amine and sulfhydryl-reactive groups, and further wherein the amine and sulfhydryl-reactive groups are capable of covalent reaction with the amine and sulfhydryl groups upon admixture of polymers A and B under effective crosslinking conditions to form a gel in less than one day; and (b) allowing the components of the reactive composition to crosslink and thereby form a gel.
  • a biocompatible crosslinking polymer having two different nucleophilic groups such as sulfhydryl and
  • Another aspect of the present invention relates to dendritic or branched polymers or copolymers composed of monomers synthesized by combining branching compounds with other linear or branched building blocks.
  • Both components are known to be biocompatible or are natural metabolites in vivo including but not limited to glycerol, citric acid, lactic acid, glycolic acid, adipic acid, caproic acid, ribose, glucose, succinic acid, malic acid, amino acids, peptides, synthetic peptide analogs, poly(ethylene glycol), poly(hydroxyacids) [e.g., PGA. PLA], including where one of the monomers is a branched structure such as glycerol combined with one of the other components.
  • the present invention relates to the aforementioned polymers derivatized with peripheral compounds possessing an olefin including but not limited to acrylate, methacrylate.
  • the present invention relates to the aforementioned polymers derivatized with peripheral compounds including but not limited to cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (including but not limited to amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones).
  • peripheral compounds including but not limited to cysteine, lysine, other amino acids, or any other compounds that would provide terminal nucleophiles (including but not limited to amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones).
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslmking/reaction with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively to form a gel.
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure via a photopolymerization process (single or multi-photon process) to form a gel.
  • Another aspect of the present invention relates to a branching structure with at least three functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic strucutures synthesized to produce terminal olefins (including but not limited to acrylate or methacrylate groups), nucleophiles (including but not limited to amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones) for subsequent polymerization/crosslinking with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively.
  • functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic strucutures synthesized to produce terminal olefins (including but not limited to acrylate
  • Another aspect of the present invention relates to a branching structure with at least three functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic structures derivatized with peripheral compounds including but not limited to cysteine, lysine, other amino acids, or any other compounds that would provide terminal olefins (including but not limited to acrylate or methacrylate groups), nucleophiles (including but not limited to amines, thiols, hydroxyl groups) or electrophiles (including but not limited to NHS esters, maleimides, aldehydes, ketones) for subsequent polymerization/crosslinking with another linear or branched structure with either olefinic, electrophilic or nucleophilic groups, respectively.
  • functional groups composed of but not limited to glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs, or other dendritic structures
  • Another aspect of the present invention relates to a branching structure composed of three lysine amino acids with four cysteine amino acids on the periphery with the structure CysLys(Cys)Lys(CysLys(Cys))OMe » 4HCl as described in the examples.
  • Another aspect of the present invention relates to a branching structure composed of three lysine amino acids with amines on the periphery with the structure (Lys)Lys(Lys)OMe*4HCl as described in the examples.
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure with olefinic, electrophilic or nucleophilic groups to form a gel.
  • the present invention relates to the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure through thiazolidine linkages to form a gel.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with at least two electrophilic groups.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with at least two nucleophilic groups
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with functional groups including but not limited to olefins, aldehydes, maleimides, or NHS esters.
  • the present invention relates to the aforementioned polymers undergoing polymerization/crosslinking with a poly(ethylene glycol) molecular weight of about 200 to about 200,000 with aldehyde functional groups to form hydrogels through the formation of thiazolidine linkages.
  • the present invention relates to the aforementioned formulations in which each of the components are dissolved or suspended in an aqueous solution wherein the said aqueous solution is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates or combinations of any two or more thereof.
  • the present invention relates to the application of the aforementioned formulation through a delivery device which physically separates the components until the components are physically mixed by the end user, including but not limited to a dual barrel syringe with a mixing device.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds in an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above and the packaging of the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds in an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above and the packaging of the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above.
  • the contents are packaged free of oxygen and shielded from light.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to packaging of the aforementioned branching compounds as a powder and adding an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above before use.
  • the second component may either be packaged by dissolving the second compound in an aqueous solution at another preselected pH and molarity selected from the aqueous solutions described above or packaged similar to the first compound in which the compound stored as a powder and an aqueous solution at a preselected pH and molarity selected from the aqueous solutions described above is added before use.
  • the contents are packaged free of oxygen and shielded from light.
  • the pH and molarities of the two solutions produce a final desired solution with a different pH.
  • Another aspect of the present invention relates to the storage of the aforementioned cystein terminated polymers in an acidic, oxygen free solution to minimize the formation of disulfide bonds.
  • Another aspect of the present invention relates to the storage of the aforementioned aldehyde terminated polymers in an acidic, oxygen free solution to maximize the percent reactivity of the polymer and minimize aldol condensation and reverse Michael additions.
  • Another aspect of the present invention relates to the addition of various additives that might be incorporated into the polymer formulations including, but not limited to, antioxidants, colorants, viscosity modifiers, plasticizers, small molecule carbohydrates, large molecule carbohydrates, amino acids, peptides, or other water soluble polymers (linear or branched).
  • additives may be added to increase the shelf life, increase the polymerization rate, modifiy the pH or molarity of the solution, change the refractive index, modify the mechanical properties, change crosslinking density, decrease swelling, or aid in visualization.
  • Another aspect of the present invention relates to the addition of various additives or anti-microbial agents such has polyhexamethylene biguanide (PHMB) that might be incorporated into the polymer formulations.
  • PHMB polyhexamethylene biguanide
  • Another aspect of the present invention relates to the resulting hydrogels formed by mixing the aforementioned compounds as described and prepared above.
  • the present invention relates to hydrogels formed by photopolymerization of the aforementioned compounds.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels for ophthalmic applications.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as an ophthalmic sealant.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as an intraocular lens replacement.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels to seal or repair corneal incisions, lacerations, perforations, ulcerations.
  • Another aspect of the present invention relates to the use of the polymers, branching structures, and their hydrogels to seal or close a corneal transplant with or without the use of sutures.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels to seal or repair trabeculectomy incisions or leaking blebs.
  • Another aspect of the present invention relates to the use of the polymers, branching structures, and their hydrogels to seal or repair blepharoplasty or skin incisions.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels to seal or repair ocular wounds or lacerations.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound wherein the durg has antimicrobial or antibacterial properties.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels wherein the adhesive/sealant also acts as a physical barrier to prevent or reduce microbial infection.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as a drug delivery vehicle to treat one or more ophthalmic diseases.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels as a drug delivery vehicle to treat glaucoma and macular degeneration.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels for wound care or wound management.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels for seeding cells in vitro for subsequent in vivo placement.
  • Another aspect of the present invention relates to a method of using the polymers, branching structures, and their hydrogels for repair or restoration of cornea tissue.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for ophthalmic applications.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as an ophthalmic sealant.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as an intraocular lens replacement.
  • Another aspect of the present invention relates to a method of using the a crosslinkable/polymerizable/reactionary polymers, branching structures, and their hydrogels for an injectable in situ polymerizing/crosslinking intraocular lens replacement.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels to seal or repair sclerotomy incisions.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels to seal or repair corneal incisions, lacerations, perforations, ulcerations.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, and their hydrogels to seal or close a corneal transplant with or without the use of sutures.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels to seal or repair trabeculectomy incisions or leaking blebs.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels to seal or repair blepharoplasty or skin incisions.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels to seal or repair ocular wounds or lacerations.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as a drug delivery vehicle and an adhesive/sealant to aid in the repair or sealing of an ophthalmic wound wherein the drug has antimicrobial or antibacterial properties.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels wherein the adhesive/sealant also acts as a physical barrier to prevent or reduce microbial infection.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as a drug delivery vehicle to treat one or more ophthalmic diseases.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels as a drug delivery vehicle to treat glaucoma and macular degeneration
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for wound care or wound management.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for seeding cells in vitro for subsequent in vivo placement.
  • Another aspect of the present invention relates to a method of using crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for repair or restoration of cornea tissue.
  • Another aspect of the present invention relates to a method of using crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for delivery of therapeutics.
  • Another aspect of the present invention relates to a method of using crosslinkable/polymerizable/reactionary dendritic polymers, branching structures, and their hydrogels for drug delivery in the eye.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymer or monomer for seeding with cells and subsequent in situ polymerization in vivo.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary dendritic polymer or monomer for delivery of therapeutics while performing as a sealant/adhesive.
  • Another aspect of the present invention relates to a method of using a crosslinkable/polymerizable/reactionary branched or dendritic polymer for drug delivery.
  • Another aspect of the present invention relates to a crosslinkable/polymerizable/reactionary dendritic polymer or monomer wherein the crosslinking is of covalent, ionic, electrostatic, and/or hydrophobic nature.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction involves a nucleophile and electrophile.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction is a peptide ligation reaction.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction is a Diels- Alder reaction.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction is a Michael Addition reaction.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the crosslinking reaction is a photochemical reaction using a UV or vis photoinitator chromophore.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer in combination with a linear, comb, multi-block, star, or dendritic polymer(s) as a tissue sealant/adhesive.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer in combination with a crosslinkable linear, comb, multi-block, star, or dendritic polymer(s) for a medical or tissue engineering application.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer in combinaton with a crosslinkable monomer(s) for a medical or tissue engineering application.
  • Another aspect of the present invention relates to a method of using a crosslinkable branched or dendritic polymer combined with a crosslinkable small molecule(s) (molecule weight less than about 1000 daltons) for a medical or tissue engineering application.
  • Another aspect of the present invention relates to a crosslinkable branched or dendritic polymer or monomer wherein the said crosslinking dendritic polymer is combined with one or more linear, comb, multi-block, star polymers or crosslinkable comb, multi- block, star polymers.
  • Another aspect of the present invention relates to a crosslinkable dendritic polymer or monomer wherein the final polymeric form is a gel, film, fiber, or woven sheet.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the final polymeric form is a gel, film, fiber, or woven sheet.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the polymer or crosslinkable monomer is D or L configuration or a mixture.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their resulting hydrogels wherein the branching structure, linkages and or the incorporation of aromatic or hterocyclic groups changes the refractive index.
  • Another aspect of the present invention relates to the aforementioned polymers, branching structures, and their hydrogels wherein the dendritic structure is asymmetric at the surface such as a surface block structure where a carboxylate acid(s) and alkyl chains, or acrylate(s) and PEG(s) are present, for example, or within the core and inner layers of the dendrimer such as amide and ester linkages in the structure.
  • Another aspect of the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer wherein the polymer is a star biodendritic polymer or copolymer as shown in at least one of the formulas below: where Y and X are the same or different at each occurrence and are O, S, Se, N(H), or P(H) and where R 1 , R 2 , R 3 , R 4 , R 5 ,
  • R 6 , R 7 , R 8 , A or Z are the same or different and include -H, -CH 3 , -OH, carboxylic acid, sulfate, phosphate, aldehyde, methoxy, amine, amide, thiol, disulfide, straight or branched chain alkane, straight or branched chain alkene, straight or branched chain ester, straight or branched chain ether, straight or branched chain silane, straight or branched chain urethane, straight or branched chain, carbonate, straight or branched chain sulfate, straight or branched chain phosphate, straight or branched chain thiol urethane, straight or branched chain amine, straight or branched chain thiol urea, straight or branched chain thiol ether, straight or branched chain thiol ester, or any combination thereof.
  • Another aspect of the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer where the straight or branched chain is of about 1-50 carbon atoms wherein the chain is fully saturated, fully unsaturated or any combination therein
  • the present invention relates to the aforementioned crosslmkable or noncrosslinkable polymer where the straight or branched chain is of about 1-50 carbon atoms wherein the chain is fully saturated, fully unsaturated or any combination therein.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer wherein straight or branched chains are the same number of carbons or different wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A or Z are any combination of the linkers including ester, silane, urea, amide, amine, carbamate, urethane, thiol-urethane, carbonate, thio-ether, thio-ester, sulfate, phosphate and ether.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer which includes at least one chain selected from the group consisting of hydrocarbons, flourocarbons, halocarbons, alkenes, and alkynes.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer which includes at least one chain selected from the group consisting of linear and dendritic polymers.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer wherein said linear and dendritic polymers include at least one selected from the group consisting of polyethers, polyesters, polyamines, polyacrylic acids, polycarbonates, polyamino acids, polynucleic acids and polysaccharides of molecular weight ranging from about 200-1,000,000, and wherein said chain contains 0, 1 or more than 1 photopolymerizable group.
  • Another aspect of the present invention relates to a crosslinkable or noncrosslinkable polymer, wherein the polyether is PEG, and wherein the polyester is PLA, PGA or PLGA.
  • Another aspect of the present invention relates to a linear polymer wherein the chain is a polymer or copolymer of a polyester, polyamide, polyether, or polycarbonate of or the aforementioned polymer in combination with a polyester, polyamide, polyether, or polycarbonate of:
  • the present invention relates to the aforementioned polymer comprised of repeating units of general Structure I, where A is O, S, Se, or N-R 7 .
  • the present invention relates to the aforementioned polymer, where W, X, and Z are the same or different at each occurrence and are O, S, Se, N(H), or P(H).
  • the present invention relates to the aforementioned polymer, where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer, where R 1 is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • the present invention relates to the aforementioned polymer, where R 1 is a polymer (such as poly(ethylene glycol), poly(ethylene oxide), or a poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor.
  • R 1 is a polymer (such as poly(ethylene glycol), poly(ethylene oxide), or a poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor.
  • R 1 is a poly
  • the present invention relates to the aforementioned polymer, where R 1 is a photocrosslinkable, chemically, or ionically crosslinkable group.
  • the present invention relates to the aforementioned polymer, in which D is a straight or branched alkyl chain of about 1-5 carbons, m is 0 or 1, and R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are the same or different at each occurrence and are hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, alkoxy, aryloxy, olefin, alkylamine, dialkylamine, arylamine, diarylamine, alkylamide, dialkylamide, arylamide, diarylamide, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer comprised of repeating units of General Structure II, where L, N, and J are the same or different at each occurrence and are O, S, Se, N(H), or P(H).
  • the present invention relates to the aforementioned polymer where Ri is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned polymer where R 1 is hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkyl group substituted internally or terminally by one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • the present invention relates to the aforementioned polymer where Ri is a polymer selected from the group consisting of poly(ethylene glycols), poly(ethylene oxides), and poly(hydroxyacids, or is a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, a DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or an epitope for a biological receptor.
  • the present invention relates to the aforementioned polymer where Ri is a photocrosslinkable, chemically, or ionically crosslinkable group.
  • the present invention relates to the aforementioned polymer, where D is a straight or branched alkyl chain of about 1-5 carbons, q and r are the same or different at each occurrence and are 0 or 1, and R 7 , R 8 , R 9 , Ri 0 , Rn, R 12 , Ri 3 , and Ri 4 are the same or different at each occurrence and are hydrogen, a straight or branched alkyl chain of about 1-20 carbons, cycloalkyl, aryl, alkoxy, aryloxy, olefin, alkylamine, dialkylamine, arylamine, diarylamine, alkylamide, dialkylamide, arylamide, diarylamide, alkylaryl, or arylalkyl group.
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), e is 0 or 1-9, and R 15 is a straight or branched alkyl chain of about 1-5 carbons, unsubstituted or substituted with one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), and R 45 is a straight or branched alky
  • the present invention relates to the aforementioned block or random copolymer comprised of repeating units of general Structure III, where M, T, and Q are the same or different at each occurrence and are O, S, Se, N(H), or P(H), and Rl 5 is a straight or branched alkyl chain of about 1-5 carbons, unsubstituted or substituted with one or more hydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents.
  • Another aspect of the present invention relates to a higher order block or random copolymer comprised of three or more different repeating units, and having one or more repeating units described above, such as a polyglyerol glycine carbonate-polyglycerol succinic acid copolymer.
  • Another aspect of the present invention relates to a block or random copolymer as described above, which includes at least one terminal crosslinkable group selected from the group consisting of amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
  • the present invention relates to the aforementioned block or random copolymer where X, Y, M is O, S, N-H, N-R, and wherein R is -H, CH 2 , CR 2 , Se or an isoelectronic species of oxygen.
  • the present invention relates to the aforementioned block or random copolymer wherein an amino acid(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a polyp eptide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein an antibody(ies) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z. In certain instances, the present invention relates to the aforementioned block or random copolymer wherein a nucleotide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a nucleoside(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein an oligonucleotide(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or
  • the present invention relates to the aforementioned block or random copolymer wherein a ligand(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z that binds to a biological receptor.
  • the present invention relates to the aforementioned block or random copolymer wherein a pharmaceutical agent(s) is attached to R 1 , R 2 , R 3 , R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned crosslinkable or noncrosslinkable polymer or copolymer wherein the polymer is a dendritic macromolecule including at least one polymer selected from the group consisting of dendrimers, hybrid linear-dendrimers, dendrons, or hyperbranched polymers according to one of the general formulas or such similar structures below: where R 3 , R 4 , which may be the same or different, are a repeat pattern of B, and n is about 0 to 50. etc
  • the present invention relates to the aforementioned polymer, wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen
  • the present invention relates to the aforementioned polymer, wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen.
  • the present invention relates to the aforementioned polymer where R 3 and R 4 are carboxylic acid with a protecting group such as but not limited to a phthalimidomethyl ester, a t-butyldimethylsilyl ester, or a t-butyldiphenylsilyl ester.
  • a protecting group such as but not limited to a phthalimidomethyl ester, a t-butyldimethylsilyl ester, or a t-butyldiphenylsilyl ester.
  • the present invention relates to the aforementioned polymer where R 3 , R 4 , A, and Z are the same or different, R 3 and R 4 are repeated a certain number of times, and terminate in -H, -OH, -CH 3 , carboxylic acid, sulfate, phosphate, aldehyde, activated ester, methoxy, amine, amide, thiol, disulfide, straight or branched chain alkane, straight or branched chain alkene, straight or branched chain ester, straight or branched chain ether, straight or branched chain silane, straight or branched chain urethane, straight or branched chain, carbonate, straight or branched chain sulfate, straight or branched chain phosphate, straight or branched chain thiol urethane, straight or branched chain amine, straight or branched chain thiol urea, straight or branched chain thiol ether, straight or
  • the present invention relates to the aforementioned polymer having a straight or branched chain of 1-50 carbon atoms and wherein the chain is fully saturated, fully unsaturated or any combination therein.
  • the present invention relates to the aforementioned polymer wherein straight or branched chains are the same number of carbons or different and wherein R 3 , R 4 , A, Z are any combination of linkers selected from the group consisting of esters, silanes, ureas, amides, amines, urethanes, thiol-urethanes, carbonates, carbamates, thio-ethers, thio-esters, sulfates, phosphates and ethers.
  • the present invention relates to the aforementioned polymer wherein chains include at least one selected from hydrocarbons, flourocarbons, halocarbons, alkenes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein said chains include polyethers, polyesters, polyamines, polyacrylic acids, polyamino acids, polynucleic acids and polysaccharides of molecular weight ranging from
  • the present invention relates to the aforementioned polymer wherein the chains include at least one of PEG, PLA, PGA, PGLA, and PMMA.
  • the present invention relates to the aforementioned block or random copolymer, which includes at least one terminal crosslinkable or photopolymerizable group selected from the group consisting of amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, activated esters, malemides, aldehydes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with amino acid(s), such as cysteine, attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with polypeptide(s) attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with an antibody(ies) or single chain antibody(ies) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a nucleotide(s) attached to Z, A, R 3 , and/or R 4 ..
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a nucleoside(s) attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with oligonucleotide(s) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with ligand(s) attached to Z, A, R 3 , and/or R 4 that binds to a biological receptor.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a pharmaceutical agent(s) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a pharmaceutical agent attached to Z, A, R 3 , and/or R 4 and is at least one selected from the group consisting of antibacterial, anticancer, anti-inflammatory, and antiviral.
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times to produce a polymer in which a pharmaceutical agent(s) is encapsulated or chemically bound to the polymer.
  • the present invention relates to the aforementioned polymer wherein camptothecin or a deriviative of campothethcin is encapsulated
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a carbohydrate(s) attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with a PET or MRI contrast agent(s) attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein the contrast agent is Gd(DPTA).
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with an iodated compound for X-ray imagaging attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein R 3 and R 4 are repeated a certain number of times and terminates with the carbohydrate mannose or sialic acid attached to the polymer.
  • the present invention relates to the aforementioned polymer which includes a polymer or copolymer of a polyester, polyamide, polyether, or polycarbonate at the center or periphery of the polymers above taken from the structures below.
  • the present invention relates to the aforementioned polymer block or random copolymer which includes at least one terminal or internal crosslinkable group selected from the group consisting of amines, thiols, amides, pnospnates, suipna ⁇ es, hydroxides, alkenes, and alkynes.
  • the present invention relates to the aforementioned polymer wherein X, Y, M is O, S, N-H, N-R, wherein R is -H, CH 2 , CR 2 or a chain as defined above, Se or any isoelectronic species of oxygen.
  • the present invention relates to the aforementioned polymer wherein an amino acid(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a polypeptide(s) is attached to Z, A, R 3 , and/or R 4 . In certain instances, the present invention relates to the aforementioned polymer wherein an antibody(ies) or single chain antibody(ies) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a nucleotide(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a nucleoside(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein an oligonucleotide(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a ligand(s) is attached to Z, A, R 3 , and/or R 4 that binds to a biological receptor. In certain instances, the present invention relates to the aforementioned polymer wherein a pharmaceutical agent(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a carbohydrate(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a PET or MRI contrast agent(s) is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein the contrast agent is Gd(DPTA).
  • the present invention relates to the aforementioned polymer wherein an iodated compound(s) for X-ray imagaging is attached to Z, A, R 3 , and/or R 4 .
  • the present invention relates to the aforementioned polymer wherein a pharmaceutical agent(s) is attached to Z, A, R 3 , and/or R 4 and is at least one selected from the group consisting of antibacterial, anticancer, anti-inflammatory, and antiviral.
  • the present invention relates to the aforementioned polymer wherein the carbohydrate is mannose or sialic acid is covalently attached to the polymer.
  • Another aspect of the present invention relates to a surgical procedure which comprises using a photopolymerizable, or chemically crosslinkable, or non-covalently crosslinkable dendritic polymer or copolymer.
  • Another aspect of the present invention relates to an ophthalimic surgical procedure wherein said dendritic polymer or copolymer is dissolved or suspended in an non-aqueous liquid such as soybean oil, mineral oil, corn oil, rapeseed oil, coconut oil, olive oil, saflower oil, cottonseed oil, aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms, aliphatic or aromatic alcohols having 1-30 carbon atoms, aliphatic or aromatic esters having 2-30 carbon atoms, alkyl, aryl or cyclic ethers having 2-30 carbon atoms, alkyl or aryl halides having 1-30 carbon atoms and optionally having more than one halogen substituent, ketones having 3-30 carbon atoms, polyal
  • the present invention relates to the ophthalimic surgical procedure wherein the supramolecular structure of the dendrimer is an emulsion.
  • the present invention relates to the dendritic polymer or copolymer which optionally contains at least one stereochemical center.
  • the present invention relates to the dendritic polymer or copolymer which is of D or L configuration. In certain instances, the present invention relates to the dendritic polymer or copolymer wherein the final dendritic polymer or monomer is chiral or is achiral.
  • the present invention relates to the dendritic polymer or copolymer which contains at least one site where the branching is incomplete.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete. In certain instances, the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete which forms a hydrogel.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete and used in an ophthalmic surgical procedure(s).
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete and used for drug delivery.
  • the present invention relates to a crosslinkable/photocrosslinkable/reactionary dendritic polymer or copolymer which contains at least one site where the branching is incomplete and used as a lens.
  • the present invention relates to a dendritic polymer or copolymer made by a convergent or divergent synthesis.
  • the dendritic polymer of the invention relates to
  • a variety of procedures are known in the art for sterilizing a chemical composition. Sterilization may be accomplished by chemical, physical, or irradiation techniques. Examples of chemical methods include exposure to ethylene oxide or hydrogen peroxide vapor. Examples of physical methods include sterilization by heat (dry or moist), retort canning, and filtration. The British Pharmacopoeia recommends heating at a minimum of 160 0 C for not less than 2 hours, a minimum of 170 0 C for not less than 1 hour and a minimum of 180 0 C for not less than 30 minutes for effective sterilization. For examples of heat sterilization, see U.S. Patent 6,136,326, which is hereby incorporated by reference. Passing the chemical composition through a membrane can be used to sterilize a composition.
  • the composition is filtered through a small pore filter such as a 0.22 micron filter which comprises material inert to the composition being filtered.
  • a small pore filter such as a 0.22 micron filter which comprises material inert to the composition being filtered.
  • the filtration is conducted in a Class IUU 5 UUU or better clean room.
  • irradiation methods include gamma irradiation, electron beam irradiation, microwave irradiation, and irradiation using visible light.
  • One preferred method is electron beam irradiation, as described in U.S. Patents 6,743,858; 6,248,800; and 6,143,805, each of which is hereby incorporated by reference.
  • the two main groups of electron beam accelerators are: (1) a Dynamitron, which uses an insulated core transformer, and (2) radio frequency (RF) linear accelerators (linacs).
  • the Dynamitron is a particle accelerator (4.5 MeV) designed to impart energy to electrons.
  • the high energy electrons are generated and accelerated by the electrostatic fields of the accelerator electrodes arranged within the length of the glass-insulated beam tube (acceleration tube).
  • These electrons traveling through an extension of the evacuation beam tube and beam transport (drift pipe) are subjected to a magnet deflection system in order to produce a "scanned" beam, prior to leaving the vacuum enclosure through a beam window.
  • the dose can be adjusted with the control of the percent scan, the beam current, and the conveyor speed.
  • the electron-beam radiation employed may be maintained at an initial fluence of at least about 2 ⁇ Curie/cm 2 , at least about 5 ⁇ Curie/cm 2 , at least about 8 ⁇ Curie/cm 2 , or at least about 10 ⁇ Curie/cm 2 .
  • the electron-beam radiation employed has an initial fluence of from about 2 to about 25 ⁇ Curie/cm 2 .
  • the electron- beam dosage is from about 5 to 50 kGray, or from about 15 to about 20 kGray with the specific dosage being selected relative to the density of material being subjected to electron-beam radiation as well as the amount of bioburden estimated to be therein. Such factors are well within the skill of the art.
  • the composition to be sterilized may be in any type of at least partially electron beam permeable container such as glass or plastic.
  • the container may be sealed or have an opening.
  • glass containers include ampules, vials, syringes, pipettes, applicators, and the like.
  • the penetration of electron beam irradiation is a function of the packaging. If there is not enough penetration from the side of a stationary electron beam, the container may be flipped or rotated to achieve adequate penetration. Alternatively, the electron beam source can be moved about a stationary package. In order to determine the dose distribution and dose penetration in product load, a dose map can be performed. This will identify the minimum and maximum dose zone within a product.
  • the visible light for sterilization can be generated using any conventional generator of sufficient power and breadth of wavelength to effect sterilization. Generators are commercially available under the tradename PureBright® in-line sterilization systems from PurePulse Technologies, Inc. 4241 Ponderosa Ave, San Diego, Calif. 92123, USA.
  • PureBright® in-line sterilization system employs visible light to sterilize clear liquids at an intensity approximately 90000 times greater than surface sunlight. If the amount of UV light penetration is of concern, conventional UV absorbing materials can be used to filter out the UV light.
  • the composition is sterilized to provide a Sterility
  • the Sterility Assurance Level may be at least about 10 "4 , at least about 10 "5 , or at least about 10 "6 .
  • the materials used to form the sealant of the present invention may be delivered to the wound of a patient using a large number of known delivery devices.
  • the delivery system may be a single-barrel syringe system.
  • the single- barrel syringe is a double acting, single-barrel syringe system as displayed in Figure 10.
  • a double- or multi-barrel syringe system as displayed in Figure 11, may be preferable.
  • a delivery device that flows two or more streams of liquid in a mixing chamber may be preferable.
  • a delivery device that mixes two solids and two liquids and then separately flows these streams of liquid to a mixing chamber may be advantageous.
  • a delivery system is used to deliver the sealant-forming materials to the wound of a patient, wherein at least two dry, reactive components are stored together in a dry state and introduced into a liquid component(s) at the time of use to form a mixture that forms a hydrogel.
  • the two components could be mixed (without gelation) prior to applying the mixture to a patient.
  • the pH of the mixing solution may be adjusted in order to slow or prevent crosslinking of hydrogel components.
  • the resultant solution may be contacted with a frit or resin designed to raise or lower the pH to a level suitable for crosslinking.
  • PEG-SPA and Lys3Cys4 could be mixed during packaging and dissolved prior to use in a buffer designed to provide a solution with a pH of about 6.
  • the solution is mixed, and then the solution is contacted with a resin embedded in the delivery device.
  • the resin would raise the pH to about 7 for initiate crosslinking.
  • pharmaceutical agent includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • Non-limiting examples of broad categories of useful pharmaceutical agents include the following therapeutic categories: anabolic agents, antacids, anti-asthmatic agents, anti- cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics, anti-infective agents, anti-inflammatory agents, anti-manic agents, anti- nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements
  • non-limiting examples of useful pharmaceutical agents include the following therapeutic categories: analgesics, such as nonsteroidal anti-inflammatory drags, opiate agonists and salicylates; antihistamines, such as Hi-blockers and H 2 -blockers; anti-infective agents, such as anthelmintics, antianaerobics, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, miscellaneous beta-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antituberculosis antimycobacterials, antiprotozoals, antimalarial antiprotozoals, antiviral agents, anti- retroviral agents, scabicides, and urinary anti-infectives; antineoplastic agents, such as alkylating agents, nitrogen mustard aklylating agents, nitrosourea alky,
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • analgesics such as diclofenac, ibuprofen, ketoprofen, and naproxen
  • opiate agonist analgesics such as codeine, fentanyl, hydromorphone, and morphine
  • salicylate analgesics such as aspirin (ASA) (enteric coated ASA)
  • Hi -blocker antihistamines such as clemastine and terfenadine
  • H 2 -blocker antihistamines such as cimetidine, famotidine, nizadine, and ranitidine
  • anti-infective agents such as mupirocin
  • antianaerobic anti-infectives such as chloramphenicol and clindamycin
  • antifungal antibiotic anti-infectives such as amphotericin b, clotrimazole
  • -blocker antihypertensives such as atenolol, metoprolol, nadolol, and propanolol
  • calcium- channel blocker antihypertensive agents such as diltiazem and nifedipine
  • central- acting adrenergic antihypertensives such as clonidine and methyldopa
  • diurectic antihypertensive agents such as amiloride, furosemide, hydrochlorothiazide (HCTZ), and spironolactone
  • peripheral vasodilator antihypertensives such as hydralazine and minoxidil
  • antilipemics such as gemfibrozil and probucol
  • bile acid sequestrant antilipemics such as cholestyramine
  • HMG-CoA reductase inhibitor antilipemics such as lovastatin and prava
  • vitamin B.sub.3 (vitamin B.sub.3); (128) vitamin C compounds, such as ascorbic acid; and (129) vitamin D compounds, such as calcitriol.
  • the following less common drugs may also be used: chlorhexidine; estradiol cypionate in oil; estradiol valerate in oil; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa; nafarelin; and somatropin.
  • the following drugs may also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; the formulation comprising fluorouracil, epinephrine, and bovine collagen; recombinant hirudin (r-Hir), HIV-I immunogen; human anti-TAC antibody; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant human mecasermin (r-IGF-1); recombinant interferon beta- Ia; lenograstim (G- CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan.
  • recombinant beta-glucan bovine immunoglobulin concentrate
  • bovine superoxide dismutase the formulation comprising fluorouracil, epinephrine, and bovine collagen
  • recombinant hirudin r-Hir
  • intravenous products may be used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; carmustine; dactinomycin, daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin alfa; etoposide (VP- 16); fluorouracil (5-FU); ganciclovir sodium; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine HCl; methadone HCl; methotrexate sodium; paclitaxel; ranitidine HCl; vinblastin sulfate; and zidovudine (AZT).
  • aldesleukin aldesleukin
  • salmon calcitonin carb
  • useful pharmaceutical agents from the above categories include: (a) anti-neoplasties such as androgen inhibitors, antimetabolites, cytotoxic agents, and immunomodulators; (b) anti-tussives such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlorphedianol hydrochloride; (c) antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonates, magnesium
  • TGF-beta fibroblast growth factor
  • FGF tumor necrosis factor-alpha & beta
  • NGF-alpha & beta nerve growth factor
  • GRF growth hormone releasing factor
  • EGF epidermal growth factor
  • FGFHF fibroblast growth factor homologous factor
  • HGF hepatocyte growth factor
  • IGF insulin growth factor
  • IIF-2 invasion inhibiting factor-2
  • BMP 1--7 bone morphogenetic proteins 1-7
  • SOD superoxide dismutase
  • complement factors hGH, tPA, calcitonin, ANF, EPO and insulin
  • anti-infective agents such as antifungals, anti-virals, antiseptics and antibiotics.
  • the pharmaceutical agent may be a radiosensitizer, such as metoclopramide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (made by Vion); RSRl 3 (made by Allos); Thymitaq (made by Agouron), etanidazole or lobenguane (manufactured by Nycomed); gadolinium texaphrin (made by Pharmacyclics); BuDR/Broxine (made by NeoPharm); IPdR (made by Sparta); CR2412 (made by Cell Therapeutic); LlX (made by Terrapin); or the like.
  • a radiosensitizer such as metoclopramide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (made by Vion); RSRl 3 (made by Allos); Thymitaq (made by Agouron), etanidazole or lobenguane (manu
  • the biologically active substance is selected from the group consisting of peptides, poly-peptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs.
  • the biologically active substance is a therapeutic drug or pro-drug, most preferably a drug selected from the group consisting of chemotherapeutic agents and other anti-neoplasties such as paclitaxel, antibiotics, anti-virals, antifungals, antiinflammatories, and anticoagulants.
  • the biologically active substances are used in amounts that are therapeutically effective. While the effective amount of a biologically active substance will depend on the particular material being used, amounts of the biologically active substance from about 1% to about 65% may be desirable. Lesser amounts may be used to achieve efficacious levels of treatment for certain biologically active substances.
  • One aspect of the present invention relates to a method of sealing a wound of a patient, comprising the steps of:
  • a 2 is alkyl, aryl, aralkyl, -Si(R 3 ) 3 , or
  • a 3 represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y 1 represents independently for each occurrence R 4 , A 4 ,
  • Z 1 represents independently for each occurrence -X r ⁇ 1 -R ⁇ > 4 4 , E, or h ⁇ 1 -®-(- ⁇ 2 ⁇ 2 ) t.
  • Y represents independently for each occurrence R , A ,
  • Z 2 represents independently for each occurrence -X'-R 5 , E, or h ⁇ 1 -@-f ⁇ 2 - ⁇ 3 ) t .
  • Y 3 represents independently for each occurrence R 6 , A 4 ,
  • Z 3 represents independently for each occurrence -X 1 -R 6 , E, or
  • Y ⁇ represents independently for each occurrence R , A , x /J
  • Z 4 represents independently for each occurrence -X 1 -R 7 , E, or
  • Y 5 represents independently for each occurrence R 8 , A 4 ,
  • Z 7 5 represents independently for each occurrence -X -R , E, or
  • Y 6 represents independently for each occurrence R 9 , A 4 ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R'") 2 , -SH, hydroxyalkyl, or -[CCR't ⁇ dR 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 1 ' represents independently for each occurrence H, -OH, -N(R 10 ) 2 , -SH, alkyl, hydroxyalkyl, or
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ;
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or - C(NH 2 )N(R 10 ),;
  • v 1 and v 2 each represent independently for each occurrence 2, 3, or 4; w 1 and w 2 each represent independently for each occurrence an integer from about 5 to about 700, inclusive; x is 1, 2, or 3; y is O 5 1, 2, 3, 4, or 5; z 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z 2 and z 3 each represent independently for each occurrence 1, 2, 3, 4, or 5; X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-; X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 );
  • A represents independently for each occurrence
  • R 1"11 represents independently for each occurrence H or
  • R 2"11 represents independently for each occurrence H or alkyl
  • R 3'11 represents independently for each occurrence H, halogen, or alkyl
  • R 4"11 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5"11 represents independently for each occurrence H or and z represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; and said compound of formula III is represented by:
  • R 1 - 111 is -(C(R z - m ) 2 ) x C(O)H, -C(O)(C(R z - m ) 2 ) y C(O)H, -(C(R z - m ) 2 ) x C(O)R 3 J --i m ⁇ , or -
  • R'' " " 1 represents independently for each occurrence H, alkyl, or halogen
  • R ,3 3 - ' i 1 n 11 is fluoroalkyl, chloroalkyl, -CH 2 NO 2 ,
  • B " is alkyl diradical, heteroalkyl diradical , or
  • x represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • y represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;
  • v represents independently for each occurrence 2, 3, or 4;
  • w is an integer in the range of about 5 to about 1000, inclusive.
  • a 2 is alkyl, aryl, aralkyl,r
  • Z 1 represents independently for each occurrence -X '-R 4 , E, or
  • Z 2 represents independently for each occurrence -X 1 -R 5 , E, or
  • Y represents independently for each occurrence R ,
  • Z 3 represents independently for each occurrence -X 1 -R , E, or
  • Z represents independently for each occurrence -X -R , E, or
  • Y 6 represents independently for each occurrence R 9 ,
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R 1 °) 2 , -SH, hydroxyalkyl, or
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl;
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H;
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 11 represents independently for each occurrence H, -OH, -N(R 10 ) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R ⁇ 2 I d R 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl; R represents independently for each occurrence H, alkyl, aryl, or aralkyl; R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ; R 15 represents independently for each occurrence H, alkyl, or -OR 10 ; R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or - C(NH 2 )N(R 10 ),;
  • v 1 and v 2 each represent independently for each occurrence 2, 3, or 4; w 1 and w 2 each represent independently for each occurrence an integer from about 5 to about 700, inclusive; x is 1, 2, or 3; y is O, 1, 2, 3, 4, or 5; z 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z 2 and z 3 each represent independently for each occurrence 1, 2, 3, 4, or 5;
  • X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-; X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 ); and
  • E represents independently for each occurrence H, - [C(R 1 ⁇ ] n C(O)H,
  • the present invention relates to the aforementioned method, wherein said polymerization agent is ultraviolet light, visible light, a compound of formula II, a compound of formula III, or an oxidizing agent.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein Z 1 represents independently for each occurrence -X 1 -R 4 or
  • the present invention relates to the aforementioned method, wherein Z 2 represents independently for each occurrence -X 1 -R 5 or
  • the present invention relates to the aforementioned method, wherein Z represents independently for each occurrence -X -R 6 or
  • the present invention relates to the aforementioned method, wherein Z 4 represents independently for each occurrence -X ⁇ R 7 or
  • the present invention relates to the aforementioned method, wherein Z 5 represents independently for each occurrence -X 1 -R 8 or
  • the present invention relates to the aforementioned method, wherein X 1 is O.
  • the present invention relates to the aforementioned method, wherein X 1 and X 2 are O. In certain instances, the present invention relates to the aforementioned method, wherein n is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, 3, or 4. In certain instances, the present invention relates to the aforementioned method, wherein p 2 is 1.
  • the present invention relates to the aforementioned method, wherein R 1 is H.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H, B , m
  • said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is R1 V , A 2 , m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , A 2 m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , m
  • Y 4 groups are and said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned method, wherein p 1 is 4.
  • the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H, B , m is 1
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is x > ⁇
  • a 2 is 1
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , , A 2 , m is 1
  • the present invention relates to the aforementioned method
  • R is H, B is , m is 1
  • the present invention relates to the aforementioned method,
  • the present invention relates to the aforementioned method
  • R is H, B is , m is 1
  • said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is '
  • K A 2 1 i-s , m is 1
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned method, wherein p 1 is 4.
  • the present invention relates to the aforementioned method, wherein m is 1. In certain instances, the present invention relates to the aforementioned method, wherein R 2 is (C r C 3 )alkyl.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , and v 1 is 2.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is A 2
  • the present invention relates to the aforementioned method
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R is H
  • B is , V 1 is 2, A 2
  • the present invention relates to the aforementioned method
  • Y 3 is V v R x1 R " 7'. ⁇ 2 R" 1
  • said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is is 2
  • the present invention relates to the aforementioned method
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • wherin w 1 is an integer in the range of about 50 to about 250.
  • the present invention relates to the aforementioned method, wherein w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method, wherein p 1 is 2.
  • the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-C 5 )alkyl. In certain instances, the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, R 3 is (Ci-Cs)alkyl, and w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is ,
  • a 2 is R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is R 1 R V favourv1
  • R 3 is alkyl
  • v 2 i is
  • V R 1 R 1 / P 2 R 1 said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is .”
  • V is alkyl
  • v 2 i IS
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein p is 2. In certain instances, the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-C 5 )alkyl.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-C 5 )alkyl, and w 2 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , AMs m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is 2
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , m
  • the present invention relates to the aforemention method, wherein said polymerization agent is a compound of formula II. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 1"11 is -C(O)H, and R " is H. In certain instances, the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 1"111 is -C(O)H, R 2"m is
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 2"111 is -C(O)H, R 2"111 is
  • w is an integer in the range of about 60-90.
  • the present invention relates to the aforemention method, wherein said polymerization agent is an oxidizing agent.
  • the present invention relates to the aforemention method, wherein said polymerization agent is O 2 .
  • the present invention relates to the aforemention method, wherein said polymerization agent is ultraviolet light or visible light. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is ultraviolet light.
  • the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 400-600 nm. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 450-550 nm.
  • the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 488-514 nm.
  • the present invention relates to the aforemention method, wherein said patient is a primate, bovine, equine, feline, or canine.
  • the present invention relates to the aforemention method, wherein said patient is a human.
  • the present invention relates to the aforemention method, wherein said wound is an ophthalmic wound. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is a wound to the cornea of an eye.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, corneal ulceration, retinal hole, leaking bleb, corneal transplant, trabeculectomy incision, sclerotomy incision, blepharoplasty, or skin incision.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, or corneal ulceration.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision or corneal laceration.
  • the present invention relates to the aforemention method, wherein said wound is less than 25 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 15 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is less than 10 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 5 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is sterile.
  • the present invention relates to the aforemention method, said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 "3 . In certain embodiments, the present invention relates to the aforemention method, said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 "6 .
  • Another aspect of the present invention relates to a method of sealing a wound of a patient, comprising the steps of:
  • R 1 represents independently for each occurrence H, -(C(R J ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H or alkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH,
  • R ]"VI represents independently for each occurrence -(C(R 2"VI ) 2 ) X C(O)H, -C(O)(C(R 2"
  • R 2"VI represents independently for each occurrence H, alkyl, or halogen; R represents independently for each occurrence fluoroalkyl, chloroalkyl, -
  • B is alkyl diradical, heteroalkyl diradical, or v 2"VI represents independently for each occurrence 2, 3, or 4; w 2"VI is an integer in the range of about 5 to 1000, inclusive; and x and y each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is an oxidizing agent.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is O 2 .
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula VI.
  • the present invention relates to the aforementioned method, wherein w 2"VI is an integer in the range of about 50 to about 250. In certain instances, the present invention relates to the aforementioned method, wherein w 2"VI is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula VI, R ⁇ vI is -C(O)H, and R 2"VI is H. In certain instances, the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula VI, R " is -C(O)H, R >2- " VI . is
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula VI, R' "VI is -C(O)H, R 2"VI is
  • the present invention relates to the aforementioned method, wherein R 1 ⁇ is -(C(R 2'VI ) 2 ) X C(O)R 3 ⁇ " or -C(O)(C(R 2'vl ) 2 ) y C(O)R 3"VI , R 2'VI is H, and R 3 ⁇ "
  • the present invention relates to the aforementioned method, wherein R 1 ⁇ " is -(C(R 2"V1 ) 2 ) X C(O)R 3 - VI or -C(O)(C(R 2 - VI ) 2 ) y C(O)R 3'VI , R 2"VI is H, R 3 ⁇ is
  • w 2"VI is an integer in the range of about 15-
  • the present invention relates to the aforementioned method, wherein n is 3, 4, or 5.
  • the present invention relates to the aforementioned method, wherein n is 4.
  • the present invention relates to the aforementioned method, wherein R 2 is H.
  • the present invention relates to the aforementioned method, wherein R 3 is H. In certain instances, the present invention relates to the aforementioned method, wherein R 4 is alkyl.
  • the present invention relates to the aforementioned method, wherein R 4 is methyl or ethyl.
  • the present invention relates to the aforementioned method, wherein n is 4, R 2 and R 3 is H, and R 4 is alkyl.
  • the present invention relates to the aforementioned method
  • R 1 is In certain instances, the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is and p is l.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is R 3 SH R 2 , and p is 1.
  • said pharmaceutically acceptable salt is a complex formed by said compound of formula V and a Bronstead acid.
  • the present invention relates to the aforementioned method, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula V and HA, wherein A is halogen or -O 2 CR 0 , and R° is alkyl, fluoroalkyl, aryl, or aralkyl.
  • the present invention relates to the aforementioned method, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula V and an acid selected from group consisting of HCl and HBr.
  • the present invention relates to the aforementioned method, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula V and HO 2 CR 6 , wherein R 6 is fluoroalkyl.
  • the present invention relates to the aforementioned method, wherein said pharmaceutically acceptable salt is a complex formed by said compound of formula V and CF 3 CO 2 H.
  • the present invention relates to the aforemention method, wherein said patient is a primate, bovine, equine, feline, or canine.
  • the present invention relates to the aforemention method, wherein said patient is a human.
  • the present invention relates to the aforemention method, wherein said wound is an ophthalmic wound.
  • the present invention relates to the aforemention method, wherein said wound is a wound to the cornea of an eye.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, corneal ulceration, retinal hole, leaking bleb, corneal transplant, trabeculectomy incision, sclerotomy incision, blepharoplasty, or skin incision.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, or corneal ulceration.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision or corneal laceration
  • the present invention relates to the aforemention method, wherein said wound is less than 25 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is less than 15 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 10 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is less than 5 mm long.
  • the present invention relates to the aforemention method, wherein said polymerization agent is sterile.
  • the present invention relates to the aforemention method, said sterilized compound of formula V and said polymerization agent have a sterility assurance level of at least about 10 "3 .
  • the present invention relates to the aforemention method, said sterilized compound of formlula V and said polymerization agent have a sterility assurance level of at least about 10 ⁇ 6 .
  • Another aspect of the present invention relates to a method of sealing a wound of a patient, comprising the steps of:
  • R 1 represents independently for each occurrence H, OH, -(C(R ) 2 ) m N(R )OH, - (C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -CO 2 (C(R 3 ) 2 ) m SH, -C(O)N(R 2 )(C(R 3 ) 2 ) m SH,
  • R 2 represents independently for each occurrence H or alkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence OH, -(C(R 3 ) 2 ) m N(R 2 )OH, - (C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -CO 2 (C(R 3 ) 2 ) m SH, -C(O)N(R 2 )(C(R 3 ) 2 ) m SH,
  • R 1 represents independently for each occurrence H, -(C(R 3 ) 2 ) m N(H)R 4 , - (C(R 3 ) 2 ) m N(R 4 )OH, -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -CO 2 (C(R 3 ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H, alkyl, or -(C(R ) 2 ) X OR ;
  • R 3 represents independently for each occurrence H, halogen, or alkyl;
  • R 4 represents independently for each occurrence H, alkyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence OH, -(C(R 3 ) 2 ) m N(R 2 )OH, - (C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -CO 2 (C(R 3 ) 2 ) m SH, -C(O)N(R 2 )(C(R 3 ) 2 ) m SH,
  • R 1 represents independently for each occurrence H, -(C(R J ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H, alkyl, -(C(R 3 ) 2 ) m YR 1 , OH, - (C(R 3 ) 2 ) m N(H)R 4 , -(C(R 3 ) 2 ) m N(R 4 )OH, -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence OH, -(C(R 3 ) 2 ) m N(R 2 )OH, -
  • Y represent independently for each occurrence O or NR 4 ; n and m each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p represents independently for each occurrence 1, 2, 3, 4, or 5; and x represents independently for each occurrence 1, 2, 3, or 4; formula X is represented by:
  • R 1 represents independently for each occurrence H, -(C(R 3 ) 2 ) m N(H)R 4 , - (C(R 3 ) 2 ) m N(R 4 )OH, -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH, -CO 2 (C(R 3 ) 2 ) m SH, -
  • R 2 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence OH, -(C(R 3 ) 2 ) m N(R 4 )OH, -
  • n and m each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p represents independently for each occurrence 1, 2, 3, 4, or 5; and x is 1 or 2; and formula XI is represented by:
  • R 2"X1 represents independently for each occurrence H, alkyl, or halogen
  • R 3"XI represents independently for each occurrence alkyl, fluoroalkyl, chloroalkyl,
  • R , 5-XI represents independently for each occurrence H, alkyl, or aralkyl
  • B is alkyl diradical, heteroalkyl diradical, or •
  • V " represents independently for each occurrence 2, 3, or 4; w 2"XI is an integer in the range of about 5 to 1000, inclusive; and x and y each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is an oxidizing agent.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is O 2 .
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula XI. In certain instances, the present invention relates to the aforementioned method, wherein w 2"XI is an integer in the range of about 50 to about 250.
  • the present invention relates to the aforementioned method, wherein w 2"XI is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula XI, R > l- " xi . is -(C(R 2-
  • R 2"XI is H
  • R 3"XI is or
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula XI, R* "XI is -(C(R 2"
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula XI, R' "XI is -(C(R 2"
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula XI, wherein B is
  • d 2"XI , e 2"XI , and g 2'XI represent independently an integer greater than zero, provided that the sum of d 2"XI , e 2"XI , and g 2'x ⁇ is an integer in the range of about 5 to 1000, inclusive.
  • the present invention relates to the aforementioned method, wherein, R 1 ⁇ 1 is -(C(R 2 - ⁇ i ) 2 ) x C(O)R 3"xl or -C(O)(C(R 2"XI ) 2 ) y C(O)R 3 - ⁇ i , R 2"XI is H, and R 3 ⁇ XI
  • the present invention relates to the aforementioned method
  • formula XI is and s is an integer in the range of about 1-20, inclusive.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VII.
  • the present invention relates to the aforementioned method, wherein n is 3, 4, or 5.
  • the present invention relates to the aforementioned method, wherein n is 4.
  • the present invention relates to the aforementioned method, wherein R 2 is H. In certain instances, the present invention relates to the aforementioned method, wherein R 3 is H.
  • the present invention relates to the aforementioned method, wherein R 4 is alkyl. In certain instances, the present invention relates to the aforementioned method, wherein R 4 is methyl or ethyl.
  • the present invention relates to the aforementioned method, wherein n is 4, R 2 and R 3 is H, and R 4 is alkyl. In certain instances, the present invention relates to the aforementioned method,
  • R 3 N-R2 wherein R 1 is R 2
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is and p is 1.
  • the present invention relates to the aforementioned method
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is and p is 1.
  • the present invention relates to the aforementioned method,
  • n 4, R 2 and R 3 are H, R 4 is methyl, R 1 is , and p is 1.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VIII. In certain instances, the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VIII, x and y are 1, R 2 is - CH 2 OR 1 , and R 3 is H.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VIII, x is 1, y is O, and R 2 and R 3 are H.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula IX.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula IX, x is 2, Y is O, R is - CH 2 CH 2 OR 1 , and R 3 is H.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula IX, x is 2, Y is NR 4 , and R 2 and R 3 are H. In certain instances, the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula X.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula X, R 2 is methyl, and x is 2.
  • the present invention relates to the aforementioned method, further comprising the step of exposing said dendrimeric compound to a compound of formula XII, wherein formula XII is represented by:
  • R ]"x ⁇ represents independently for each occurrence -(C(R 2'XII ) 2 ) x C(O)R 3"x ⁇ , -
  • R z"xu represents independently for each occurrence H, alkyl, or halogen
  • R 3"x represents independently for each occurrence alkyl, fluoroalkyl, chloroalkyl,
  • R 5'XI represents independently for each occurrence H, alkyl, or aralkyl
  • B -,XII is alkyl diradical, heteroalkyl diradical, or v 2"x ⁇ represents independently for each occurrence 2, 3, or 4; w 2"XI1 is an integer in the range of about 5 to 1000, inclusive; and x and y each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the present invention relates to the aforemention method
  • the present invention relates to the aforemention method
  • B X A I"I is W 2-Xll ⁇ v2-XII .
  • s 2j Rl-x ⁇ J 8 _ (c(R 2-xii )2) ⁇ C(O)R 3- XII or -C(O)(C(R ,2-- " X ⁇ I U K) 2 ) y C(O)R ,3 > -X ⁇ I 1 I 1 , ⁇ R,2"--X A I 1 I 1 is H, and or
  • the present invention relates to the aforemention method
  • B x ⁇ is v 2"x ⁇ is 2
  • R lo ⁇ i is -(C(R 2 - ⁇ iI ) 2 ) ⁇ C(O)R 3-
  • d " , e , and g represent independently an integer greater than zero, provided that the sum of d 2"XI , e 2"XI , and g 2"XI is an integer in the range of about 5 to 500, inclusive.
  • the present invention relates to the aforemention method, wherein said patient is a primate, bovine, equine, feline, or canine.
  • the present invention relates to the aforemention method, wherein said patient is a human. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is an ophthalmic wound.
  • the present invention relates to the aforemention method, wherein said wound is a wound to the cornea of an eye.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, corneal ulceration, retinal hole, leaking bleb, corneal transplant, trabeculectomy incision, sclerotomy incision, blepharoplasty, or skin incision.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, or corneal ulceration.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision or corneal laceration
  • the present invention relates to the aforemention method, wherein said wound is less than 25 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 15 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 10 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is less than 5 mm long.
  • the present invention relates to the aforemention method, further comprising the step of sterilizing said dendrimeric compound.
  • the present invention relates to the aforemention method, further comprising the step of sterilizing said dendrimeric compound and said polymerization agent, wherein said polymerization agent is a compound of formula XI.
  • the present invention relates to the aforemention method, wherein said sterilizing is performed by treatment with ethylene oxide, hydrogen peroxide, heat, gamma irradiation, electron beam irradiation, microwave irradiation, or visible light irradiation.
  • the present invention relates to the aforemention method, wherein said dendrimeric compound is sterile.
  • the present invention relates to the aforemention method, wherein said polymerization agent is sterile. In certain embodiments, the present invention relates to the aforemention method, said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 "3 .
  • the present invention relates to the aforemention method, said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 "6 .
  • Another aspect of the present invention relates to a method of sealing a wound of a patient, comprising the steps of:
  • a 2 is alkyl, aryl, aralkyl, -Si(R 3 ) 3 , or
  • a 3 represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y 1 represents independently for each occurrence R 4 , A 4 ,
  • Z 1 represents independently for each occurrence -X 1 -R 4 , E, or
  • Y 2 represents independently for each occurrence R , A ,
  • Z 2 represents independently for each occurrence -X 1 -R 5 , E, or h ⁇ 1 -@-f ⁇ 2 - ⁇ 3 ) t .
  • Y 3 represents independently for each occurrence R 6 , A 4
  • Z represents independently for each occurrence -X 1 - nR6 , E, or
  • Y 4 represents independently for each occurrence R 7 , A 4 ,
  • Z 4 represents independently for each occurrence -X'-R 7 , E, or
  • Y 5 represents independently for each occurrence R 5 A ,
  • Z 5 represents independently for each occurrence -X ⁇ R 8 , E, or
  • Y 6 represents independently for each occurrence R 9 , A 4 ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R 1 °) 2 , -SH, hydroxyalkyl, or
  • R represents independently for each occurrence alkyl, aryl, or aralkyl; r 6 R. 0 , ⁇ R>7', R s , and R y are H; i
  • R , 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl;
  • R 1 ' represents independently for each occurrence H, -OH, -N(R 1 °) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R ⁇ 2 ] C1 R 16 ;
  • R 12 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R'"
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R 16 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or - C(NH 2 )N(R 10 ),;
  • v 1 and v 2 each represent independently for each occurrence 2, 3, or 4; w 1 and w 2 each represent independently for each occurrence an integer from about 5 to about 700, inclusive; x is 1, 2, or 3; y is O, 1, 2, 3, 4, or 5; z 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z 2 and z 3 each represent independently for each occurrence 1, 2, 3, 4, or 5;
  • X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-; X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 );
  • a 4 represents independently for each occurrence CH 3 NH 2
  • R 1"11 represents independently for each occurrence H or
  • R " represents independently for each occurrence H or alkyl
  • R 3"11 represents independently for each occurrence H, halogen, or alkyl
  • R 4"11 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R " represents independently for each occurrence H or and z represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; and said formula III is represented by:
  • R , i'--i m ⁇ is -C(O)(C(R ,2 2 --I m IK) 2 ) y C(O)H, -(C(R 2 z --I m Ik) 2 ) x C(0)R ,3 > -i m n, or -
  • R 2"111 represents independently for each occurrence H, alkyl, or halogen
  • B ,1- ' i ⁇ is alkyl diradical, heteroalkyl diradical, or x represents independently for each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • y represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8;
  • v represents independently for each occurrence 2, 3, or 4;
  • w is an integer in the range of about 5 to about 1000, inclusive.
  • a 2 is alkyl, aryl, aralkyl,r -Si(R 3 ) 3 , 5H ⁇ 2 - ⁇ 1 ), or
  • a 3 represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y represents independently for each occurrence R ,
  • Z 1 represents independently for each occurrence -X 1 -R 4 , E, or
  • Y represents independently for each occurrence R ,
  • Z represents independently for each occurrence -X 1 - rR.5 , E, or
  • Y represents independently for each occurrence R ,
  • Z represents independently for each occurrence -X 1- n R6 , E, or
  • i represents independently for each occurrence -X'-R 7 , E, or
  • Z 5 represents independently for each occurrence -X'-R 8 , E, or
  • Y represents independently for each occurrence R ,
  • R 1 represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R 1 °) 2 , -SH, hydroxyalkyl, or -[C(R') 2 ] d R 16 ;
  • R 3 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H;
  • R 10 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 1 ' represents independently for each occurrence H, -OH, -N(R l ⁇ ) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R 1 ) 2 ] d R 16 ;
  • R 1 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 13 represents independently for each occurrence H, alkyl, aryl, or aralkyl
  • R 14 represents independently for each occurrence H, alkyl, or -CO 2 R 10 ;
  • R 15 represents independently for each occurrence H, alkyl, or -OR 10 ;
  • R represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 R 10 , -C(O)N(R 10 ) 2 , or - C(NH 2 )N(R 10 ),;
  • v 1 and v 2 each represent independently for each occurrence 2, 3, or 4; w 1 and w 2 each represent independently for each occurrence an integer from about 5 to about 700, inclusive; x is 1, 2, or 3; y is O, 1, 2, 3, 4, or 5; z 1 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z 2 and z 3 each represent independently for each occurrence 1, 2, 3, 4, or 5; X 1 and X 2 each represent independently for each occurrence O or -N(R 10 )-;
  • X 3 represents independently for each occurrence O, N(R 10 ), or C(R 15 )(CO 2 R 10 ); and E represents independently for each occurrence H, - [C(R 1 ⁇ ] n C(O)H, or
  • the present invention relates to the aforementioned method, wherein said polymerization agent is ultraviolet light, visible light, a compound of formula II, a compound of formula III, or an oxidizing agent.
  • the present invention relates to the aforementioned method
  • a 1 , and m is 1 or 2.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein Z 1 represents independently for each occurrence -X ! -R 4 or
  • the present invention relates to the aforementioned method, wherein Z 2 represents independently for each occurrence -X 1 -R 5 or
  • the present invention relates to the aforementioned method, wherein Z represents independently for each occurrence -X -R or
  • the present invention relates to the aforementioned method, wherein Z 4 represents independently for each occurrence -X 1 -R 7 or
  • the present invention relates to the aforementioned method, wherein Z 5 represents independently for each occurrence -X 1 -R 8 or
  • the present invention relates to the aforementioned method, wherein X 1 is O.
  • the present invention relates to the aforementioned method, wherein X 1 and X 2 are O.
  • the present invention relates to the aforementioned method, wherein n is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein p 2 is 1. In certain instances, the present invention relates to the aforementioned method, wherein R 1 is H. In certain instances, the present invention relates to the aforementioned method,
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • Y 1 is Z 1 Is
  • Y 2 is is
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R is H
  • B is , m
  • said polymerization agent is a compound of formula in.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is ,
  • a 2 is , m
  • the present invention relates to the aforementioned method
  • Y 4 groups are and said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method,
  • R 1 is H
  • B is , m
  • the present invention relates to the aforementioned method, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned method, wherein p 1 is 4.
  • the present invention relates to the aforementioned method, wherein m is 1. In certain instances, the present invention relates to the aforementioned method,
  • the present invention relates to the aforementioned method
  • R 1 is H, B is , m is 1
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R is H, B , m is 1 or 2, Y 1 is ,Y 2 is
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method,
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is '
  • a 2 is
  • said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is ,
  • a A 2 " i •s , m is 1
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is '
  • a 2 is 1
  • the present invention relates to the aforementioned method, wherein p 1 is 1, 2, 3, or 4.
  • the present invention relates to the aforementioned method, wherein p 1 is 2.
  • the present invention relates to the aforementioned method, wherein p 1 is 4. In certain instances, the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method, wherein R 2 is (d-C 3 )alkyl.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R is H, B is and v 1 is 2.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , v 1 is 2, A 2
  • the present invention relates to the aforementioned method
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method,
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is v 1 is 2
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein w 1 is an integer in the range of about 50 to about 250.
  • the present invention relates to the aforementioned method, wherein w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method, wherein p is 2.
  • the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-Cs)alkyl. In certain instances, the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, R 3 is (C]-C 5 )allcyl, and w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is V 1 is 2
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • said polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method
  • R is H, B is , R 3 is alkyl, v 2 is
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is ,
  • R 3 is alkyl
  • v 2 is
  • the present invention relates to the aforementioned method
  • polymerization agent is ultraviolet light or visible light.
  • the present invention relates to the aforementioned method, wherein p 1 is 2. In certain instances, the present invention relates to the aforementioned method, wherein m is 1.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-C 5 )alkyl.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, and R 3 is (Ci-Cs)alkyl, and w 2 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , A m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is In certain instances, the present invention relates to the aforementioned method
  • R is H
  • B is , m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , m
  • the present invention relates to the aforemention method, wherein said polymerization agent is a compound of formula II. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 1"111 is -C(O)H, and R 2"111 is H. In certain instances, the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 1"111 is -C(O)H, R 2"111 is
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 2"111 is -C(O)H, R 2"111 is
  • H 5 B and w is an integer in the range of about 60-90.
  • the present invention relates to the aforemention method, wherein said polymerization agent is an oxidizing agent.
  • the present invention relates to the aforemention method, wherein said polymerization agent is O 2 .
  • the present invention relates to the aforemention method, wherein said polymerization agent is ultraviolet light or visible light. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is ultraviolet light.
  • the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 400-600 nm. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 450-550 nm.
  • the present invention relates to the aforemention method, wherein said polymerization agent is light with a ⁇ of 488-514 nm.
  • the present invention relates to the aforemention method, wherein said patient is a primate, bovine, equine, feline, or canine.
  • the present invention relates to the aforemention method, wherein said patient is a human.
  • the present invention relates to the aforemention method, wherein said wound is an ophthalmic wound. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is a wound to the cornea of an eye.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, corneal ulceration, retinal hole, leaking bleb, corneal transplant, trabeculectomy incision, sclerotomy incision, blepharoplasty, or skin incision.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision, corneal laceration, corneal perforation, or corneal ulceration.
  • the present invention relates to the aforemention method, wherein said wound is a corneal incision ojr corneal laceration.
  • the present invention relates to the aforemention method, wherein said wound is less than 25 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 15 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said wound is less than 10 mm long.
  • the present invention relates to the aforemention method, wherein said wound is less than 5 mm long. In certain embodiments, the present invention relates to the aforemention method, wherein said polymerization agent is sterile.
  • the present invention relates to the aforemention method, wherein said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 ⁇ 3 . In certain embodiments, the present invention relates to the aforemention method, wherein said dendrimeric compound and said polymerization agent have a sterility assurance level of at least about 10 ⁇ 6 .
  • Another aspect of the present invention relates to a method of sealing a wound of a patient, comprising the steps of:
  • R 1 represents independently for each occurrence H, -(C(R J ) 2 ) m SH, -
  • R 2 represents independently for each occurrence H or alkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 4 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence -(C(R 3 ) 2 ) m SH, -C(O)(C(R 3 ) 2 ) m SH,
  • R ]"VI represents independently for each occurrence -(C(R 2"VI ) 2 ) X C(O)H, -C(O)(C(R 2
  • R 2"VI represents independently for each occurrence H, alkyl, or halogen;
  • R ,3-VI represents independently for each occurrence fluoroalkyl, chloroalkyl, -
  • B is alkyl diradical, heteroalkyl diradical, or v 2 ⁇ 1 represents independently for each occurrence 2, 3, or 4; w 2 ⁇ VI is an integer in the range of about 5 to 1000, inclusive; and x and y each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is an oxidizing agent.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is O 2 .
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula VI.

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Abstract

La présente invention a trait à des compositions et des procédés pour le scellement d'une plaie et la préparation d'une lentille. Les procédés de l'invention utilisent des macromolécules dendritiques formées par le traitement d'un composé dendritique avec de la lumière ou un composé de liaison. Dans certains modes de réalisation, les composés dendritiques ont un résidu de lysine, de cystéine, d'isocystéine ou autre groupe nucléophile lié à la périphérie du dendrimère. L'addition d'un composé contenant au moins deux groupes électrophiles tels que des aldéhydes, des esters activés, ou des acrylates aux dendrimères coiffés de lysine, de cystèine, ou d'isocystéine produit un composé polymérique qui peut former un scellement ou une lentille. Un autre mode de réalisation de l'invention a trait à un procédé de traitement de maladies mettant en oeuvre les compositions pharmaceutiques de l'invention. D'autres modes de réalisation de l'invention on trait à des trousses pour le scellement d'une plaie ou la préparation d'une lentille, de dispositifs d'administration, et à des procédés pour contrôler la polymérisation d'un système hydrogel.
PCT/US2005/029097 2004-08-13 2005-08-15 Polymeres dendritiques, gels reticules, et leurs utilisations comme agents de scellement et lentilles ophtalmiques WO2006031358A2 (fr)

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Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005051334A1 (de) * 2005-10-25 2007-06-21 Degussa Gmbh Präparate umfassend hyperverzweigte Polymere
WO2008016983A2 (fr) * 2006-08-02 2008-02-07 Baxter International Inc. Moyen de scellement sec agissant rapidement et procédés d'utilisation et de préparation
US7597882B2 (en) 2006-04-24 2009-10-06 Incept Llc Protein crosslinkers, crosslinking methods and applications thereof
WO2010093873A2 (fr) 2009-02-12 2010-08-19 Incept, Llc Délivrance de médicament par bouchons d'hydrogels
US7862538B2 (en) 2008-02-04 2011-01-04 Incept Llc Surgical delivery system for medical sealant
WO2011084465A2 (fr) 2009-12-15 2011-07-14 Incept, Llc Implants et marqueurs de référence biodégradables
US8211450B2 (en) 2010-05-05 2012-07-03 Senju Usa, Inc. Ophthalmic composition
US8262608B2 (en) 2007-01-25 2012-09-11 Hyperbranch Medical Technology, Inc. Applicators for multiple component formulations and the like, and methods of use thereof
US8282959B2 (en) 2006-11-27 2012-10-09 Actamax Surgical Materials, Llc Branched end reactants and polymeric hydrogel tissue adhesives therefrom
US8426492B2 (en) 2007-11-14 2013-04-23 Actamax Surgical Materials, Llc Oxidized cationic polysaccharide-based polymer tissue adhesive for medical use
US8431114B2 (en) 2004-10-07 2013-04-30 Actamax Surgical Materials, Llc Polysaccharide-based polymer tissue adhesive for medical use
US8445024B2 (en) 2005-10-25 2013-05-21 Evonik Degussa Gmbh Preparations containing hyperbranched polymers
WO2013086015A1 (fr) 2011-12-05 2013-06-13 Incept, Llc Procédés et compositions associés à un organogel médical
US8466327B2 (en) 2008-11-19 2013-06-18 Actamax Surgical Materials, Llc Aldehyde-functionalized polyethers and method of making same
US8551136B2 (en) 2008-07-17 2013-10-08 Actamax Surgical Materials, Llc High swell, long-lived hydrogel sealant
WO2013152999A1 (fr) * 2012-04-10 2013-10-17 Stratley Ag Procédé de production de caprolactame
US8580951B2 (en) 2009-07-02 2013-11-12 Actamax Surgical Materials, Llc Aldehyde-functionalized polysaccharides
US8580950B2 (en) 2009-07-02 2013-11-12 Actamax Surgical Materials, Llc Aldehyde-functionalized polysaccharides
US8796242B2 (en) 2009-07-02 2014-08-05 Actamax Surgical Materials, Llc Hydrogel tissue adhesive for medical use
US8961501B2 (en) 2010-09-17 2015-02-24 Incept, Llc Method for applying flowable hydrogels to a cornea
US9005609B2 (en) 2003-08-07 2015-04-14 Ethicon, Inc. Hemostatic compositions containing sterile thrombin
US9039783B2 (en) 2009-05-18 2015-05-26 Baxter International, Inc. Method for the improvement of mesh implant biocompatibility
US9044529B2 (en) 2008-11-19 2015-06-02 Actamax Surgical Materials, Llc Hydrogel tissue adhesive formed from aminated polysaccharide and aldehyde-functionalized multi-arm polyether
US9066779B2 (en) 2009-01-29 2015-06-30 Forsight Vision4, Inc. Implantable therapeutic device
US9084728B2 (en) 2010-06-01 2015-07-21 Baxter International Inc. Process for making dry and stable hemostatic compositions
US9125807B2 (en) 2007-07-09 2015-09-08 Incept Llc Adhesive hydrogels for ophthalmic drug delivery
WO2016094646A1 (fr) 2014-12-10 2016-06-16 Incept, Llc Implants d'administration de médicament à base d'hydrogel
US9393344B2 (en) 2006-01-11 2016-07-19 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
WO2016183296A1 (fr) 2015-05-12 2016-11-17 Incept, Llc Administration de médicament à partir d'hydrogels
WO2017091749A1 (fr) 2015-11-25 2017-06-01 Incept, Llc Dispositifs d'administration de médicaments à changement de forme et procédés
US9724078B2 (en) 2013-06-21 2017-08-08 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US9821025B2 (en) 2011-10-11 2017-11-21 Baxter International Inc. Hemostatic compositions
US9833541B2 (en) 2011-10-27 2017-12-05 Baxter International Inc. Hemostatic compositions
US9851351B2 (en) 2009-01-29 2017-12-26 Forsight Vision4, Inc. Posterior segment drug delivery
US9861521B2 (en) 2010-08-05 2018-01-09 Forsight Vision4, Inc. Injector apparatus and method for drug delivery
US9872934B2 (en) 2009-12-16 2018-01-23 Baxter International Inc. Hemostatic sponge
US9883968B2 (en) 2011-09-16 2018-02-06 Forsight Vision4, Inc. Fluid exchange apparatus and methods
US9895369B2 (en) 2014-08-08 2018-02-20 Forsight Vision4, Inc Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
WO2018058048A1 (fr) 2016-09-23 2018-03-29 Incept, Llc Dépôts pour l'administration de médicament en intracaméral
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US9999703B2 (en) 2012-06-12 2018-06-19 Ferrosan Medical Devices A/S Dry haemostatic composition
US10010448B2 (en) 2012-02-03 2018-07-03 Forsight Vision4, Inc. Insertion and removal methods and apparatus for therapeutic devices
US10111980B2 (en) 2013-12-11 2018-10-30 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
US10207021B2 (en) 2013-07-29 2019-02-19 Actamax Surgical Materials, Llc Low sweel tissue adhesive and sealant formulations
US10226417B2 (en) 2011-09-16 2019-03-12 Peter Jarrett Drug delivery systems and applications
US10258503B2 (en) 2014-07-15 2019-04-16 Forsight Vision4, Inc. Ocular implant delivery device and method
US10322170B2 (en) 2011-10-11 2019-06-18 Baxter International Inc. Hemostatic compositions
US10398592B2 (en) 2011-06-28 2019-09-03 Forsight Vision4, Inc. Diagnostic methods and apparatus
US10398593B2 (en) 2013-03-28 2019-09-03 Forsight Vision4, Inc. Ophthalmic implant for delivering therapeutic substances
US10441674B2 (en) 2010-04-07 2019-10-15 Baxter International Inc. Hemostatic sponge
JP2019532924A (ja) * 2016-09-13 2019-11-14 ヘンケル・アクチェンゲゼルシャフト・ウント・コムパニー・コマンディットゲゼルシャフト・アウフ・アクチェンＨｅｎｋｅｌ ＡＧ ＆ Ｃｏ．ＫＧａＡ シラン及び該シランを含む硬化性組成物
US10500091B2 (en) 2014-11-10 2019-12-10 Forsight Vision4, Inc. Expandable drug delivery devices and methods of use
US10550187B2 (en) 2014-10-24 2020-02-04 Incept, Llc Extra luminal scaffold
US10617557B2 (en) 2010-08-05 2020-04-14 Forsight Vision4, Inc. Combined drug delivery methods and apparatus
US10653837B2 (en) 2014-12-24 2020-05-19 Ferrosan Medical Devices A/S Syringe for retaining and mixing first and second substances
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US10918796B2 (en) 2015-07-03 2021-02-16 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
US11046818B2 (en) 2014-10-13 2021-06-29 Ferrosan Medical Devices A/S Dry composition for use in haemostasis and wound healing
US11109849B2 (en) 2012-03-06 2021-09-07 Ferrosan Medical Devices A/S Pressurized container containing haemostatic paste
US11419759B2 (en) 2017-11-21 2022-08-23 Forsight Vision4, Inc. Fluid exchange apparatus for expandable port delivery system and methods of use
US11432959B2 (en) 2015-11-20 2022-09-06 Forsight Vision4, Inc. Porous structures for extended release drug delivery devices
CN115414360A (zh) * 2022-08-30 2022-12-02 上海交通大学医学院附属仁济医院 全反式维甲酸联合抗生素在治疗假体周围感染中的应用
US11617680B2 (en) 2016-04-05 2023-04-04 Forsight Vision4, Inc. Implantable ocular drug delivery devices
US11801324B2 (en) 2018-05-09 2023-10-31 Ferrosan Medical Devices A/S Method for preparing a haemostatic composition
USD1033637S1 (en) 2022-01-24 2024-07-02 Forsight Vision4, Inc. Fluid exchange device

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8603511B2 (en) 1996-08-27 2013-12-10 Baxter International, Inc. Fragmented polymeric compositions and methods for their use
US8303981B2 (en) 1996-08-27 2012-11-06 Baxter International Inc. Fragmented polymeric compositions and methods for their use
US8834864B2 (en) 2003-06-05 2014-09-16 Baxter International Inc. Methods for repairing and regenerating human dura mater
EP2259803B2 (fr) 2008-02-29 2019-03-13 Ferrosan Medical Devices A/S Dispositif pour la promotion de l homéostasie et/ou la cicatrisation des plaies
EP2416811B1 (fr) 2009-04-09 2015-09-09 Actamax Surgical Materials LLC Adhésif de type hydrogel pour tissus, ayant un temps de dégradation réduit
JP5719355B2 (ja) 2009-06-16 2015-05-20 バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ 止血スポンジ
US8940335B2 (en) 2010-06-01 2015-01-27 Baxter International Inc. Process for making dry and stable hemostatic compositions
BR112012030457B1 (pt) 2010-06-01 2021-03-09 Baxter International Inc. processo para fabricar uma composição hemostática seca e estável, recipiente acabado final, método para prover uma composição hemostática pronta para uso, e, kit para administrar uma composição hemostática
CN103209664A (zh) 2010-08-05 2013-07-17 弗赛特影像4股份有限公司 可植入的治疗装置
US8859705B2 (en) 2012-11-19 2014-10-14 Actamax Surgical Materials Llc Hydrogel tissue adhesive having decreased gelation time and decreased degradation time

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6224898B1 (en) * 2000-03-23 2001-05-01 The United States Of America As Represented By The Secretary Of The Army Antimicrobial dendrimer nanocomposites and a method of treating wounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6224898B1 (en) * 2000-03-23 2001-05-01 The United States Of America As Represented By The Secretary Of The Army Antimicrobial dendrimer nanocomposites and a method of treating wounds

Cited By (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9005609B2 (en) 2003-08-07 2015-04-14 Ethicon, Inc. Hemostatic compositions containing sterile thrombin
US8771738B2 (en) 2004-10-07 2014-07-08 Actamax Surgical Materials, Llc Polysaccharide-based polymer tissue adhesive for medical use
US8715636B2 (en) 2004-10-07 2014-05-06 Actamax Surgical Materials, Llc Polysaccharide-based polymer tissue adhesive for medical use
US8431114B2 (en) 2004-10-07 2013-04-30 Actamax Surgical Materials, Llc Polysaccharide-based polymer tissue adhesive for medical use
US8445024B2 (en) 2005-10-25 2013-05-21 Evonik Degussa Gmbh Preparations containing hyperbranched polymers
DE102005051334A1 (de) * 2005-10-25 2007-06-21 Degussa Gmbh Präparate umfassend hyperverzweigte Polymere
US9393344B2 (en) 2006-01-11 2016-07-19 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
US10688216B2 (en) 2006-01-11 2020-06-23 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
US11027043B1 (en) 2006-01-11 2021-06-08 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
US11826485B2 (en) 2006-01-11 2023-11-28 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
US9878066B2 (en) 2006-01-11 2018-01-30 Hyperbranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
US7597882B2 (en) 2006-04-24 2009-10-06 Incept Llc Protein crosslinkers, crosslinking methods and applications thereof
US9498557B2 (en) 2006-04-24 2016-11-22 Incept, Llc Crosslinking methods and applications thereof
EP3909619A1 (fr) * 2006-08-02 2021-11-17 Baxter International Inc Produit d'étanchéité sec à action rapide et procédés d'utilisation et de fabrication
KR101401873B1 (ko) * 2006-08-02 2014-05-29 박스터 헬쓰케어 에스에이 속효성 무수 밀봉제 및 그의 사용 및 제조 방법
WO2008016983A2 (fr) * 2006-08-02 2008-02-07 Baxter International Inc. Moyen de scellement sec agissant rapidement et procédés d'utilisation et de préparation
WO2008016983A3 (fr) * 2006-08-02 2009-03-26 Baxter Int Moyen de scellement sec agissant rapidement et procédés d'utilisation et de préparation
AU2007281138B2 (en) * 2006-08-02 2013-05-02 Baxter Healthcare S.A. Rapidly acting dry sealant and methods for use and manufacture
JP2013048936A (ja) * 2006-08-02 2013-03-14 Baxter Internatl Inc 急速作用性の組織密閉材およびその使用および製造方法
JP2009545405A (ja) * 2006-08-02 2009-12-24 バクスター・インターナショナル・インコーポレイテッド 急速作用性の組織密閉材およびその使用および製造方法
EP2468310A1 (fr) * 2006-08-02 2012-06-27 Baxter International Inc Produit d'étanchéité sec à action rapide et procédés d'utilisation et de fabrication
US8282959B2 (en) 2006-11-27 2012-10-09 Actamax Surgical Materials, Llc Branched end reactants and polymeric hydrogel tissue adhesives therefrom
US8262608B2 (en) 2007-01-25 2012-09-11 Hyperbranch Medical Technology, Inc. Applicators for multiple component formulations and the like, and methods of use thereof
US9775906B2 (en) 2007-07-09 2017-10-03 Incept Llc Hydrogel polymeric compositions and methods
US11324828B2 (en) 2007-07-09 2022-05-10 Incept, Llc Hydrogel polymeric compositions and methods
US10251954B2 (en) 2007-07-09 2019-04-09 Incept, Llc Hydrogel polymeric compositions and methods
US9125807B2 (en) 2007-07-09 2015-09-08 Incept Llc Adhesive hydrogels for ophthalmic drug delivery
US8426492B2 (en) 2007-11-14 2013-04-23 Actamax Surgical Materials, Llc Oxidized cationic polysaccharide-based polymer tissue adhesive for medical use
US7862538B2 (en) 2008-02-04 2011-01-04 Incept Llc Surgical delivery system for medical sealant
US8551136B2 (en) 2008-07-17 2013-10-08 Actamax Surgical Materials, Llc High swell, long-lived hydrogel sealant
US8466327B2 (en) 2008-11-19 2013-06-18 Actamax Surgical Materials, Llc Aldehyde-functionalized polyethers and method of making same
US9044529B2 (en) 2008-11-19 2015-06-02 Actamax Surgical Materials, Llc Hydrogel tissue adhesive formed from aminated polysaccharide and aldehyde-functionalized multi-arm polyether
US9066779B2 (en) 2009-01-29 2015-06-30 Forsight Vision4, Inc. Implantable therapeutic device
US10656152B2 (en) 2009-01-29 2020-05-19 Forsight Vision4, Inc. Posterior segment drug delivery
US10813788B2 (en) 2009-01-29 2020-10-27 Forsight Vision4, Inc. Implantable therapeutic device
US9851351B2 (en) 2009-01-29 2017-12-26 Forsight Vision4, Inc. Posterior segment drug delivery
US11642310B2 (en) 2009-01-29 2023-05-09 Forsight Vision4, Inc. Posterior segment drug delivery
WO2010093873A2 (fr) 2009-02-12 2010-08-19 Incept, Llc Délivrance de médicament par bouchons d'hydrogels
US8409606B2 (en) 2009-02-12 2013-04-02 Incept, Llc Drug delivery through hydrogel plugs
US9039783B2 (en) 2009-05-18 2015-05-26 Baxter International, Inc. Method for the improvement of mesh implant biocompatibility
US8580951B2 (en) 2009-07-02 2013-11-12 Actamax Surgical Materials, Llc Aldehyde-functionalized polysaccharides
US8796242B2 (en) 2009-07-02 2014-08-05 Actamax Surgical Materials, Llc Hydrogel tissue adhesive for medical use
US8580950B2 (en) 2009-07-02 2013-11-12 Actamax Surgical Materials, Llc Aldehyde-functionalized polysaccharides
US10272164B2 (en) 2009-12-15 2019-04-30 Incept, Llc Implants and biodegradable tissue markers
US11083802B2 (en) 2009-12-15 2021-08-10 Incept, Llc Echolucent implant compositions and methods
US11786612B2 (en) 2009-12-15 2023-10-17 Incept, Llc Implant and biodegradable tissue marker compositions and methods
US9669117B2 (en) 2009-12-15 2017-06-06 Incept, Llc Implants and biodegradable tissue markers
EP3583960A1 (fr) 2009-12-15 2019-12-25 Incept, LLC Implants et marqueurs de repère biodégradables
US8383161B2 (en) 2009-12-15 2013-02-26 Incept, Llc Radioopaque covalently crosslinked hydrogel particle implants
US10786581B2 (en) 2009-12-15 2020-09-29 Incept, Llc Implants and biodegradable tissue markers
US11154624B2 (en) 2009-12-15 2021-10-26 Incept, Llc Echolucent implant compositions and methods
WO2011084465A2 (fr) 2009-12-15 2011-07-14 Incept, Llc Implants et marqueurs de référence biodégradables
EP3960215A1 (fr) 2009-12-15 2022-03-02 Incept, LLC Implants et marqueurs de repère biodégradables
US11160883B2 (en) 2009-12-15 2021-11-02 Incept, Llc Echolucent implant composition and methods
US9872934B2 (en) 2009-12-16 2018-01-23 Baxter International Inc. Hemostatic sponge
US11071804B2 (en) 2009-12-16 2021-07-27 Baxter International Inc. Hemostatic sponge
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
US10441674B2 (en) 2010-04-07 2019-10-15 Baxter International Inc. Hemostatic sponge
US11478566B2 (en) 2010-04-07 2022-10-25 Baxter International Inc. Hemostatic sponge
US8211450B2 (en) 2010-05-05 2012-07-03 Senju Usa, Inc. Ophthalmic composition
US10245348B2 (en) 2010-06-01 2019-04-02 Baxter International Inc. Process for making dry and stable hemostatic compositions
US12208176B2 (en) 2010-06-01 2025-01-28 Baxter International Inc. Process for making dry and stable hemostatic compositions
US9084728B2 (en) 2010-06-01 2015-07-21 Baxter International Inc. Process for making dry and stable hemostatic compositions
US10994045B2 (en) 2010-06-01 2021-05-04 Baxter International Inc. Process for making dry and stable hemostatic compositions
US9861521B2 (en) 2010-08-05 2018-01-09 Forsight Vision4, Inc. Injector apparatus and method for drug delivery
US11786396B2 (en) 2010-08-05 2023-10-17 Forsight Vision4, Inc. Injector apparatus and method for drug delivery
US10265215B2 (en) 2010-08-05 2019-04-23 Forsight Vision4, Inc. Injector apparatus and method for drug delivery
US10617557B2 (en) 2010-08-05 2020-04-14 Forsight Vision4, Inc. Combined drug delivery methods and apparatus
US11679027B2 (en) 2010-08-05 2023-06-20 Forsight Vision4, Inc. Combined drug delivery methods and apparatus
US8961501B2 (en) 2010-09-17 2015-02-24 Incept, Llc Method for applying flowable hydrogels to a cornea
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US11065151B2 (en) 2010-11-19 2021-07-20 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US10398592B2 (en) 2011-06-28 2019-09-03 Forsight Vision4, Inc. Diagnostic methods and apparatus
US11813196B2 (en) 2011-06-28 2023-11-14 Forsight Vision4, Inc. Diagnostic methods and apparatus
US10226417B2 (en) 2011-09-16 2019-03-12 Peter Jarrett Drug delivery systems and applications
US9883968B2 (en) 2011-09-16 2018-02-06 Forsight Vision4, Inc. Fluid exchange apparatus and methods
US10653554B2 (en) 2011-09-16 2020-05-19 Forsight Vision4, Inc. Fluid exchange apparatus and methods
US10322170B2 (en) 2011-10-11 2019-06-18 Baxter International Inc. Hemostatic compositions
US9821025B2 (en) 2011-10-11 2017-11-21 Baxter International Inc. Hemostatic compositions
US9833541B2 (en) 2011-10-27 2017-12-05 Baxter International Inc. Hemostatic compositions
WO2013086015A1 (fr) 2011-12-05 2013-06-13 Incept, Llc Procédés et compositions associés à un organogel médical
EP3613413A1 (fr) 2011-12-05 2020-02-26 Incept, LLC Procédés d'organogel médical et compositions
US10010448B2 (en) 2012-02-03 2018-07-03 Forsight Vision4, Inc. Insertion and removal methods and apparatus for therapeutic devices
US10603209B2 (en) 2012-02-03 2020-03-31 Forsight Vision4, Inc. Insertion and removal methods and apparatus for therapeutic devices
US11109849B2 (en) 2012-03-06 2021-09-07 Ferrosan Medical Devices A/S Pressurized container containing haemostatic paste
WO2013152999A1 (fr) * 2012-04-10 2013-10-17 Stratley Ag Procédé de production de caprolactame
US10799611B2 (en) 2012-06-12 2020-10-13 Ferrosan Medical Devices A/S Dry haemostatic composition
US9999703B2 (en) 2012-06-12 2018-06-19 Ferrosan Medical Devices A/S Dry haemostatic composition
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US10398593B2 (en) 2013-03-28 2019-09-03 Forsight Vision4, Inc. Ophthalmic implant for delivering therapeutic substances
US12115102B2 (en) 2013-03-28 2024-10-15 Forsight Vision4, Inc. Ophthalmic implant for delivering therapeutic substances
US11510810B2 (en) 2013-03-28 2022-11-29 Forsight Vision4, Inc. Ophthalmic implant for delivering therapeutic substances
US9724078B2 (en) 2013-06-21 2017-08-08 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US10595837B2 (en) 2013-06-21 2020-03-24 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
US10207021B2 (en) 2013-07-29 2019-02-19 Actamax Surgical Materials, Llc Low sweel tissue adhesive and sealant formulations
US10111980B2 (en) 2013-12-11 2018-10-30 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US11103616B2 (en) 2013-12-11 2021-08-31 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
US11337853B2 (en) 2014-07-15 2022-05-24 Forsight Vision4, Inc. Ocular implant delivery device and method
US10258503B2 (en) 2014-07-15 2019-04-16 Forsight Vision4, Inc. Ocular implant delivery device and method
US9895369B2 (en) 2014-08-08 2018-02-20 Forsight Vision4, Inc Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US10765677B2 (en) 2014-08-08 2020-09-08 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US10363255B2 (en) 2014-08-08 2019-07-30 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US11046818B2 (en) 2014-10-13 2021-06-29 Ferrosan Medical Devices A/S Dry composition for use in haemostasis and wound healing
US10550187B2 (en) 2014-10-24 2020-02-04 Incept, Llc Extra luminal scaffold
US11377498B2 (en) 2014-10-24 2022-07-05 Incept, Llc Extra luminal scaffold
US12251336B2 (en) 2014-11-10 2025-03-18 Forsight Vision4, Inc. Expandable drug delivery devices and methods of use
US11110001B2 (en) 2014-11-10 2021-09-07 Forsight Vision4, Inc. Expandable drug delivery devices and methods of use
US10500091B2 (en) 2014-11-10 2019-12-10 Forsight Vision4, Inc. Expandable drug delivery devices and methods of use
EP3858329A1 (fr) 2014-12-10 2021-08-04 Incept, LLC Implants d'administration de médicament à base d'hydrogel
WO2016094646A1 (fr) 2014-12-10 2016-06-16 Incept, Llc Implants d'administration de médicament à base d'hydrogel
US10653837B2 (en) 2014-12-24 2020-05-19 Ferrosan Medical Devices A/S Syringe for retaining and mixing first and second substances
WO2016183296A1 (fr) 2015-05-12 2016-11-17 Incept, Llc Administration de médicament à partir d'hydrogels
EP4279064A2 (fr) 2015-05-12 2023-11-22 Incept, LLC Administration de médicament à partir d'hydrogels
US11369591B2 (en) 2015-05-12 2022-06-28 Incept, Llc Drug delivery from hydrogels
US10918796B2 (en) 2015-07-03 2021-02-16 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
US11432959B2 (en) 2015-11-20 2022-09-06 Forsight Vision4, Inc. Porous structures for extended release drug delivery devices
US12201556B2 (en) 2015-11-20 2025-01-21 Forsight Vision4, Inc. Porous structures for extended release drug delivery devices
US10786462B2 (en) 2015-11-25 2020-09-29 Incept, Llc Shape changing drug delivery devices and methods
US10420724B2 (en) 2015-11-25 2019-09-24 Incept, Llc Shape changing drug delivery devices and methods
US11413250B2 (en) 2015-11-25 2022-08-16 Incept, Llc Shape changing drug delivery devices and methods
WO2017091749A1 (fr) 2015-11-25 2017-06-01 Incept, Llc Dispositifs d'administration de médicaments à changement de forme et procédés
US11938223B2 (en) 2015-11-25 2024-03-26 Incept, Llc Shape changing drug delivery devices and methods
US11617680B2 (en) 2016-04-05 2023-04-04 Forsight Vision4, Inc. Implantable ocular drug delivery devices
US12102560B2 (en) 2016-04-05 2024-10-01 Forsight Vision4, Inc. Implantable ocular drug delivery devices
JP2019532924A (ja) * 2016-09-13 2019-11-14 ヘンケル・アクチェンゲゼルシャフト・ウント・コムパニー・コマンディットゲゼルシャフト・アウフ・アクチェンＨｅｎｋｅｌ ＡＧ ＆ Ｃｏ．ＫＧａＡ シラン及び該シランを含む硬化性組成物
US12171869B2 (en) 2016-09-23 2024-12-24 Incept, Llc Intracameral drug delivery depots
EP4197527A1 (fr) 2016-09-23 2023-06-21 Incept, LLC Dépôts d'administration de médicament par caméra
WO2018058048A1 (fr) 2016-09-23 2018-03-29 Incept, Llc Dépôts pour l'administration de médicament en intracaméral
US11419759B2 (en) 2017-11-21 2022-08-23 Forsight Vision4, Inc. Fluid exchange apparatus for expandable port delivery system and methods of use
US11801324B2 (en) 2018-05-09 2023-10-31 Ferrosan Medical Devices A/S Method for preparing a haemostatic composition
USD1033637S1 (en) 2022-01-24 2024-07-02 Forsight Vision4, Inc. Fluid exchange device
CN115414360A (zh) * 2022-08-30 2022-12-02 上海交通大学医学院附属仁济医院 全反式维甲酸联合抗生素在治疗假体周围感染中的应用

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