WO2006031388A2 - Polymeres dendritiques et gels reticules: utilisations dans des applications orthopediques - Google Patents

Polymeres dendritiques et gels reticules: utilisations dans des applications orthopediques Download PDF

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WO2006031388A2
WO2006031388A2 PCT/US2005/029915 US2005029915W WO2006031388A2 WO 2006031388 A2 WO2006031388 A2 WO 2006031388A2 US 2005029915 W US2005029915 W US 2005029915W WO 2006031388 A2 WO2006031388 A2 WO 2006031388A2
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WO2006031388A3 (fr
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Mark W. Grinstaff
Michael A. Carnahan
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Hyperbranch Medical Technology, Inc.
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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Definitions

  • Dendritic Polymers Crosslinked Gels, and Their Uses in Orthopedic Applications
  • Cartilaginous tissues play important roles in contributing to load support and energy dissipation in the joints of the musculoskeletal system.
  • These tissues include articular cartilage which is predominantly an avascular and alymphatic tissue with very low cell- density.
  • articular cartilage has limited capacity for self-repair following injury or aging. Degeneration of cartilage in the meniscus, interverebral disks, or joints can lead to severe and debilitating pain in patients. Injuries to these tissues are often retained for many years and may eventually lead to more severe secondary damage. See Moskowitz, R. W., Osteoarthritis: diagnosis and medical/surgical management. 2" ed.; W.B. Saunders Company: 1984.
  • the nearly frictionless surface of articular cartilage is unmatched in vivo and provides for important sliding articulations in the shoulder, hip, and knee.
  • the meniscus contributes to overall joint stability which may be compromised with injury. See Levy, I. M.; Torzilli, P. A.; Fisch, I. D. The contribution of the menisci to the stability of the knee. In Knee Meniscus. Basic and Clinical Foundations; Mow, V. C; Arnoczky, S. P.; Jackson, D. W., Eds.; Raven Press: New York, 1992; pp 107-116.
  • Articular cartilage and meniscus contain collagen fibers that are highly, and variably, oriented through the tissue. See Heinegard, D.; Bayliss, M. J.; Lorenzo, P. Biochemistry and metabolism of normal and osteoarthritic articular cartilage. In Osteoarthritis; Brandt, K. D.; Doherty, M.; Lohmander, L. S., Eds.; Oxford University Press: New York, 1998; pp 74-84.
  • the collagen fibril network in articular cartilage consists principally of type II collagen (a defining characteristic), while the meniscus mostly contains large diameter and circumferentially oriented type I collagen fibers.
  • Both matrices are distributed with smaller amounts of other collagens (i.e., types III, V, and VI for meniscus; types XI, VI, and IX for articular cartilage) and negatively-charged proteoglycans including aggrecan, decorin and biglycan. See Adams, M. E.; Hukins, D. W. L. The extracellular matrix of the meniscus. In Knee meniscus: Basic and Clinical Foundations; Mow VC, A. S., Jackson DW, Eds.; Raven Press: New York, 1992; pp 15-28 and Eyre, D. Collagen structure and function in articular cartilage.
  • the meniscus contains complex subpopulations of cells that exhibit both fibroblast-like and chondrocyte-like morphologies and biological activities that may vary with region.
  • native cells are responsible for both the synthesis and maintenance of the composition and structure of the extracellular matrix over the lifetime of a joint.
  • articular cartilage In a healthy joint, articular cartilage is able to withstand the large forces associated with load-bearing and joint motion over the lifetime of an individual. Following injury or with osteoarthritis, cartilage may exhibit fibrillation or cracking of the articular surface with partial or complete loss of the tissue. See Pritzker, K. P. H., Pathology of osteoarthritis. In Osteoarthritis; Brandt, K. D.; Doherty, M.; Lohmander, L. S., Eds.; Oxford University Press: New York, 1998; pp 50-62. Articular cartilage is limited in its ability to self-repair due to the lack of a vascular supply.
  • Osteoarthritis and Cartilage 1995, 3(4), 261-267 Although partial or total meniscectomy may be performed for a range of injuries from small radial tears to more severe and complex tears, restoration of normal meniscal function is the treatment of choice when technically possible.
  • the ability of a meniscal lesion to heal, either spontaneously or following surgical repair, is dependent on the proximity of the tear to the peripheral vascular supply, the size and complexity of the tear, and the integrity of the extracellular matrix. See Arnoczky, S. P.; Warren, R. F. Am. J. Sports Med. 1983, 11(3), 131-141.
  • Representative synthetic linear polymers include polyethylene glycol (PEG), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(caprolactone), poly(propylene fumarate), poly(NIPAMM), polyurethanes and various co-polymers.
  • PEG polyethylene glycol
  • PGA poly(glycolic acid)
  • PLA poly(lactic acid)
  • PCA poly(caprolactone)
  • NIPAMM polyurethanes and various co-polymers.
  • Natural scaffolds have also been widely studied for cartilage repair, including alginate, agarose, hyaluronan, chitosan, fibrin, type I and II collagen, and small intestine submucosa.
  • Some scaffolds have been evaluated in animal models of osteochondral defects with evidence of some "positive outcomes" as evaluated by histological appearance, biochemistry, or immunohistochemistry.
  • the overwhelming majority of the scaffolds studied for in vivo repair were formed in vitro and implanted into the tissue defect.
  • the implantation generally used suture fixation and often resulted in problems integrating the implant with the adjacent tissue.
  • Biomaterials that polymerize in situ are generally low-viscosity solutions that permit mixing with cells and/or bioactive factors which may be polymerized or crosslinked in situ.
  • the polymerization or crosslinking is usually accomplished via chemical initiation or the use of light. Thus, these polymers may readily flow into and fill an irregularly shaped defect and be subsequently transformed from a liquid to a solid in a controlled manner.
  • Alginate was one of the earliest materials to be investigated as an injectable in situ polymerizing scaffold for articular cartilage repair. More recently, investigators have proposed formulations for articular cartilage repair based on synthetic linear polymers that are either thermally or photochemically activated such as poly(N-isopropylacrylamide), poly(propylene fumarate), PEG, PVA, and poly(anhydrides). See Stile, R. A.; Burghardt, W. R.; Healy, K. E. Macromolecules 1999, 32(22), 7370-7379; Burkoth, A.; Anseth, K. Biomaterials 2000, 21, 2395-404; Schmedlen, R. H.; Masters, K. S.; West, J. L.
  • a thermally responsive elastin-like polypeptide (ELP) scaffold for cartilage repair has been described as well as an injectable, photopolymerizing hyaluronan for cartilage repair.
  • the hyaluronan-based hydrogels were evaluated in a rabbit osteochondral defect model with results that demonstrated good filling and integration with native tissue, cellular infiltration, and synthesis of a type II collagen-containing extracellular matrix.
  • Tissue engineering approaches promise the ability to repair or regenerate cartilaginous tissues by using combinations of cells, biomaterials, and biologically active molecules.
  • the present invention fulfills this need, and has other related advantages.
  • the present invention generally relates to methods of repairing defects in cartilaginous tissue.
  • the cartilaginous tissue is articular.
  • the compositions used to repair the tissue defect 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 gel.
  • the dendritic polymers have a lysine, cysteine, isocysteine residue or other nucleophilic group attached to the periphery of the dendrimer.
  • compositions used to repair the defect 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-capped or isocysteine-capped polylysine compounds produces a polymeric compound that can form a gel.
  • the compound containing the electrophilic groups comprises a copolymer of polyethylene glycol and polypropylene glycol.
  • 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 dendrimer amenable to the present invention.
  • Figure 11 depicts photocrosslinkable PEG 34 oo-(PGLSA-MA 4 ) 2 macromer 1 for hydrogel formation.
  • Figure 13 depicts the complex modulus ⁇ G* ⁇ , storage modulus G', loss modulus G" and loss angle J of crosslinked hydrogel samples at 4 different concentrations of macromer 1 in PBS.
  • Figure 14 depicts a determination of the compressive modulus E, as a function of concentration of macromer 1 in PBS.
  • the compression-relaxation experiment for 20 % 1 is shown on the left, the linear curve fits for all concentrations and the resulting compressive modulus E is shown on the right.
  • Figure 15 depicts histological sections of hydrogels with 7.5 % or 15 % macromer 1 after 2 or 4 weeks incubation. Top: Proteoglycans were stained in the Safranin-0 sections; collagen was stained in the Masson's Trichrome sections. Bottom: Type I and type II collagen were immunostained; no significant type I collagen was detected at either concentration. The length of the inserted bar is 100 ⁇ m.
  • the present invention generally relates to the use of dendritic polymers in treating defects in cartilaginous tissue.
  • the dendrimers are treated with a polymerization agent to form a polymeric gel.
  • the dendrimer-based hydrogels provide a temporary scaffold for new tissue growth, can be used to deliver growth factors, can be used with cartilage or bone cells, and can be used with stem cells to regenerate tissue.
  • the dendritic polymers of the invention provide a lower viscosity solution, a higher mechanical-strength network, a lower weight-percent polymer requirement, and a greater water content when crosslinked than end-functionalized linear polymers.
  • the properties of the dendrimers of the invention provide significant advantages over existing polymers for in situ forming scaffolds, as well as the ability to confer diverse functionalization of the dendritic branches.
  • the dendritic macromolecules of the invention are used in conjuction with a natural polymer such as HA, collagen, or GAG fragments such that a hydrogel is formed that contains both the dendritic components and the natural polymer.
  • the dendritic polymers/macromolecule compositions of the invention are useful in orthopedic surgery.
  • the dendritic polymers/macromolecule compositions of the invention can be used to repair articular cartilage.
  • repair of cartilaginous tissue is just one orthopedic application, and one skilled in the art can readily determine the utility of these polymers and their hydrogels for other orthopedic applications.
  • the dendritic compounds of the invention contain a reactive functional group on the terminus of the dendrimer that undergoes reaction with a polymerization agent to form a repair agent used to treat the cartilage defect.
  • the reactive functional group is an acrylate group or a nucleophile.
  • Dendrimeric compounds functionalized with acrylate groups polymerize under the influence of ultraviolet light.
  • a photoinitiator is added to the monomelic dendrimer. A large number of photoinitiators are known in the art and are amenable to the present invention.
  • Photoinitiators include ethyl eosin, eosin Y, fluorescein, 2,2-dimethoxy-2 -phenyl acetophenone, 2- methoxy-2-phenylacetophenone, camphorquinone, rose bengal, methylene blue, erythrosin, phloxime, thionine, riboflavin, methylene green, acridine orange, xanthine dye, and thioxanthine dyes.
  • the photoinitiator is eosin Y.
  • the polymerized dendrimeric composition can be used to repair a cartilage defect.
  • the reactive functional group on the terminus of the dendrimer is a cysteine group.
  • the cysteine functionalized dendrimers form polymers when treated with a compound containing multiple electrophilic groups, such as an aldehyde or an activated ester.
  • the compound bearing the electrophilic groups is a polyethylene glycol.
  • a large number of chemical compounds can be used to prepare the core and branching portions of the dendrimer.
  • the core and/or branching portion of the dendrimer may be derived from succinic acid, adipic acid, glycolic acid, or lactic acid.
  • the dendritic macromolecules possess two or more different linkages within the macromolecule.
  • the dendrimer may be composed of glycerol, succinic acid, and/or glycine residues and the aforementioned residue is bonded to an adjacent group to form an ester or carbamate.
  • the dendritic macromolecule is a dendritic-linear hybrid wherein the linear core is a polyethylene glycol and the dendritic wedges contain ester and/or carbamate linkages.
  • Another aspect of the invention relates to dendritic macromolecules comprising hydrogen bonding linkages within the dendrite framework.
  • the hydrogen bonding linkages e.g., amide or carbamate, enable non-covalent interations between the dendritic polymer and proteins, glycoproteins, and the like.
  • the polymers after being crosslinked, can be seeded with cells and then used to repair the damaged cartilaginous tissue. Alternatively, 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 template 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 anti-inflammatory compounds to aid/enhance repair of the cartilaginous tissue.
  • pharmaceutical agents/drugs such as bioactive peptides (e.g., growth factors), antibacterial compositions, antimicrobial compositions, and anti-inflammatory compounds to aid/enhance repair of the cartilaginous tissue.
  • the cartilage defect can be filled using the photocrosslinkable dendritic macromolecule and subsequently photocrosslinked with light to afford the hydrogel.
  • the defect is filled with a self-gelling dendritic system.
  • a Iys3cys4 dendron can be mixed with a polyethylene glycol containing two or more reactive electrophilic groups, e.g., NHS-activated ester, malemide, or aldehyde, where a gel is formed quickly, e.g., within 1 minute.
  • Hydrogel materials are particularly successful as tissue engineering scaffolds because they are water-saturated turgid networks that mimic the three-dimensional environment of cells in native cartilaginous tissues.
  • the high water-content allows for rapid diffusion of nutrients and oxygen to, and waste products and carbon dioxide from, the cells. This rapid diffusion has a positive influence on the metabolic activity of cells within the scaffold material.
  • cartilage repair material As a stress-absorbing tissue, the mechanical properties of cartilage define its function in the body, and are thus an important selection criterion for a cartilage repair material.
  • Cartilaginous tissues including articular cartilage, meniscus and intervertebral disk, are porous, water saturated viscoelastic materials that exhibit high mechanical stiffness. The mechanical properties reflected in the compressive and (dynamic) shear moduli strongly depend on the specific tissue-type. See Table 1 and the following references: Setton, L. A.; Elliot, D. M.; Mow, V. C, Osteoarthr.
  • Restoring mechanical function at the time of cartilage repair is highly desirable for maintaining tissue and joint function, reducing inflammation at the trauma site, and maintaining the environment governing cell metabolism and matrix homeostasis. See Guilak, F.; Kapur, R.; Sefton, M. V.; Vandenburgh, H. H.; Koretsky, A. P.; Kriete, A.; O'Keefe, R. J., Ann. K Y. Acad. ScL 2002, 961, 207-209. Consequently, there is significant interest in manipulating the mechanical properties of a biomaterial during synthesis and implantation in order to obtain a functional scaffold that will support load and permit integration with native tissue.
  • the in situ photocrosslinking ability of these systems is highly desirable in a cartilage tissue-engineering application for a variety of reasons.
  • Second, the uncrosslinked macromer solution can easily flow into irregularly shaped defects common to damaged or diseased cartilage, facilitating integration with the surrounding native tissue.
  • Third, the liquid state of the macromer solution allows access to surgically inaccessible trauma sites via endoscope-assisted (micro)surgery.
  • micro endoscope-assisted
  • a significant limitation of the poly(ethylene glycol) dimethacrylate hydrogels is the lack of (bio)degradation, which hampers long-term viability of incorporated cells and inhibits formation of neocartilage throughout the scaffold.
  • One solution to this problem is the introduction of degradation sites into these hydrogels, allowing chondrocytes to degrade the scaffold while extracellular matrix is deposited. It was shown recently by Hubbell and Anseth that both linear oligopeptides and linear esters allow biodegradation when incorporated into the scaffold design. See Halstenberg, S.; Panitch, A.; Rizzi, S.; Hall, H.; Hubbell, J.
  • Dendrimers are highly branched, well-defined macromolecules that are ideal compounds for the assembly of such materials. See Frechet, J. M. J. Proc. Natl. Acad. ScL U. S. A. 2002, 99 (8), 4782-4787; Frechet, J. M. J.; Tomalia, D. A. Dendrimers and other dendritic polymers .
  • Dendritic polymers provide a multivalent and modular base for the design and optimization of novel macromers for tissue engineering scaffold applications. The branched structure allows considerable degradation before the crosslinked network breaks down, maintaining mechanical integrity during degradation.
  • Branched structures through their multivalency, also allow higher crosslink densities at low concentrations compared to linear functionalized polymers, providing the potential to achieve the seemingly conflicting requirements of high mechanical strength and high water content critical for cartilage repair.
  • the well-defined nature of these macromolecules allows analysis of structure-property relationships between the molecular features of the macromers and the mechanical and physiochemical properties of the hydrogel constructs, allowing subsequent structure-based optimization of these constructs for specific applications.
  • Biocompatible dendrimers, or f ⁇ odendrimers, constructed from moieties known to be biocompatible have been reported. See Grinstaff, M. W. Chem. Eur. J. 2002, 8 (13), 2839-2846.
  • Tissue adhesives based on methacrylated block copolymers consisting of a polyethylene glycol (PEG) core and biodendrimer wedges synthesized from glycerol and succinic acid, display excellent corneal tissue adhesion and show considerable promise as an ocular sealant for sutureless eye-surgery.
  • PEG polyethylene glycol
  • biodendrimer wedges synthesized from glycerol and succinic acid
  • the equilibrium compressive modulus E was determined from the equilibrium compressive stress following a stepwise increase in compressive strain ( Figure 14).
  • the compressive modulus increased substantially from 3.7 ⁇ 0.1 kPa at the lowest macromer concentration to 34 ⁇ 5 kPa at the highest macromer concentration, showing strong non ⁇ linear stiffening of the hydrogels with increasing macromer concentration.
  • Histological sections prepared from cell-hydrogel constructs showed chondrocytes displaying a rounded morphology in hydrogels prepared from both the 15 and 7.5 % macromer concentrations, throughout the duration of culture. After two weeks of culture,
  • hydrogels constructed from chemically crosslinked methacrylated macromer 1, at a range of macromer concentrations support chondrocyte proliferation and cartilaginous tissue growth in vitro.
  • These hydrogels additionally exhibit mechanical properties superior to previously published crosslinked alginate and hyaluronan hydrogels, and show mechanical performance comparable to non-degradable PEG-based hydrogel systems previously reported in the literature. See LeRoux, M. A.; Guilak, F.; Setton, L. A., J. Biomed. Mater. Res. 1999, 47 (1), 46-53; Smeds, K. A.; Grinstaff, M. W., J. Biomed. Mater. Res. 2001, 54 (1), 115-121; Bryant, S.
  • the biodendrimer-based hydrogel scaffolds support cartilaginous extracellular matrix production.
  • Encapsulated chondrocytes show no signs of dedifferentiation; they retain their rounded morphology and produce extracellular matrix similar to native articular cartilage, including type II collagen and proteoglycans.
  • the lower macromer concentration hydrogel scaffolds were especially supportive of cartilaginous extracellular matrix synthesis.
  • the more rapid synthesis of proteoglycans and collagen by chondrocytes encapsulated in the lower macromer concentration hydrogel may be due to beneficial diffusion characteristics for nutrients, waste products, oxygen, and carbon dioxide, in a hydrogel with higher water content.
  • the scaffold degradation rate is another important parameter for a tissue- engineering material.
  • the degradation rate of the hydrogel-cell constructs at 7.5 % macromer concentration is rapid, with rates comparable to the PLA-PEG-PLA hydrogels.
  • the hydrogel-cell constructs at the higher macromer concentration do not show appreciable degradation, even after 12 weeks in culture, impeding cell proliferation and matrix deposition.
  • the differences in degradation kinetics are likely due to crosslink density.
  • the metabolic activity of the encapsulated chondrocytes, secreting hydrolytic enzymes is another important factor.
  • the negligible degradation in the absence of cells illustrates that the presence of cells has a profound influence on degradation kinetics.
  • the results obtained with the biodendrimer hydrogel support the strategy of using a dendritic macromolecule to control hydrogel properties and promote cartilaginous tissue formation.
  • the photocrosslinked scaffold presented here allows for the variation of generation, degree of branching, crosslink density, hydrolysable linkage, and end-group functionality, allowing tailoring of the physical, (bio)chemical, and mechanical properties of the scaffold for repair of cartilage defects.
  • the successful formation of new cartilaginous material in the biodendrimer-based hydrogel scaffold demonstrates the remarkable versatility and utility of the invention.
  • Dendritic polymers are globular monodispersed polymers composed of repeated branching units emanating 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
  • MRI, gene delivery, and cancer treatment are derivatives of aromatic polyether or aliphatic amides, and thus are not ideal for in vivo uses. (Service, R. F. Science 1995, 267, 458-459.
  • Biodendrimers are a novel class of dendritic macromolecules composed entirely of building blocks known to be biocompatible or degradable to natural metabolites in vivo.
  • This application describes the synthesis, characterization, and use of novel dendrimers and dendritic macromolecules called "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.
  • the dendrimer is terminated with a photoreactive group or nucleophilic group.
  • 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).
  • 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 varying 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.
  • polyester, polyether ester, polyester-amines, etc. materials which include a sufficient concentration of derivatizable groups to permit the chemical modification of the polymer for different biomedical applications.
  • a dendritic polymer includes multiple end groups for functionalization, crosslinked gels with high crosslinking densities at low polymer concentration, globular structure, low viscosities, and well-defined composition.
  • Conventional linear polymers for medical applications cannot be easily controlled or modified through changes in the polymer's structure, because these polymers (e.g., PLA) do not possess functional groups, other than end groups, that permit chemical modification to change their properties, and these polymers do not adopt a well-defined structure in solution, thereby limiting the applications of these polymers. Consequently the novel polymers described herein are substantially different.
  • 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), softness, 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. contact lenses, burn dressings, and dentures), and as devices (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 been 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.
  • 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.
  • biologically active agents may be incorporated in the 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 example
  • dendrimers or dendritic polymers are crosslinked using either light or a chemical crosslinking reaction that is not activated by light.
  • a large number of crosslinking reactions are amenable to the present invention.
  • 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; such gels are often 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, succinimidyl 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 dend
  • 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 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 cartilege defect 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 cartilege defect 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 cartilege defect of a patient, and then the dendrimeric compound is exposed to a compound having electrophilic groups.
  • a polymerization agent is applied to a cartilege defect of a patient, and then the polyermization agent is exposed to a dendrimeric compound.
  • PEG(NHS) 2 is applied to a cartilege defect 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 be a copolymer containing either nucleophilic or electrophilic endgroups.
  • a large number of copolymers are known the art and are amenable 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.
  • Cartilage is a tough, flexible, elastic biomaterial that serves as flexible connective tissue commonly found covering the surface on many joints in animals. Cartilage serves to reduce friction between bones and absorb shocks due to sudden increases in the amount of weight applied to the skeletal system. Cartilage is made of chondrocytes and chondroblasts dispersed in a lipoprotein that is reinforced with collagen fibers. Cartilage is located in many parts of the human body. For example, cartilage is found in the tip of the nose, in the ribs, in the external portion of the ear, walls of the trachea, and covering the surface of bones where joints occur. The three main types of cartilage are articular (hyaline), fibrocartilage, and elastic cartilage.
  • Articular cartilage also known as hyaline cartilage
  • hyaline cartilage is present in the human body on the ends of bones that form joints and on the ends of ribs.
  • joints containing cartilage tissue include knee, hip, ankle, elbow, wrist, shoulder, fingers, toes, spinal column, and the like.
  • Fibrocartilage contains a substantial amount of collagen. Fibrocartilage is located between bones in the spinal column, hip, and pelvis. The meniscus is a type of fibrocartilage that can be found covering bone tissue in the knee.
  • Elastic cartilage can be found in the outer ear and epiglottis.
  • cartilage tissue A number of defects are known to occur in cartilage tissue.
  • One of the more common defects that occurs to cartilage tissue is tearing. Tearing of cartilage tissue is a common knee injury that often requires surgery and extension physical therapy in order to recover.
  • Another common cartilage defect is when cartilage tissue simply deteriorates due to prolonged wear and tear. This type of cartilage defect is more common in those patients that have performed hard physical labor over a period of many years. Activities such as heavy lifting or repetitive motions can accentuate the rate at which cartilage tissue deteriorates. In certain instances, deterioration of the cartilage tissue causes the layer of cartilage tissue protecting the bone at a joint to become too thin for sufficient protection.
  • Other types of cartilege defects include cracking, fibrillation, strains, and rough cartilage surfaces.
  • the size of the defect can vary considerably. In certain instances, the defect can apply to nearly the entire portion of the cartilage tissue that covers the bone tissue of a certain joint. In other instances, the defective cartilage tissue is located on only a small, localized portion of the cartilage tissue covering a joint. In certain instances, the cartilage tissue defect is less than about 15 cm . In certain instances, the cartilage tissue defect is less than about 10 cm 2 . In certain instances, the cartilage tissue defect is less than about 5 cm 2 . In certain instances, the cartilage tissue defect is less than about 2 cm 2 . In certain instances, the cartilage tissue defect is less than about 1 cm 2 . In certain instances, the cartilage tissue defect is less than about 0.5 cm 2 .
  • the cartilage tissue defect is a tear in the cartilage tissue. In certain instances, the cartilage tissue defect is less than about 3 cm long. In certain instances, the cartilage tissue defect is less than about 2 cm long. In certain instances, the cartilage tissue defect is less than about 1 cm long. In certain instances, the cartilage tissue defect is less than about 0.5 cm long.
  • 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 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 the aforementioned polymers for subsequent polymerization/crosslinking/reaction with another linear or branched structure with either olef ⁇ nic, electrophilic or nucleophilic groups, respectively to form a gel.
  • the present invention relates to the 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 olef ⁇ nic, 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 acryl
  • 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 olef ⁇ nic, 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. In certain instances, 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 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, modif ⁇ y 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 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 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 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 visible photoinitator chromophore.
  • 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 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 Ri, R 2 , R 3 , R 4 , Rs, 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
  • 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 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 crosslinkable or noncrosslinkable polymer wherein straight or branched chains are the same number of carbons or different wherein Ri, R 2 , R 3 , R 4 , Rs , 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 Ri 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.
  • Ri 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, carb
  • the present invention relates to the aforementioned polymer, where Ri 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.
  • Ri 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.
  • Ri is a polymer (such
  • 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, 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, alkylaiyl, 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 Ri 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.
  • 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
  • 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 , R 10 , Rn, R 12 , R 13 , 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 Ri 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
  • 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 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 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], 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 polypeptide(s) is attached to Ri, R 2 , R3, R 4 , Rs, A, and/or Z. In certain instances, the present invention relates to the aforementioned block or random copolymer wherein an antibody(ies) is attached to Ri, R 2 , R3, R 4 , R 5 , A, and/or Z.
  • the present invention relates to the aforementioned block or random copolymer wherein a nucleotide(s) is attached to Ri, 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 Ri, 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 Ri, 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 ligand(s) is attached to Ri, R 2 , R 3 , R 4 , Rs, 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 Ri, 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.
  • 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 R3 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 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 .
  • 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 . 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 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 .
  • 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 .
  • 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, phosphates, sulphates, 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 .
  • 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 . In certain instances, 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 . In certain instances, 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 dendritic polymer or copolymer which optionally contains at least one stereochemical center. In certain instances, the present invention relates to the dendritic polymer or copolymer which is of D or L configuration.
  • 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.
  • 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 for drug delivery. 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 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
  • 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.
  • 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.
  • the filtration is conducted in a Class 100,000 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.
  • 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. Examples of glass containers include ampules, vials, syringes, pipettes, applicators, and the like.
  • the penetration of electron beam irradiation is a function of the packaging.
  • the container may be flipped or rotated to achieve adequate penetration.
  • the electron beam source can be moved about a stationary package.
  • 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 Assurance Level (SAL) of at least about 10 "3 .
  • SAL Sterility Assurance Level
  • the Sterility Assurance Level measurement standard is described, for example, in ISO/CD 14937, the entire disclosure of which is incorporated herein by reference.
  • 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 repair the cartilaginous tissue may be delivered to the cartilage defect 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 materials to the cartilage defect 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.
  • One aspect of the present invention relates to a method of repairing cartilaginous tissue, comprising the steps of: applying an effective amount of a dendrimeric compound of formula Ia or formula Ib to a cartilage defect of a patient and exposing said dendrimeric compound to a polymerization agent sufficient to polymerize said dendrimeric compound, wherein said polymerization agent is ultraviolet light, visible light, a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, or an oxidizing agent, wherein formula Ia is represented by:
  • A is alkyl, aryl, aralkyl, -Si(R J 3) X3 , 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 5 , A 4 ,
  • Z represents independently for each occurrence -X -R , E, or
  • Y 3 represents independently for each occurrence R 6 , A 4 ,
  • Z 3 represents independently for each occurrence -X 1 -R 6 , E, or - ⁇ 1-
  • 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 represents independently for each occurrence -X 1 - ⁇ R,8 , E, or
  • Y 6 represents independently for each occurrence R 9 , A 4 ,
  • R represents independently for each occurrence H, alkyl, or halogen
  • R represents independently for each occurrence H, alkyl, -OH, -N(R ) 2 , -SH, hydroxyalkyl, or -[C(R') 2 ] d R 16 ;
  • R 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 -[C(R') 2 ] d 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 10
  • R represents independently for each occurrence H, alkyl, or -OR
  • 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 ) 2 ;
  • 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 1000, 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 )
  • X represents independently for each occurrence O or -N(R 22N )-;
  • R 17 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 18 represents independently for each occurrence H or alkyl
  • R 19 represents independently for each occurrence H, halogen, or alkyl
  • R 20 represents independently for each occurrence H or alkyl
  • R 21 represents independently for each occurrence H, -(C(R I9 ) 2 ) h SH, -
  • R 22 represents independently for each occurrence H, alkyl, aryl, or aralkyl; n 1 and h each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; p 5 represents independently for each occurrence 1, 2, 3, 4, or 5; v represents independently for each occurrence 2, 3, or 4; and w is an integer in the range of about 5 to about 1000, inclusive; said formula II is represented by:
  • 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 " represents independently for each occurrence H or and z represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; said formula HI is represented by:
  • R 1 - 1 " is -(C(R 2 - m ) 2 ) x C(O)H, -C(O)(C(R z -'") 2 ) y C(O)H, -(C(R"" ⁇
  • R > 2- " III represents independently for each occurrence H, alkyl, or halogen
  • R ,3- " m represents independently for each occurrence fluoroalkyl, chloroalkyl, -
  • R 5"1 represents independently for each occurrence H, alkyl, or aralkyl
  • B , 1- ' HI 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 , or
  • a 3 represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Z represents independently for each occurrence -X ⁇ l - rR.4 , E, or
  • Y 2 represents independently for each occurrence R 5 ,
  • Z 2 represents independently for each occurrence -X'-R 5 , E, or h ⁇ 1 -(?)-f ⁇ 2" ⁇ 3 ) t.
  • Z represents independently for each occurrence -X -R , E, or
  • Y 4 represents independently for each occurrence R 7 ,
  • Z represents independently for each occurrence -X 1 - rR>7 , E, or
  • Y represents independently for each occurrence R ,
  • Z 5 represents independently for each occurrence -X 1 -R , E, or
  • Y represents independently for each occurrence
  • R represents independently for each occurrence H, alkyl, or halogen
  • R represents independently for each occurrence H, alkyl, -OH, -N(R ) 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 10 ) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R 1 ),], ⁇ 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 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 ) 2 ;
  • 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 1000, 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 XCO 2 R 1 °); E represents independently for each occurrence H, -[C(R 1 ⁇ ] n C(O)H, -(C(R 13 ) 2 ) X R 17 ,
  • R ,24 represents independently for each occurrence H or alkyl
  • R ,25 represents independently for each occurrence H, halogen, or alkyl
  • R ,26 represents independently for each occurrence H or alkyl
  • R ,27 represents independently for each occurrence H, alkyl, or halogen
  • R 28 represents independently for each occurrence H, alkyl, -OH, -N(R 30 ) 2 , -SH, or hydroxyalkyl;
  • R ,29 represents independently for each occurrence H, -OH, -N(R 3O )x 2 , -SH, alkyl, or hydroxyalkyl;
  • R 30 and R 31 represent independently for each occurrence H, alkyl, aryl, or aralkyl;
  • Z 6 represents independently for each occurrence E 1 or
  • Z 7 represents independently for each occurrence E 1 or
  • R 33 represents independently for each occurrence
  • R 34 represents independently for each occurrence H, alkyl, or -CO 2 R 30 ;
  • E 1 represents independently for each occurrence H, -[C(R 24 ) 2 ] j C(O)H, -
  • p 6 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8
  • p 7 represents independently for each occurrence 0, 1, 2, 3, or 4
  • p 8 represents independently for each occurrence 1, 2, or 3
  • p 9 represents independently for each occurrence 0, 1, 2, or 3
  • n 2 and j each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8
  • m 1 represents independently for each occurrence 1 or 2
  • v represents independently for each occurrence 2, 3, or 4
  • w is an integer in the range of about 5 to about 1000, inclusive.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula Ia, and 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, 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'-R 5 or
  • the present invention relates to the aforementioned method, wherein Z represents independently for each occurrence -X 1 - rR>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 and X are O.
  • the present invention relates to the aforementioned method, wherein n is 1. In certain instances, 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.
  • 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
  • the present invention relates to the aforementioned method
  • R 1 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 aforementioned method
  • R 1 is H
  • B is X ' P
  • a 2 is , m
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • said polymerization agent is a compound of formula III.
  • 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
  • the present invention relates to the aforementioned method
  • R' is H
  • B is A ⁇ 2 Ms m
  • the 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 , A 2 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.
  • 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. 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
  • the present invention relates to the aforementioned method
  • R is H, B is , 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
  • R 1 is H
  • B is x 7 P
  • a 2 is , m is 1
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is X ' P , A 2 , m 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. 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 (Ci-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 VR 1 RV pI VR 1 RVv I
  • v 1 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
  • 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
  • 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. In certain instances, 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.
  • the present invention relates to the aforementioned method, wherein p 1 is 2, p 2 is 0, R 3 is (Ci-C 5 )alkyl, and w 1 is an integer in the range of about 60 to about 90.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 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
  • R 1 is H
  • B is ,
  • a 2 is ,
  • R 3 is alkyl
  • v 2 is
  • 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, 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.
  • 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 m
  • the present invention relates to the aforementioned method
  • R is H
  • B is m
  • the present invention relates to the aforementioned method
  • Y 1 is x V , Z 1 , Y 2 is
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula II. In certain embodiments, the present invention relates to the aforementioned 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' “ 1 is -CH 2 C(O)H, and R 2 - 1 " 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 -CH 2 C(O)H, R " '"
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R l- " III is -CH 2 C(O)H, R J 2 -III
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R l- " III is -(C(R * ") 2 ) X C(O)R J -"' or - C(O)(C(R ⁇ ul ) 2 ) y C(O)R >IU , R'-" 1 is H, and R MU or
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R 1"111 is -(C(R 2'
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula III, R M ⁇ is -(C(R 2"
  • B 1 - 111 is - w , and w is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned method, wherein said compound of formula Ia is
  • n is an integer in the range of about 70 to about 80, and said polymerization agent is UV light.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is compound of formula Ib.
  • the present invention relates to the aforementioned method, wherein v is 2.
  • the present invention relates to the aforementioned method, wherein X 5 is -N(H)-. In certain embodiments, the present invention relates to the aforementioned method, wherein R 18 is H.
  • the present invention relates to the aforementioned method, wherein R 19 is H.
  • the present invention relates to the aforementioned method, wherein R 20 is H.
  • the present invention relates to the aforementioned method, wherein w is an integer in the range of about 20-500.
  • the present invention relates to the aforementioned method, wherein w is an integer in the range of about 40-250. In certain embodiments, the present invention relates to the aforementioned method, wherein w is an integer in the range of about 60-90. In certain embodiments, the present invention relates to the aforementioned method, said compound of formula Ib is
  • said polymerization agent is a compound of formula V.
  • the present invention relates to the aforementioned method, wherein v is 2. In certain embodiments, the present invention relates to the aforementioned method, wherein X 6 is -N(H)-.
  • the present invention relates to the aforementioned method, wherein R 24 is H.
  • the present invention relates to the aforementioned method, wherein R 25 is H.
  • the present invention relates to the aforementioned method, wherein R 26 is H.
  • the present invention relates to the aforementioned method, wherein w is an integer in the range of about 20-500. In certain embodiments, the present invention relates to the aforementioned method, wherein w is an integer in the range of about 40-250.
  • the present invention relates to the aforementioned method, wherein w is an integer in the range of about 60-90.
  • the present invention relates to the aforementioned method, wherein R represents independently for each occurrence
  • the present invention relates to the aforementioned method, wherein R 23 represents independently for each occurrence
  • the present invention relates to the aforementioned method, said compound of formula V is
  • 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 ultraviolet light or visible light. In certain embodiments, the present invention relates to the aforementioned method, wherein said polymerization agent is ultraviolet light.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is light with a ⁇ of 400-600 ran.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is light with a ⁇ of 450-550 nm.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is light with a ⁇ of 488-514 nm.
  • the present invention relates to the aforementioned method, wherein said patient is a primate, bovine, equine, feline, or canine. In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a human. In certain embodiments, the present invention relates to the aforementioned method, wherein said cartilage defect is a tear, strain, void, fibrillation, or a decrease in the amount of cartilage.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is a tear.
  • the present invention relates to the aforementioned method, wherein said tear is less than about 5 mm long.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in articular cartilage. In certain embodiments, the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in f ⁇ brocartilage.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in the meniscus.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 10 cm 2 in size.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 5 cm 2 in size.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 1 cm 2 in size. In certain embodiments, the present invention relates to the aforementioned method, wherein said compound of formula Ia is dissolved in at least one solvent, and said compound of formula Ia has a concentration in the range of about 2% w/w to about 40% w/w.
  • the present invention relates to the aforementioned method, wherein said compound of formula Ia is dissolved in at least one solvent, and said compound of formula Ia has a concentration in the range of about 5% w/w to about 20% w/w. In certain embodiments, the present invention relates to the aforementioned method, wherein said compound of formula Ia is dissolved in at least one solvent, and said compound of formula Ia has a concentration in the range of about 6% w/w to about 10% w/w. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of admixing a photoinitiator with said compound of formula Ia prior to exposing said compound of formula Ia to said polymerization agent.
  • the present invention relates to the aforementioned method, wherein said photoinitiator is eosin-Y. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of admixing a natural polymer with said dendrimeric compound.
  • the present invention relates to the aforementioned method, wherein said natural polymer is HA, collagen, or a GAG fragment. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of admixing at least one cell with said dendrimeric compound.
  • the present invention relates to the aforementioned method, wherein said cell is a cartilage cell or a stem cell.
  • the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound.
  • the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound and said polymerization agent.
  • the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound and said polymerization agent, wherein said polymerization agent is selected from the group consisting of a compound of formula II, a compound of formula III, a compound of formula IV, and a compound of formula V.
  • the present invention relates to the aforementioned 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 aforementioned method, wherein said sterilizing is effective to achieve a sterility assurance level of at least about 10 "
  • the present invention relates to the aforementioned method, wherein said sterilizing is effective to achieve a sterility assurance level of at least about 10 " 6 .
  • Another aspect of the present invention relates to a method of repairing cartilaginous tissue, comprising the steps of: applying an effective amount of a dendrimeric compound of formulae VI , VII, VIII, or IX to a cartilage defect of a patient and exposing said dendrimeric compound to a polymerization agent sufficient to polymerize said dendrimeric compound, wherein said polymerization agent is an oxidizing agent or a compound of formula X, wherein formula VI is represented by:
  • R 1 represents independently for each occurrence H, 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 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,
  • n and m each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; and p is 1, 2, 3, 4, or 5;
  • formula VII 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, - C(O)N(R 2 )(C(R 3 ) 2 ) m SH,
  • R 2 represents independently for each occurrence H, alkyl, or -(C(R 3 ) 2 ) X OR 1 ;
  • 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 3 )2) m SH, - o /R 3 R 3 ⁇ P
  • 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 represents 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 IX is represented by:
  • R 1 represents independently for each occurrence H, -(C(R ) 2 ) m N(H)R , (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 represents independently for each occurrence alkyl, aryl, or aralkyl
  • R 3 represents independently for each occurrence H, halogen, or alkyl
  • R 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, - (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,
  • 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 X is represented by:
  • R i'- " x ⁇ represents independently for each occurrence -(C(R >2-X ⁇ ) 2 ) X C(O)H, -C(O)(C(R ' x ) 2 ) y C(0)H, -(C(R 2 - ⁇ ) 2 ) ⁇ C(O)R 3 - ⁇ , -C(O)(C(R 2 - ⁇ ) 2 ) y C(O)R 3 - ⁇ , -(C(R 2 - ⁇ ) 2 ) x R 4 - ⁇ , -
  • R 2"x represents independently for each occurrence H, alkyl, or halogen
  • R 3"x represents independently for each occurrence alkyl, fluoroalkyl, chloroalkyl, -
  • R , 5- ' X represents independently for each occurrence H, alkyl, or aralkyl
  • B is alkyl diradical, heteroalkyl diradical, or •
  • v 2"x represents independently for each occurrence 2, 3, or 4; w 2"x 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 . In certain instances, the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X.
  • w 2" x is an integer in the range of about 50 to about 250.
  • w 2' x 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 X, R !x is -CH 2 C(O)H, and R 2 X is H.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, R' "X is -CH 2 C(O)H, R 2'x is
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, R ux is -CH 2 C(O)H, R 2 X is
  • H, B is y 2 -x j s 2 ( an( j w 2 -x j s an j n teger in the range of about 15-90.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, R* "x is -(C(R 2"X ) 2 ) X C(O)R 3"
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, R' "x is -(C(R 2"X ) 2 ) X C(O)R 3"
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, R !'x is -(C(R 2 X ) 2 ) X C(O)R 3"
  • w 2"x is an integer in the range of about 15-90.
  • the present invention relates to the aforementioned method, wherein said polymerization agent is a compound of formula X, wherein B is
  • d 2"x , e 2"x , and g 2'x represent independently an integer greater than zero, provided that the sum of d 2'x , e 2"x , and g 2'x is an integer in the range of about 5 to 1000, inclusive.
  • the present invention relates to the aforementioned method, i- ,2-Xx ,3-X 2-Xx ,3-X D 2-X ,3-X wherein, R , ' " x ⁇ is -(C(R ⁇ ⁇ ) 2 ) X C(O)R J - ⁇ or -C(O)(C(R z - ⁇ ) 2 ) y C(O)R , R ⁇ ⁇ is H, and R > ⁇ is
  • the present invention relates to the aforementioned method
  • 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 VI.
  • 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. In certain instances, 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.
  • 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. In certain instances, 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 is R SH R 2 , 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 R 2 , 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 VI, and said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and a Bronsted acid.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VI, and said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and HA, wherein A is halogen or -O 2 CR 6 , and R 6 is alkyl, fluoroalkyl, aryl, or aralkyl.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VI, and said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and an acid selected from group consisting of HCl and HBr.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VI, and said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and HO 2 CR 6 , wherein R 6 is fluoroalkyl.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VI, and said pharmaceutically acceptable salt is a complex formed by said compound of formula VI and CF 3 CO 2 H.
  • 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 said dendrimeric compound is a compound of formula VII, x and y are 1, R 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 VII, 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 VIII.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula VIII, x is 2, Y is O, R 2 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 VIII, x is 2, Y is NR 4 , 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. In certain instances, the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula IX, 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 XI, wherein formula XI is represented by:
  • R' "XI represents independently for each occurrence -(C(R 2'X1 ) 2 ) X C(O)H, -C(O)(C(R 2"
  • R ,2- " XI represents independently for each occurrence H, alkyl, or halogen
  • R 3'XI represents independently for each occurrence alkyl, fluoroalkyl, chloroalkyl, -
  • R5-x ⁇ R 5-x ⁇ or R5-XI X R5-XI .
  • R 5"XI represents independently for each occurrence H, alkyl, or aralkyl
  • B iXI is alkyl diradical, heteroalkyl diradical, or v 2- " Xl 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
  • the present invention relates to the aforementioned method
  • B XI is w2- ⁇ t v2-x i is 2)
  • R'- X1 is -(C(R 2 - ⁇ i ) 2 ) ⁇ C(0)R 30 ⁇
  • the present invention relates to the aforementioned method
  • R 20CI is H, R > 3 > -X ⁇ I 1 .
  • said polymerization agent is a compound of formula X, B is
  • e 2"x , and g 20C represent independently an integer greater than zero, provided that the sum of d 2"x , e 2"x , 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 said patient is a primate, bovine, equine, feline, or canine.
  • the present invention relates to the aforementioned method, wherein said patient is a human.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is a tear, strain, void, fibrillation, or a decrease in the amount of cartilage.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is a tear.
  • the present invention relates to the aforementioned method, wherein said tear is less than about 5 mm long. In certain embodiments, the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in articular cartilage.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in fibrocartilage.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is an abnormality in the meniscus.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 10 cm 2 in size.
  • the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 5 cm 2 in size. In certain embodiments, the present invention relates to the aforementioned method, wherein said cartilage defect is less than about 1 cm in size. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of admixing a natural polymer with said dendrimeric compound.
  • the present invention relates to the aforementioned method, wherein said natural polymer is HA, collagen, or a GAG fragment.
  • the present invention relates to the aforementioned method, further comprising the step of admixing at least one cell with said dendrimeric compound.
  • the present invention relates to the aforementioned method, wherein said cell is a cartilage cell or a stem cell. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound.
  • the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound and said polymerization agent. In certain embodiments, the present invention relates to the aforementioned method, further comprising the step of sterilizing said dendrimeric compound and said polymerization agent, wherein said polymerization agent is a compound of formula X.
  • the present invention relates to the aforementioned 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 aforementioned method, wherein said sterilizing is effective to achieve a sterility assurance level of at least about 10 "
  • the present invention relates to the aforementioned method, wherein said sterilizing is effective to achieve a sterility assurance level of at least about 10 "
  • Another aspect of the present invention relates to a method of repairing cartilaginous tissue, comprising the steps of: exposing a dendrimeric compound of formula Ia or formula Ib to a polymerization agent to form a repair agent and applying said repair agent to a cartilage defect of a patient, wherein said polymerization agent is ultraviolet light, visible light, a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, or an oxidizing agent, wherein formula Ia is represented by:
  • a 2 is alkyl, aryl, aralkyl, -Si(R 3 ) 3 , or
  • A represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Y represents independently for each occurrence R , A ,
  • Z represents independently for each occurrence -X 1 - rR>4 , E, or
  • Y represents independently for each occurrence R , A ,
  • Z 2 represents independently for each occurrence -X'-R 5 , E, or hx 1" ( ⁇ )-(- ⁇ 2 - ⁇ 3 ) t .
  • Y represents independently for each occurrence R 6 , A A 4 ,
  • Z represents independently for each occurrence -X 1 - rR.6 , E, or
  • Y 4 represents independently for each occurrence R 7 , A 4 ,
  • Z 4 represents independently for each occurrence -X 1 -R 7 , E, or
  • Y represents independently for each occurrence R , A ,
  • Z 5 represents independently for each occurrence -X 1 -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 10 ) 2 , -SH, hydroxyalkyl, or -[C(R') 2 ]dR 16 ;
  • R represents independently for each occurrence alkyl, aryl, or aralkyl; ⁇ R)6 0 , ⁇ R)7', R 8 , and R y 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 -[C(R') 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 1 represents independently for each occurrence phenyl, hydroxyphenyl, pyrrolidyl, imidazolyl, indolyl, -N(R 10 ) 2 , -SH, -S-alkyl, -CO 2 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 1000, inclusive; x is 1, 2, or 3; y is O, 1, 2, 3, 4, or 5; z represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8; z and z each represent independently for each occurrence 1, 2, 3, 4, or 5; X and X 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 ); H 2 N-CH-C- 1 CH 2 CH 2 CH 2
  • A represents independently for each occurrence CH 3 NH 2
  • R 18 represents independently for each occurrence H or alkyl
  • R 19 represents independently for each occurrence H, halogen, or alkyl
  • R 20 represents independently for each occurrence H or alkyl
  • R 21 represents independently for each occurrence H, -(C(R 19 ) 2 ) h SH, -
  • R 22 represents independently for each occurrence H, alkyl, aryl, or aralkyl; n 1 and h 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; v represents independently for each occurrence 2, 3, or 4; and w is an integer in the range of about 5 to about 1000, inclusive; said formula II is represented by:
  • R 1'11 represents independently for each occurrence H or R 5" "
  • R 2"11 represents independently for each occurrence H or alkyl
  • R 3' 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; said formula HI is represented by:
  • R 1 " 1 is -(C(R 2 - m ) 2 ) x C(O)H, -C(O)(C(R 2 - m ) 2 ) y C(O)H, -(C(R 2 - ⁇ i ) 2 ) x C(O)R j m , C(O)(C(R 2 - i ⁇ ) 2 ) y C(O)R 3 - m , -(C(R 2 - m ) 2 ) x R 4 - m , -C(O)(C(R 2 - m ) 2 ) y R 4 - m , or
  • R 2'111 represents independently for each occurrence H, alkyl, or halogen
  • R 3"1 represents independently for each occurrence fluoroalkyl, chloroalkyl, -
  • R 5'111 represents independently for each occurrence H, alkyl, or aralkyl
  • B , 1- ' HI 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 represents independently for each occurrence alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, or aralkyl;
  • Z represents independently for each occurrence -X rl - rR.4 , E, or
  • Z 2 represents independently for each occurrence -X 1 -R 5 , E, or
  • Y 3 represents independently for each occurrence R 6 .
  • Z represents independently for each occurrence -X 1 -R Ti 6 , E, or
  • Z represents independently for each occurrence -X 1 - ⁇ R.7 , E, or
  • Z represents independently for each occurrence -X -R , E, or
  • R represents independently for each occurrence H, alkyl, or halogen
  • R 2 represents independently for each occurrence H, alkyl, -OH, -N(R 10 ) 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 10 ) 2 , -SH, alkyl, hydroxyalkyl, or -[C(R') 2 ]dR 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 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 ) 2 ;
  • 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 1000, 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 ); E represents independently for each occurrence H, -[C(R 1 ⁇ ] n C(O)H, -(C(R 13 ) 2 ) X R 17 ,
  • R »24 represents independently for each occurrence H or alkyl
  • R 25 represents independently for each occurrence H, halogen, or alkyl
  • R represents independently for each occurrence H or alkyl
  • R 27 represents independently for each occurrence H, alkyl, or halogen
  • R 28 represents independently for each occurrence H, alkyl, -OH, -N(R 30 ) 2 , -SH, or hydroxyalkyl;
  • R >29 represents independently for each occurrence H, -OH, -N(R 30x ) 2 , -SH, alkyl, or hydroxyalkyl;
  • R 30 and R 31 represent independently for each occurrence H, alkyl, aryl, or aralkyl;
  • Z 6 represents independently for each occurrence E 1 or
  • R ,32 represents independently for each occurrence
  • Z 7 represents independently for each occurrence E 1 or
  • R >33 represents independently for each occurrence
  • R 34 represents independently for each occurrence H, alkyl, or -CO 2 R 30 ;
  • E 1 represents independently for each occurrence H, -[C(R 24 ) 2 ] j C(O)H, -
  • p 6 represents independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8
  • p 7 represents independently for each occurrence 0, 1, 2, 3, or 4
  • p 8 represents independently for each occurrence 1, 2, or 3
  • p 9 represents independently for each occurrence 0, 1, 2, or 3
  • n 2 and j each represent independently for each occurrence 1, 2, 3, 4, 5, 6, 7, or 8
  • m 1 represents independently for each occurrence 1 or 2
  • v represents independently for each occurrence 2, 3, or 4
  • w is an integer in the range of about 5 to about 1000, inclusive.
  • the present invention relates to the aforementioned method, wherein said dendrimeric compound is a compound of formula Ia, and 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, 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 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. In certain instances, 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.
  • 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
  • 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 is H
  • B is , m
  • UV light or light is ultraviolet light or light.
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is m
  • the present invention relates to the aforementioned method
  • said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method
  • R 1 is H, B m
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is , m
  • the present invention relates to the aforementioned method
  • At least about 1/2 of the 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 1
  • a 2 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.
  • 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. 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 is H, B is , 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
  • R 1 is H, B is , A 2 is , m is 1
  • said polymerization agent is ultraviolet light or visible light.
  • 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
  • said polymerization agent is a compound of formula III.
  • the present invention relates to the aforementioned method
  • the present invention relates to the aforementioned method
  • R 1 is H
  • B is X 7 P
  • 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. 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 (Ci-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 is 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
  • 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 , v' 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
  • R 1 is H, B is , v ] is 2, A 2 i :s,
  • the present invention relates to the aforementioned method

Abstract

L'invention concerne des compositions, des kits, et des procédés de réparation des tissus cartilagineux. Certains procédés de l'invention font intervenir des macromolécules dendritiques obtenues par phototraitement d'un composé dendritique ou d'un composé de liaison. Dans certains modes de réalisation, les composés dendritiques comportent un résidu de lysine, de cystéine, d'isocystéine ou d'un autre groupe nucléophile fixé à leur périphérie. L'ajout d'un composé contenant au moins deux groupes électrophiles, tels que les aldéhydes, les esters activés ou les acrylates aux dendrimères à extrémité lysine, cystéine, ou isocystéine, permet d'obtenir un composé polymère apte à réparer les défauts du cartilage.
PCT/US2005/029915 2004-08-20 2005-08-22 Polymeres dendritiques et gels reticules: utilisations dans des applications orthopediques WO2006031388A2 (fr)

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US60/603,502 2004-08-20
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