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  Methods for treating dental conditions using tissue scaffoldsUSPTO Application #: 20070248933Title: Methods for treating dental conditions using tissue scaffolds Abstract: The invention provides methods, apparatus and kits for regenerating dental tissue in vivo that are useful for treating a variety of dental conditions, exemplified by treatment of caries. The invention uses tissue scaffold wafers, preferably made of PGA, PLLA, PDLLA or PLGA dimensioned to fit into a hole of corresponding sized drilled into the tooth of subject to expose dental pulp in vivo. In certain embodiments the tissue scaffold wafer further comprises calcium phosphate and fluoride. The tissue scaffold wafer may be secured into the hole with a hydrogel, a cement or other suitable material. Either the wafer or the hydrogel or both contain a morphogenic agent, such as a member encoded by the TGF-β supergene family, that promotes regeneration and differentiation of healthy dental tissue in vivo, which in turn leads to remineralization of dentin and enamel. The tissue scaffold may further include an antibiotic or anti-inflammatory agent. (end of abstract)
Agent: Nixon Peabody LLP - Patent Group - Rochester, NY, US Inventors: Bruce Rutherford, Christopher Somogyi, Clinton White, Erick Rabins USPTO Applicaton #: 20070248933 - Class: 433092000 (USPTO) Related Patent Categories: Dentistry, Apparatus, Having Suction Orifice, And Suction Pump Or Material Separator The Patent Description & Claims data below is from USPTO Patent Application 20070248933. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a Continuation claiming benefit under 35 U.S.C. .sctn. 120 of U.S. patent application Ser. No. 10/684,226, filed Oct. 10, 2003, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD [0002] This invention relates generally to the field of treating dental conditions, particularly caries, and more particularly to methods, compositions and devices that promote in vivo regeneration and remineralization of dentin and enamel by inserting tissue scaffold materials in vivo, into holes drilled into a tooth having need of dentin regeneration. BACKGROUND OF THE INVENTION [0003] The development of tissue scaffold materials for regenerating tissue ex vivo and for uses of such ex vivo regenerated tissue/scaffold combinations to treat patients in vivo has been a growing subject of interest in the prior art. Of relevance to the invention described hereinafter are prior art uses of tissue scaffolds for ex vivo culture of oral tissues. [0004] U.S. Pat. No. 5,885,829 discloses use of tissue scaffolds made of a porous matrix for the ex vivo culturing and regeneration of oral tissues from isolated dental cells. Numerous polymers, both biodegradable and non-biodegradable, synthetic or natural scaffold materials were described as suitable for culturing oral tissues ex vivo. In particular, homopolymers of poly lactic acid (PLLA), poly[D,L-lactic acid] (PDLLA), poly-glycolic acid (PGA) and heteropolymers of lactic acid and glycolic acid, i.e., poly[lactic-co-glycolic acid] (PLGA), alone or in combination with polyvinyl alcohol (PVA), were shown to be effective for culturing fibroblasts isolated from dental pulp. Cells from dental pulp were first explanted, separated and propagated in a monolayer culture using ordinarily tissue culture techniques. In one exemplified method, the cultured cells were removed and then seeded onto a matrix of about 3 mm thickness made of a mat of PGA fibers. The seeded matrix was then incubated in growth medium and it was shown that the cultured fibroblasts were able to adhere to the PGA fibers and ultimately occupy the spaces between fibers. Tubular matrix scaffolds were made from porous PLLA, PDLLA and PLGA two dimensional films using a particulate leaching technique. A three dimensional tubular matrix device was constructed by stacking the films on one another and chemically sealing the edges. The tubular matrix device was shown to allow growth of vascular tissue when implanted into the mesentery and omentum of rats. Of the combinations tested, PLLA and PDLLA were shown to maintain their structure in vivo, while PLGA based devices did not. PGLA devices were determined to have less resistance against compressional forces than PLLA or PDLLA. Other techniques for forming tubular matrices were also described, including bonding of PLLA, PGA, and PLGA tubes using a chloroform spray. In another example, a three dimensional "sponge matrix" was described for a tissue scaffold formed of PLA infiltrated with PVA or of PLGA at a ratio of 85:15 D,L lactic acid:glycolic acid. These sponge devices were shown to support growth of seeded liver cells ex vivo. The devices were also implanted into the mesentery of rats with and without seeded cells and shown to support in growth of vascular tissue in vivo. [0005] Human dental pulp cells were shown to propagate ex vivo better on a PGA matrix than on collagen or alginate based hydrogel matrices. Seeded cells grown in this manner ex vivo filled the spaces within the PGA matrix, which was eventually replaced by new tissue including tissue containing collagen indicating formation of an extracellular matrix. In another experiment, human gingival cells and pulp derived fibroblasts were shown to infiltrate a PGA matrix when seeded and cultured ex vivo, and to express human gene products when the seeded and cultured matrix was implanted subcutaneous in mice in vivo, even though the majority of cells in the implant were mouse fibroblasts. In addition it was disclosed that tissue scaffold materials could be used to deliver drugs by demonstrating that epidermal growth factor (EGF) could be entrapped in microspheres made of a 75:25 PLGA copolymer and slowly released into a buffer in vitro over 30 days. Further, hepatocyte cells seeded into cylindrical microspheres containing EGF and implanted into the mesentery of rats were shown to exhibit the biological effects of EGF on hepatocyte cellular activity over a 4 day period when implanted in vivo. Although this patent discloses a utility for using scaffold material for ex vivo propagation of oral tissues, it fails to disclose any therapeutic methods for the use of such ex vivo cultured cells for treating teeth in vivo, and fails to disclose the use of tissue scaffolds in the absence of ex vivo culturing. [0006] U.S. Pat. No. 6,281,256 discloses a process of preparing open pore matrices of a biodegradable polymer made of PLLA, PGA or PGLA polymers by using gas forming and particulate leaching steps to form pores in the matrices of the polymers. In a typical example of the disclosed process, a PLGA copolymer is formed in a mixture that includes a leachable particulate material. The mixture is molded, optionally under compression, to a desired size and shape and is subject to a high pressure gas atmosphere to dissolve gas in the copolymer. Then a thermodynamic instability is created by reduction of the pressure so that the dissolved gas nucleates and forms gas pores within the copolymer, causing expansion and fusion of the copolymer particles, creating continuous polymeric matrix still containing the particulate material. The particulate material is then leached from the polymeric matrix with a leaching agent creating a porous matrix. The amount and size of the particulate material used in the mixture determines the level of interconnectivity between open pores, the size of the pores and the amount of pores in the final matrix (porosity). The interconnected matrices formed by this method have a porosity of between about 25% to 95-97% and exhibit high tensile strength with a tensile modulus of about 850 to 1100 kPa and a compression modulus of about 250 kPa or larger. Such matrices were disclosed as being useful for bone formation and guided tissue regeneration (GTR) where tissues could be grown within the matrix pores guided by the scaffolding material, which provides a surface for cellular attachment. The porous matrices could also be made to have a non-porous barrier one on end by forming an impermeable skin, or could be made of different levels of porosity throughout by altering the amount of leachable particulate material in different sections so that one section forms open pores and another does not. Such matrices where also shown to be capable of releasing a growth factor VEGF in vitro, over a period of 20 to 21 days. Use of such matrices was generally mentioned as having utility in regenerating oral tissues. The use of such matrices configured with an impermeable side was particularly suggested for treating periodontal disease by using the pores in one section of the matrix to grow periodontal ligament cells and providing a barrier in another surface of the matrix to prevent down growth of epithelial cells. However, no actual method was described for the use of such matrices in vivo without previously seeding the matrix and culturing the cells ex-vivo. [0007] U.S. provisional patent application No. 60/166,191 describes methods for producing tissue scaffolds of PGLA using fused salt crystals of selected sizes to control the porosity, interconnectivity and ease of manufacture of the scaffolds. [0008] U.S. Pat. No. 6,472,210 discloses a method of making a polymer scaffold having an interconnected passage-way of strutted pores with diameters in the range of about 0.5 to 3.5 mm. The polymer may be PLGA. The polymer is prepared by mixing a liquid polymer in a solution with an organic solvent such as DMSO, methylene chloride, ethyl acetated chloroform, acetone, benzene butanone, carbon tetrachloride, heptane, hexane or pentane. The liquid polymer solution is mixed with particles of 0.5 to about 3.5 mm in diameter. The particle/polymer mixture is then treated with a "non solvent" for the polymer, such as water, alcohol, dioxane or aniline, in a phase inversion step that precipitates the polymer/particle. The particle is then leached from the precipitate by treatment with a solvent that dissolves the particle material but not the polymer. The method and composition are said to be suitable for forming tissue scaffolds for use in regenerating tabecular bone, which has a high porosity and large strutted trabeculae widths on the order of about 0.14 mm to about 0.3 mm. Such large macrospores would not be suitable for regenerating dentin or other oral tissues in the teeth. [0009] WO 00/56375 and Murphy and Mooney, (2002) J. American Chemical Society 124(9) 1910-1917, disclose methods for patterning (mineralizing) tissue scaffold material formed into three dimensional wafers for bioimplants. In one aspect, the surface of tissue scaffolds such as PGA, PLA and PLGA are coated with minerals such as calcium chloride, and phosphate useful for orthopedic tissue mineralization. The scaffold material is treated by electromagnetic radiation or by an electron beam to cause surface degradation via photolysis or electrolysis. Lithographic techniques are disclosed for forming patterns on the surface to create the desired sites of degradation. Alternatively, chemical hydrolysis of the surface or direct soaking of the scaffold material in an appropriate mineral solution may be used to pattern the wafer. In any case, the modified surface of the scaffold contains functional groups, such as polar oxygen groups (carboxylates in particular) that promote calcium phosphate formation on the surfaces of the materials used to form the scaffold materials when the treated scaffold is immersed in an appropriate solution. Osteogenic cell precursors may be seeded onto the mineralized biomaterial ex vivo. Alternatively, bone cells were said to attach to the mineralized scaffold material in vivo. The growth factor VEGF was shown to be released from such mineralized tissue scaffold materials over time. While numerous utilities of this patterning technique are disclosed, the patent fails to teach any therapeutic method that uses the patterned tissue scaffolds for a therapeutic treatment of dental conditions in vivo. [0010] Other publications describe use of tissue scaffold material or hydrogels to deliver morphogenic agents (or genes encoding the same) that promote growth or development of various tissues in vivo after ex vivo culture. Rutherford, R. B., (2001) Euro. J. Oral Science 109(6) 422-444 disclosed that ex vivo grown dermal fibroblasts transduced with an adenovirus expression vector expressing a cDNA encoding bone morphogenic protein 7 (BMP-7) were effective at inducing reparative dentinogenesis with apparent regeneration of the dentin-pulp complex when transplanted in vivo in ferrets having pulpitis. However, no effect was seen when a 10 fold range (2.5 .mu.g to 25 .mu.g recombinant protein) was delivered directly to the pulp tissue. Rutherford R. B., et al (2000) Eur. J. of Oral Science 108(3) 202-206. [0011] Sloan et. al. (2000) Archives of Oral Biology 45(2) 173-177 used a hydrogel of agarose beads soaked in BMP-7 to deliver the protein to tooth slices cultured ex vivo in a semi solid agar and disclosed a localized increase in extracellular matrix secretion by odontoblasts at the site of application. Nakashima, M., (1994) Archives of Oral Biology (12) 1085-89 demonstrated that recombinant BMP-2 and BMP-4 induced dentin formation in amputated pulp of dogs in vivo when condensed on a powdered carrier comprised of dried type 1 collagen and proteoglycans. In a prior publication, BMP-2 and BMP-4 were shown to induce dentin formation in amputated pulp when condensed on the same the same type of delivery material. Nakashima, M., (1994) J. Dental Research 73(9) 1515-1522. [0012] Other types of materials such as various modified hydrogels also provide tissue scaffold-like functions for propagating various tissue. Anderson et al, (2002) PNAS 17; 99(19), 12025-30, disclosed that an alginate based hydrogel modified with the tripeptide sequence RGD promoted cell multiplication and bone tissue-like growth plates when chondrocytes were transplanted ex vivo. [0013] U.S. Pat. No. 6,413,498 discloses a mixture of cationic and anionic ion exchange resins charged with Ca.sup.2+, F.sup.- and PO.sub.4.sup.3- in molar ration of 2:1:1 for use in a filler for the treatment of caries. These resins, typically made of polystyrene, promote remineralization of dentin to form tissue having a composition and hardness close to that of original dentin. Such resins are disclosed to also be useful as components of dentifrice products are not suitable as a tissue scaffold to promote regeneration of the cell types that are required for healthy dentin. Moreover, such resins are believed to leave organic residue upon contact with teeth. [0014] U.S. Pat. Publication No. 2002/0119180 A1 and Young et al., (2002) J. Dent. Res. 81 [10] p 695-700 each describe regenerating multiple dental tissues in organized tooth structures in situ by ex vivo seeding of enamel and pulp organ tissues on a PGA/PLLA or PLGA scaffold formed in the shape of [[a]] human teeth. The ex vivo cultured tissue/scaffold combinations were collagen coated and then implanted in the omentum of rats where they were cultured in situ. The in situ cultured tissue were shown to develop mineralized structures indicative of enamel surrounding dentin, and to develop into odontogenic cell types, including, ameloblasts, odontoblast-like cells, putative cemetoblasts and cementum. While the experiment demonstrated the potential feasibility of regenerating whole teeth by ex vivo seeding and in vivo culturing of isolated dental tissue, Young et al, however, did not disclose any method of treating dental tissue in vivo. [0015] While the prior art recognizes the utility of using tissue scaffolds for growing tissue in vitro or for treating bone lesions in vivo, there remains a need in the art for methods and devices for treating dental conditions in vivo using such tissue scaffold. The present invention provides for such methods and devices. SUMMARY OF THE INVENTION [0016] The present invention provides methods, compositions and devices based on the discovery that tissue scaffolding materials can be directly used to facilitate regeneration of dentin in a tooth of subject in vivo, without need of seeding of the scaffold material by ex vivo culture of cells prior to implanting the scaffold material into dental tissue. In the methods of the invention, the scaffolding material is used as a substitute or as an enhancement of prior art methods for treating various stages of dental caries or pulpitis. The methods are suitable for treating conditions ranging from asymptomatic caries where only a small portion of dentin below the crown of the tooth is degenerated, to treating deep caries where dentin is degenerated down to the root ordinarily requiring a root canal treatment by the methods of the prior art. The methods apply the scaffolding material directly into appropriately sized holes drilled into a subject's teeth so that at least a portion of the pulp is exposed. The scaffolding material is implanted into the hole so that a portion of the scaffold material is in contact with the exposed portion of the pulp. Pulp cells are stimulated to grow into the matrix of the scaffolding material causing remineralization and formation of new dentin. [0017] More particularly, one aspect of the invention is a method for treating a subject's tooth in need of regeneration of dentin that includes the acts of forming a hole in the tooth of the subject in vivo, the hole being of a depth sufficient to expose at least a portion of pulp, inserting a tissue scaffold into the hole so that a portion of the tissue scaffold contacts at least a portion of the exposed pulp; and regenerating dentin by allowing sufficient time for tissue to grow in vivo, from the pulp into the tissue scaffold and to regenerate the dentin. In certain embodiments, the invention the tissue scaffold inserted into the hole does not include an ex vivo cultured tissue within the scaffold. In other embodiments, dental pulp stem cells are seeded into the tissue scaffold and cultured therein prior to insertion of the tissue scaffold into the hole. In still other embodiments, dental pulp stem cells are added directly to the region of the exposed pulp prior to inserting the tissue scaffold into the hole. [0018] In certain embodiments, the tissue scaffold is formed into a shape dimensioned to fit snuggly into the hole that is formed so that the tissue scaffold does not move more than 0.1 mm in a lateral direction in the hole. The tissue scaffold is typically formed into a cylindrical wafer having a diameter of about 2 to about 5 mm and a height of about 0.5 to about 2 mm. [0019] In various embodiments, the tissue scaffold also contains calcium phosphate associated therewith. In particular embodiments the tissue scaffold also contains fluoride associated therewith. [0020] In certain embodiments, the tissue scaffold is comprised of scaffolding material selected from the group consisting of PLA, PGA, PDLLA PLLA and PLGA. In a particular embodiment, the tissue scaffold is comprised of scaffolding material is comprised of PLGA. [0021] In certain embodiments, the tissue scaffold may further include a physiologically effective amount of a morphogenic agent that promotes growth of dentin tissue or the mineralization thereof. In particular embodiments, the morphogenic agent is selected from a protein encoded by a TGF-.beta. supergene family. In more particular embodiments, the protein is selected from the group consisting of BMP-2, BMP 4, BMP-7, VEGF, FGF-1, FGF-2, 1GF-1, 1GF-2, PDGF, GDF-1, GDF-2, GDF-2, GDF-3, GDF-4, GDF-5, or combinations of the same. In still more particular embodiments the protein is selected from the group consisting of BMP-2, BMP 4, BMP-7, and GDF-5. In yet another more particular embodiment, the morphogenic agents includes at least one of PDGF VEGF, and a protein selected from the group consisting of BMP-2, BMP 4, BMP-7, and GDF-5. Continue reading... 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