RU2809119C2 - Molded block containing collagen - Google Patents

Abstract

FIELD: medicine; dental implants.

SUBSTANCE: group of inventions can be used to stimulate bone or soft tissue growth. A dental implant includes an implant, an abutment, and a molded block containing a dried cross-linked collagen matrix. The molded block is positioned between the abutment and the implant in such a way that it is at least partially directly contacts the implant and the abutment. The molded block of a dental implant is shaped in such a way that, after implantation, the abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the dental implant. Once implanted, a dental implant provides space and an environment for cells to grow. The dried cross-linked collagen matrix is obtained by a method including the following: obtaining an acidic solution of collagen followed by neutralization of the solution; concentration of the solution of the previous stage; lyophilizing the concentrated mixture of the previous step, thereby obtaining a dried collagen composition; incubating the composition with the crosslinking agent and the first solvent; washing the incubated composition of the previous stage with a second solvent; and lyophilizing the washed composition step.

EFFECT: achieved compaction of the connective tissue around the dental implant abutment and improved attachment of tissue cells to the implant, which reduces the probability of inflammation and peri-implantitis.

27 cl, 3 dwg, 3 ex

Description

Field of technology to which the invention relates

[001] This invention is directed to a molded block, a dental implant abutment, comprising an implant, an abutment and a molded block, wherein the molded block comprises a dried collagen matrix; as well as the method of their manufacture.

State of the art

[002] Inflammation of the gums around dental implants (peri-implant mucositis) often leads to irreversible bone loss (peri-implantitis), which if not treated correctly can lead to implant loss. This problem is estimated to affect ~30% of all dental implants and is a major concern for patients and clinicians.

[003] One of the many potential etiological factors in the development of peri-implantitis is bacterial colonization within the biological width, that is, the minimum distance between the edge of the implant and the alveolar bone crest. This often correlates with insufficient soft tissue thickness, which has been shown to increase bone atrophy after implant abutment attachment. Another widely studied factor is soft tissue compaction around implant abutments, which is often characterized by the attachment of fibroblasts and epithelial cells to titanium or zirconia. This very important attachment can be lost when abutments are reattached and detached during the implant restoration process.

[004] The need to increase and enhance soft tissue attachment and thickness around dental implants has led to the emergence of several surgical techniques, primarily based on harvesting dense autogenous connective tissue and implanting it adjacent to implants at risk or in the esthetic area. Special surgical skills limit these procedures to highly trained surgeons. Therefore, there is a need for a solution that includes the use of a medical device that is effective and easy to use. This product must be capable of supporting soft tissue augmentation and providing the formation and maintenance of biological width.

[005] This invention provides a molded block containing a dried collagen matrix. This block can be shaped into a variety of shapes, such as an O-ring, and has been found to form and increase connective tissue compaction around dental implant abutments.

Disclosure of the invention

[006] In one embodiment, the present invention is directed to a molded block containing a dried cross-linked collagen matrix. In another embodiment of the invention, the dried cross-linked collagen matrix further comprises hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof.

[007] In one embodiment, the present invention is directed to a molded block for use as an accessory device for medical devices, implants, product attachments, or any combination thereof, where the molded block contains a dried cross-linked collagen matrix. In another embodiment of the invention, the dried cross-linked collagen matrix further comprises hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof.

[008] In one embodiment, the present invention is directed to a dental implant abutment comprising an implant, an abutment, and a molded block containing a dried cross-linked collagen matrix; wherein the molded block is positioned between the abutment and the implant such that it is at least partially in direct contact with the implant and/or the abutment. In another embodiment of the invention, placement of a molded block within a dental implant abutment allows for the creation of a foundation for soft/hard tissue growth. In another embodiment of the invention, sliding movement of the molded block between the implant and the abutment allows the abutment and implant to bond to the molded block, causing ingrowth of the supported tissue.

[009] In one embodiment, the present invention is directed to a dental implant abutment for use in stimulating bone or soft tissue growth, the dental implant abutment comprising an implant, an abutment, and a molded block containing a dried cross-linked collagen matrix; wherein the molded block is positioned between the abutment and the implant such that it is at least partially in direct contact with the implant; the molded block of the dental implant abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the dental implant abutment; and the dental implant abutment of the invention provides space and environment for cell growth.

[0010] In another embodiment of the invention, the molded block is shaped like an O-ring, sleeve-shaped, or tube-shaped (Figure 2a).

[0011] In one embodiment, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the method comprising:

a. obtaining a dried cross-linked collagen matrix according to this invention; And

b. cutting a molded block from said dried matrix.

[0012] In one embodiment, the present invention is directed to a method for manufacturing a molded block of a dental implant abutment, as described above herein, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i); and pouring it into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating said composition with a cross-linking agent, a first solvent and optionally a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent; And

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded dental implant abutment block as described above herein.

[0013] In one embodiment, the present invention is directed to a method for manufacturing a molded block of a dental implant abutment as described above herein, said method comprising:

(i) obtaining an acidic solution of collagen and a cross-linking agent, followed by neutralizing the solution;

(ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating the composition with a cross-linking agent, a first solvent, and optionally a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent; And

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded dental implant abutment block as described above herein.

[0014] In one embodiment, the present invention is directed to a method of manufacturing a molded block of a dental implant abutment, as described above herein, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating the composition with a cross-linking agent and a first solvent;

(v) optionally adding a pharmaceutically active agent to the incubated composition in step (iv) and washing the resulting solution with a second solvent; And

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded dental implant abutment block as described above herein.

Brief description of drawings

[0015] The subject matter of the invention is particularly emphasized and clearly stated at the end of the specification. However, the present invention, both in organization and method of operation, as well as its objects, characteristics and advantages, can best be understood by reference to the following detailed description when read in conjunction with the accompanying illustrations, in which:

[0016] Figure 1 illustrates a dental implant abutment according to the invention, comprising an implant, an abutment and a molded block, indicated by arrows.

[0017] In FIG. 2a-2b illustrate molded blocks according to the invention. Fig. 2a : illustration of such shapes; and Fig. 2b : molded blocks made in accordance with embodiments of the invention.

[0018] It should be appreciated that for simplicity and clarity of illustration, elements illustrated in the figures are not necessarily illustrated to scale. For example, for clarity, some elements may be larger in size than other elements. In addition, if deemed appropriate, reference numerals may be repeated throughout the figures to designate corresponding or similar elements.

Carrying out the invention

[0019] In the following detailed description, numerous specific details are set forth in order to provide an understanding of the present invention. However, those skilled in the art will appreciate that the invention may be practiced without these specific details. In other cases, well-known methods, procedures and components are not described in detail so as not to obscure the understanding of the present invention.

Molded block and its uses

[0020] In one aspect, the invention provides a molded block containing a dried collagen matrix. In one embodiment of the invention, the dried collagen matrix contains cross-linked collagen. In one embodiment, the invention provides a molded block containing a dried cross-linked collagen matrix. In another embodiment of the invention, the molded block further contains hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof.

[0021] In another aspect, the invention provides a molded block for use as an accessory/component of medical devices, implants, product attachments, or any combination thereof, wherein the molded block comprises a dried cross-linked collagen matrix.

[0022] In another embodiment of the invention, the molded block is used as an additional element/component of medical devices. In another embodiment of the invention, the molded block is used as an additional element/component of the implants. In another embodiment of the invention, the molded block is used as an additional element/component of the product fastenings. In another embodiment of the invention, any medical device known in the art may be used. In another embodiment of the invention, the implants are dental implant bodies. In another embodiment of the invention, any dental implant bodies known in the art may be used. In another embodiment of the invention, non-limiting examples of product attachments include: prostheses, shaped screws, shaped plates, shaped wires, or any other fastener for surgical reconstruction of bones/vessels. Each embodiment represents a different embodiment of the present invention.

[0023] In some embodiments, the term “additional element/component” refers to a molded physical product that can be added to a known other device, article, or product. In other embodiments, the addition is performed by one skilled in the art of the invention. In another embodiment of the invention, addition includes the following non-limiting actions: placing an additional element/component on or in close proximity to another device, chemically manipulating them to ensure reliable communication between them (for example, soldering, melting and solidifying, dissolving and deposition) , mechanical manipulation of them (for example, screwing, grinding) and any combination of the above. In another embodiment of the invention, the additional component/element is a molded block of the invention that is added to a dental implant abutment, wire, plate, screw or clamp, or any other article, device or product known in the art . Each possibility represents a different embodiment of the present invention.

[0024] In some embodiments, the term “block” refers to some physical extent of a solid. In other embodiments, the solid is dry and does not contain any solvent or liquid. In other embodiments, the solid includes at least one single component. In another embodiment, non-limiting examples of the component include: a chemical compound, a small molecule, a metal, an alloy, a composite material, a biomaterial, a polymer, and an organometallic complex. In another embodiment of the invention, the solid includes more than one component selected from the above list. In another embodiment of the invention, the block contains a biocompatible material or composition. In another embodiment of the invention, the block is a biopolymer or protein. In other embodiments, the physical characteristics of the block allow it to be designed, carved, or constructed, as is known in the art, into a desired shape. In another embodiment of the invention, non-limiting examples of block characteristics include the following characteristics: dense, porous or non-porous, viscous, hard, soft or plastic. In another embodiment of the invention, the block has a porosity in the range between 10-90%. In another embodiment of the invention, the block has a porosity in the range between 10-20%. In another embodiment of the invention, the block has a porosity in the range between 20-30%. In another embodiment of the invention, the block has a porosity in the range between 30-40%. In another embodiment of the invention, the block has a porosity in the range between 40-50%. In another embodiment of the invention, the block has a porosity in the range between 50-60%. In another embodiment of the invention, the block has a porosity in the range between 60-70%. In another embodiment of the invention, the block has a porosity in the range between 70-80%. In another embodiment of the invention, the block has a porosity in the range between 80-90%. In another embodiment of the invention, the block has a porosity in the range between 10-30%. In another embodiment of the invention, the block has a porosity in the range between 30-50%. In another embodiment of the invention, the block has a porosity in the range between 50-70%. In another embodiment of the invention, the block has a porosity in the range between 70-90%. Each embodiment represents a different embodiment of the present invention.

[0025] In some embodiments of the invention, the term "molded block" refers to a block that is offered in some shape or form, i.e. designed, designed, manufactured or produced, as is known in the art, to provide some two- or three-dimensional structure of such a block. In other embodiments, non-limiting examples of a two- or three-dimensional structure include: square, circle, triangle, O-ring, sleeve, tube, pyramid, box, cuboid, cylinder, cone, prism, and any other structure containing a hole inside . In other embodiments of the invention, any conceivable development, design, production or manufacturing process may be used to produce a molded block.

[0026] In some embodiments, the term “collagen” refers to a biopolymer structured into fibrillar networks or other non-fibrillar superstructures and is a major component of connective tissue in humans or many animals. Numerous types of collagen are known and occur naturally. Non-limiting examples include types I-V. In some embodiments, the collagen has a fibrillar (eg, type I) or non-fibrillar structure. Each embodiment represents a separate embodiment of the invention.

[0027] In one embodiment, the collagen used in the methods, applications and block forms of this invention refers to native collagen, fibrillar collagen, fibrillar atelopeptide collagen, lyophilized collagen, collagen derived from animal sources, human collagen, recombinant collagen , pepsinized collagen, reduced collagen and any combination thereof. In another embodiment, the collagen includes fibrillar collagen reconstituted from monomolecular atelopeptide collagen. In another embodiment, the collagen is atelopeptide fibrillar collagen obtained by reducing monomolecular atelopeptide collagen obtained by proteolytic cleavage of native collagen. Each possibility represents a different embodiment of the present invention.

[0028] In some embodiments, the term “cross-linked collagen” refers to a covalent network containing biopolymer chains of collagen covalently and intermolecularly linked to cross-linking agents.

[0029] In some embodiments, the term “cross-linking agents” refers to small molecules or polymers containing at least two ends that can covalently connect polymer/oligomeric chains and thereby cross-link those chains.

[0030] In some embodiments, the collagen is cross-linked with sugar. In another embodiment, the sugar is selected from the group consisting of glycerose (glyceraldehyde), threose, erythrose, lyxose, xylose, arabinose, ribose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and any combination thereof. Each embodiment represents a different embodiment of the present invention.

[0031] In another embodiment of the invention, the sugar is a disaccharide. Each possibility represents a different embodiment of the present invention.

[0032] In another embodiment, the disaccharide is selected from the group consisting of maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, turanose, trehalose, and any combination thereof. Each embodiment represents a different embodiment of the present invention.

[0033] In another aspect, this invention provides a dental implant abutment (FIG. 1) comprising an implant, an abutment, and a molded block as described herein. In one embodiment, this invention provides a dental implant abutment comprising an implant, an abutment, and a molded block containing a dried cross-linked collagen matrix, wherein the molded block is positioned between the abutment and the implant such that it is at least partially in contact with the implant and/or or with an abutment. In another embodiment of the invention, placement of a molded block within a dental implant abutment allows for the creation of a foundation for soft/hard tissue growth. In another embodiment of the invention, sliding movement of the molded block between the implant and the abutment allows the abutment and implant to bond to the molded block, causing ingrowth of the supported tissue. In another embodiment of the invention, the molded block of the dental implant abutment is partially and/or completely in contact with the bone and/or soft tissue surrounding the dental implant abutment.

[0034] In another embodiment of the invention, the implant is partially in contact with the molded block. In another embodiment of the invention, the implant is completely covered with a molded block. In one embodiment, any dental implant abutment implant of the invention may be used, provided, or manufactured by any method known in the art. In another embodiment of the invention, the implant is made of a material containing polymers, ceramics, metals (eg, Ti, Zr) or alloys, or any combination thereof. In another embodiment of the invention, the shape/size of the implant includes conical, cylindrical, plate-like, wire-threaded, hole-shaped, or any combination thereof. In one embodiment of the invention, any abutment of the dental implant abutment of the invention may be used, provided, or manufactured by any method known in the art. In another embodiment of the invention, the abutment is made of a material containing polymers, ceramics, metals (eg Ti, Zr) or alloys, or any combination thereof. In another embodiment of the invention, the abutment shape/size includes cylinders, cones, cubes, or any combination thereof. In some embodiments, non-limiting examples of polymers for abutments and/or implants include: polyurethane, polymethyl methacrylate, polysiloxanes, polylactic acid, polyacrylamides, any combination thereof, and any other biocompatible polymer. In some embodiments, non-limiting examples of abutment and/or implant ceramics include zirconia, alumina, titanium oxide, calcium phosphates, any combination thereof, and any other biocompatible ceramic. In some embodiments, non-limiting examples of metals or alloys for abutments and/or implants include: Ti, Zr, Ni, NiTi, any combination thereof, and any other biocompatible metal or alloy. Each embodiment represents a different embodiment of the present invention.

[0035] In yet another aspect, a dental implant abutment of the invention is used to stimulate bone or soft tissue growth. In one embodiment of the invention, the dental implant abutment of the invention provides space and environment for cell growth. The soft yet conformable nature of the material ensures a close seal to the abutment and implant surfaces, as well as to the surrounding soft and bone tissue. This proximity, combined with the conductive properties of bone and soft tissue, allows for rapid and efficient insertion of the abutment.

[0036] In another embodiment of the invention, the molded block further comprises hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof.

[0037] In other embodiments, non-limiting examples of a pharmaceutically active agent include antibacterial agents, antifungal agents, antiseptic agents, anti-inflammatory agents, antibiotic agents, vitamins, or any combination thereof. In another embodiment of the invention, any agent from the above list known in the art may be used. Each embodiment represents a different embodiment of the present invention.

[0038] In other embodiments, non-limiting examples of the active agent include antibacterial agents, antifungal agents, antiseptic agents, anti-inflammatory agents, antibiotic agents, vitamins and vitamers, and any combination thereof. In another embodiment of the invention, any agent from the above list known in the art may be used. Each embodiment represents a different embodiment of the present invention.

[0039] In another embodiment, non-limiting examples of antibacterial agents include: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Arbekacin, Plazomycin, Streptomycin, Apramycin, Geldanamycin, Herbimycin, Loracarbef, Faropenem, Ertapenem, Doripenem, Imipenem, Meropenem, Cefazolin, Cephacetril, Cefadroxil, Cephalexin, Cephaloglycin, Cephalonium, Cephaloridine, Cefalotin, Cephapirin, Cephatrizin, Cephasedone, Cefazaflur, Cefradine, Cephroxadine, Ceftezol, Cefaclor, Cefamandole, Cef minox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cephamycin, Cefoxitin, Cefotetan, Cefmetazole, Carbacefem, Cefixime, Ceftazidime, Ceftriaxone, Cefcapen, Cefdaloxime, Cefdinir, Cefditoren, Cefetameth, Cefmenoxime, Cefodisime, Cefoperazone, Cefotaxime, C efpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, Ceftiolen, Ceftizoxime, Oxacefem, Cefepime, Cefozopran, Cefpirome, Cefkin, Ceftiofur, Cefkin, Cefovecin, CXA-101, Ceftaroline, Ceftobiprole, Clindamycin, Lincomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Solithromycin, Aztreonam, Furazolidone, Nitrofurantoin, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, Iprof loxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Levonadifloxacin, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Delafloxacin, Mafenide, Sulfonamidochryzoidine, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole , Trimethoprim, Emeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Tigecycline , Tedizolid, Linezolid, Ranbezolid, Torezolid, Radezolid, any combination thereof and any pharmaceutically acceptable salt of the above. Each embodiment represents a different embodiment of the present invention.

[0040] In another embodiment, non-limiting examples of antifungal agents include: terbinafine, naftifine, amphotericin B, butenafine, chloroxylenol, ciclopirox, flucytosine, caspofungin, griseofulvin, clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, oxyconazole, nystatin, undecylene acid, any combination thereof and any pharmaceutically acceptable salt of the above. Each embodiment represents a different embodiment of the present invention.

[0041] In another embodiment, non-limiting examples of antiseptic agents include: naftifine, tolnaftate, mediocidin, candicidin, trichomycin, gamycin, aurefungin, ascosine, aifattine, azacolutin, trichomycin, levorin, heptamicin, candymycin, griseofulvin, pradimycins, benanomycin; ambisome; nikkomycin Z; flucytosine, perimycin, any combination thereof and any pharmaceutically acceptable salt of the above. Each embodiment represents a different embodiment of the present invention.

[0042] In another embodiment, non-limiting examples of anti-inflammatory agents include: aspirin, ibuprofen, naproxen, celecoxib, diclofenac, ketoprofen, ketorolac, oxaprozin, salsalate, sulindac, any combination thereof, and any pharmaceutically acceptable salt of the foregoing. Each embodiment represents a different embodiment of the present invention.

[0043] In another embodiment, non-limiting examples of antibiotics include penicillin, cephalosporin, ciprofloxacin, erythromycin, any combination thereof, and any pharmaceutically acceptable salt of the foregoing. Each embodiment represents a different embodiment of the present invention.

[0044] In another embodiment, non-limiting examples of vitamins include: vitamin A, retinol, retinal, carotenoid, vitamin B1, thiamine, vitamin B2, riboflavin, vitamin B3, niacin, niacinamide, nicotinamide, riboside, vitamin B5, pantothenic acid , vitamin B6, pyridoxine, pyridoxamine, pyridoxal, vitamin B7, biotin, vitamin B9, folate, vitamin B12, cyanocobalamin, hydroxocobalamin, methylcobalamin, adenosylcobalamin, vitamin C, ascorbic acid, vitamin D, cholecalciferol (D3), ergocalciferol (D2), vitamin E, tocopherols, tocotrienols, vitamin K, phylloquinone, menaquinones, any combination thereof and any pharmaceutically acceptable salt of the above. Each embodiment represents a different embodiment of the present invention.

[0045] In some embodiments, the term “hydroxyapatite” refers to the naturally occurring calcium mineral https://en.wikipedia.org/wiki/Mineral having the formula Ca ₅ (PO ₄ ) ₃ (OH) or Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ . In other embodiments, hydroxyapatite can be prepared or obtained by any method known in the art. In another embodiment of the invention, hydroxyapatite is used and/or obtained in the form of a bulk substance or nanoparticles. Each embodiment represents a different embodiment of the present invention.

[0046] In some embodiments, the term “titanium” refers to titanium metal or alloy. In other embodiments of the invention, titanium is alloyed with non-limiting examples of Zr and/or Ni. In another embodiment of the invention, titanium is biocompatible. In another embodiment of the invention, titanium is a biocompatible titanium alloy. In other embodiments, the titanium metal has any form known in the art. In another embodiment of the invention, titanium or alloyed titanium may have a shape memory function. In another embodiment of the invention, the form of titanium metal includes a simple metal, a surface or a nanoparticle substance thereof. In another embodiment of the invention, the base metal is in the form of a rod, plate, cube, or any other physical shape known in the art. Each embodiment represents a separate embodiment of the invention.

[0047] In some embodiments, the term “nanoparticle substance” (eg, hydroxyapatite or titanium) refers to a substance that has at least one physical nanometric dimension. In another embodiment of the invention, the nanoparticle material is in the form of nanoparticles, nanospheres, nanocubes, nanoplates, nanoribbons, nanowires, nanorods, or any other nanometric shape known in the art.

Method for producing a molded block according to this invention

[0048] In one further aspect, the present invention is directed to a method for making a molded block containing a dried cross-linked collagen matrix according to the present invention, the method comprising:

a. obtaining a dried cross-linked collagen matrix according to this invention; And

b. cutting a molded block from said dried matrix.

[0049] In another embodiment of the invention, the dried cross-linked collagen matrix contains hydroxyapatite. In another embodiment of the invention, the dried cross-linked collagen matrix contains titanium. In another embodiment of the invention, the cross-linked collagen matrix contains a pharmaceutically active agent. In another embodiment of the invention, the dried cross-linked collagen matrix contains hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof.

[0050] In one embodiment, the present invention is directed to a method of producing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i);

(iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition;

(iv) incubating the composition with a cross-linking agent and a first solvent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining the dried cross-linked collagen matrix of the present invention.

[0051] In one embodiment, the present invention is directed to a method for producing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen and optionally hydroxyapatite, titanium, a pharmaceutically active agent, or any combination thereof, the method comprising:

(i) producing an acidic solution of collagen followed by neutralizing the solution, wherein the neutralization solution optionally contains hydroxyapatite;

(ii) concentrating the solution of step (i) and optionally adding titanium;

(iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition;

(iv) incubating said composition with a cross-linking agent, a first solvent, and optionally adding a pharmaceutically active agent;

(v) washing the incubated composition in step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining the dried cross-linked collagen matrix of the present invention.

[0052] In one embodiment, the present invention is directed to a method for producing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen and hydroxyapatite, the method comprising:

(i) obtaining an acidic solution of collagen followed by neutralization of the solution, wherein the neutralization solution contains hydroxyapatite;

(ii) concentrating the solution of step (i);

(iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition;

(iv) incubating the composition with a crosslinking agent and a first solvent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining the dried cross-linked collagen matrix of the present invention.

[0053] In one embodiment, the present invention is directed to a method for producing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen and a pharmaceutically active agent, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i);

(iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition;

(iv) incubating the composition with a cross-linking agent, a first solvent and a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining the dried cross-linked collagen matrix of the present invention.

[0054] In one embodiment, the present invention is directed to a method for producing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen, titanium and a pharmaceutically active agent, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i), adding titanium and

(iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition;

(iv) incubating the composition with a cross-linking agent, a first solvent and a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining the dried cross-linked collagen matrix of the present invention.

[0055] In another embodiment of the invention, in addition to or instead of lyophilization steps, compression steps (application of mechanical pressure using special equipment) are used.

[0056] In some embodiments, die cutting is performed by any method known in the art. In another embodiment of the invention, die cutting by the method of the invention is performed using a CNC (Computer Numerical Control) machine, laser cutting machine, water jet cutting machine, drilling or abrasive machine. Each embodiment represents a different embodiment of the present invention.

[0057] In some embodiments, the molded block of the invention is offered in a variety of forms. In some embodiments, the blocks are shaped to allow the block to be easily fitted to a dental abutment and to provide at least partial coverage of the dental implant after the abutment is placed into the implant. In another embodiment of the invention, the block is shaped like an O-ring, sleeve-shaped or tube-shaped. Each embodiment represents a different embodiment of the present invention.

Method for producing a molded block according to the present invention using a mold

[0058] In one further aspect, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the matrix comprising cross-linked collagen, optionally hydroxyapatite, and optionally a pharmaceutically active agent, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating said composition with a cross-linking agent, a first solvent and optionally a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded block according to the present invention. In another embodiment of the invention, the solution for neutralizing step (i) optionally contains hydroxyapatite.

[0059] In one embodiment, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen, optionally hydroxyapatite, and optionally a pharmaceutically active agent, the method comprising:

(i) obtaining an acidic solution of collagen and a cross-linking agent, followed by neutralizing the solution;

(ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating the composition with a cross-linking agent, a first solvent, and optionally a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent; And

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded block according to the present invention. In another embodiment of the invention, the solution for neutralizing step (i) optionally contains hydroxyapatite.

[0060] In one embodiment, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the matrix containing cross-linked collagen, optionally hydroxyapatite, optionally a pharmaceutically active agent, the method comprising:

(i) obtaining an acidic collagen solution followed by neutralization of the solution;

(ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating the composition with a cross-linking agent and a first solvent;

(v) optionally adding a pharmaceutically active agent to the incubated composition in step (iv) and washing the resulting solution with a second solvent; And

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded block according to the present invention. In another embodiment of the invention, the solution for neutralizing step (i) optionally contains hydroxyapatite.

[0061] In one embodiment, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the matrix comprising cross-linked collagen, optionally hydroxyapatite, optionally titanium and optionally a pharmaceutically active agent, the method comprising:

(i) producing an acidic solution of collagen followed by neutralizing the solution, wherein the neutralization solution optionally contains hydroxyapatite;

(ii) concentrating the solution of step (i), optionally adding titanium; and pouring into a mold with a pre-designed block shape;

(iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, optionally containing hydroxyapatite;

(iv) incubating said composition with a cross-linking agent, a first solvent and optionally a pharmaceutically active agent;

(v) washing the incubated composition of step (iv) with a second solvent;

(vi) lyophilizing the washed composition of step (v);

thereby obtaining a molded block according to the present invention.

[0062] In another embodiment of the invention, in addition to or instead of lyophilization steps, compression steps (application of mechanical pressure using special equipment) are used.

[0063] In another embodiment of the invention, the mold is cooled to a freezing temperature in the range between -10°C and -190°C before step (iii) lyophilization. In another embodiment of the invention, the mold is cooled to a freezing temperature in the range between -10 and -80°C for a period of time in the range between 0.5 and 24 hours, followed by step (iii) lyophilization. In another embodiment of the invention, cooling is carried out for 0.5-24 hours. In another embodiment of the invention, cooling is carried out for 0.5-1 hour. In another embodiment of the invention, cooling is carried out for 1-2 hours. In another embodiment of the invention, cooling is carried out for 2-5 hours. In another embodiment of the invention, cooling is carried out for 5-10 hours. In another embodiment of the invention, cooling is carried out for 10-24 hours. Each embodiment represents a different embodiment of the present invention.

[0064] In another embodiment of the invention, the mold is shaped into a block of the desired shape using a method including 3D printing, casting, or any combination thereof. Each possibility represents a different embodiment of the present invention.

Method for producing a molded block according to this invention from granules

[0065] In one embodiment, the present invention is directed to a method of making a molded block containing a dried cross-linked collagen matrix, the matrix comprising cross-linked collagen, optionally hydroxyapatite, optionally titanium and optionally a pharmaceutically active agent, the method comprising:

(i) producing an acidic solution of collagen followed by neutralizing the solution, wherein the neutralization solution optionally contains hydroxyapatite;

(ii) concentrating the solution of step (i) and optionally adding titanium;

(iii) incubating said composition with a cross-linking agent, a first solvent, and optionally adding a pharmaceutically active agent;

(iv) washing the incubated composition of step (iv) with a second solvent;

(v) homogenizing, casting and grinding the composition to obtain cross-linked collagen granules;

(vi) wetting the granules in step (v) with a first or second solvent and die cutting to obtain a molded block according to the present invention.

[0066] In some embodiments, the molded block and/or dried cross-linked collagen matrix produced by the methods of the present invention, as described above herein, is used in a dental implant abutment of the present invention, also described above; and/or they (block/matrix) are part of such a dental implant abutment.

[0067] In some embodiments, the molded block or blocks produced by the methods of the present invention are ground to form granules and then wetted with a first or second solvent and die-cut to form a molded block containing a cross-linked collagen matrix. In other embodiments of the invention, the granule size ranges from 1 to 2000 microns.

[0068] In some embodiments, the collagen used in the methods of the present invention in the solution of step "(i)" is selected from the following non-limiting examples, including: native collagen, fibrillar collagen, fibrillar atelopeptide collagen, lyophilized collagen, derived collagen from animal sources, human collagen, recombinant collagen, pepsinized collagen, reconstituted collagen, and any combination thereof. In another embodiment, the collagen includes fibrillar collagen reconstituted from monomolecular atelopeptide collagen. In another embodiment, the collagen is atelopeptide fibrillar collagen obtained by reducing monomolecular atelopeptide collagen obtained by proteolytic cleavage of native collagen. Each embodiment represents a different embodiment of the present invention.

[0069] In another embodiment of the invention, the neutralization solution contains a base or buffer. In another embodiment of the invention, the neutralization solution further contains hydroxyapatite. In another embodiment of the invention, the buffer is selected from phosphate buffered aqueous sodium chloride solution, NaHCO ₃ /Na ₂ CO ₃ buffer, Tris buffer or Tricine buffer, or any other buffer that maintains a neutral pH. In another embodiment of the invention, the acid solution includes HCl, acetic acid, nitric acid, citric acid, sulfuric acid, phosphoric acid or any other acid known in the art. In another embodiment of the invention, the base solution includes NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ , Na ₂ HPO ₄ or any other base known in the art.

[0070] In some embodiments, the term “neutral pH” refers to a pH range that resembles the physiological pH in a biological organism and/or biological system; and it is defined in the range between 6.5-7.5. In some other embodiments of the invention, the neutral pH is in the range between 6.5-6.7. In some other embodiments of the invention, the neutral pH is in the range between 6.7-6.9. In some other embodiments of the invention, the neutral pH is in the range between 6.9-7.1. In some other embodiments of the invention, the neutral pH is in the range between 7.1-7.3. In some other embodiments of the invention, the neutral pH is in the range between 7.3-7.5. In some other embodiments of the invention, the neutral pH is in the range between 7.1-7.2. In some other embodiments of the invention, the neutral pH is in the range between 7.2-7.3. In some other embodiments of the invention, the neutral pH is in the range between 7.3-7.4. In some other embodiments of the invention, the neutral pH is in the range between 7.4-7.5.

[0071] In one embodiment of the invention, the concentration step is carried out by centrifugation. In another embodiment of the invention, centrifugation is carried out at a speed in the range between 50-20,000 rpm (revolutions per minute). In another embodiment of the invention, centrifugation is carried out at a speed in the range between 50-100 rpm. In another embodiment of the invention, centrifugation is carried out at a speed in the range between 100-1000 rpm. In another embodiment of the invention, centrifugation is carried out at a speed in the range between 1000-5000 rpm. In another embodiment of the invention, centrifugation is carried out at a speed in the range between 5000-10000 rpm. In another embodiment of the invention, centrifugation is carried out at a speed in the range between 10,000-20,000 rpm. In another embodiment of the invention, centrifugation is carried out for 1-120 minutes. In another embodiment of the invention, centrifugation is carried out for 1-5 minutes. In another embodiment of the invention, centrifugation is carried out for 5-10 minutes. In another embodiment of the invention, centrifugation is carried out for 10-20 minutes. In another embodiment of the invention, centrifugation is carried out for 20-50 minutes. In another embodiment of the invention, centrifugation is carried out for 50-100 minutes. In another embodiment of the invention, centrifugation is carried out for 100-120 minutes.

Each embodiment represents a different embodiment of the present invention.

[0072] In another embodiment of the invention, the lyophilization of step (iii) is carried out for 1-48 hours. In another embodiment of the invention, the lyophilization of step (iii) is carried out for 1-2 hours. In another embodiment of the invention, the lyophilization of step (iii) is carried out for 2-5 hours. In another embodiment of the invention, the lyophilization of step (iii) is carried out for 5-10 hours. In another embodiment of the invention, the lyophilization of step (iii) is carried out for 10-24 hours. In another embodiment of the invention, the lyophilization of step (iii) is carried out for 24-48 hours. Each embodiment represents a different embodiment of the present invention.

[0073] After lyophilization, a dried collagen composition according to this invention is obtained. The dried composition is incubated with a cross-linking agent, a first solvent and optionally a pharmaceutically active agent. The incubated composition is further washed with a second solvent and lyophilized to obtain a block collagen composition.

[0074] In another embodiment of the invention, the first and second solvents are the same or different and are selected from any solvent known in the art. In another embodiment, the solvent is selected from the group consisting of: water, ethanol, aqueous sodium chloride, methanol, phosphate buffered aqueous sodium chloride, or any combination thereof.

[0075] In another embodiment of the invention, the crosslinking agent can be any crosslinking agent known in the art. In another embodiment of the invention, the crosslinking agent is a sugar. In another embodiment of the invention, the sugar is a compound represented by at least one of the following formulas I or II:

Where:

R ¹ represents H, or alkyl, or alkenyl, amino acid fragment, peptide fragment, saccharide fragment, purine or pyrimidine fragment, phosphorylated purine or pyrimidine fragment;

n is an integer between 2 and 9, and

p and q are each independently an integer between 0 and 8, and the sum of p and q is at least 2 and at most 8.

[0076] In another embodiment, the term “alkyl” group refers to a saturated aliphatic hydrocarbon, including a linear or branched hydrocarbon. In one embodiment of the invention, the alkyl group is straight or branched. In another embodiment of the invention, the alkyl is optionally linear or branched. In one embodiment of the invention, the alkyl group contains from 1 to 20 carbon atoms. In one embodiment of the invention, the alkyl group contains from 1 to 10 carbon atoms. In one embodiment of the invention, the alkyl group contains from 2 to 10 carbon atoms. In one embodiment of the invention, the alkyl group contains from 1 to 6 carbon atoms. In one embodiment of the invention, the alkyl group contains from 2 to 8 carbon atoms. In another embodiment of the invention, non-limiting examples of alkyl groups include: methyl, ethyl, propyl, isopropyl, isobutyl, butyl, pentyl, 3-pentyl, hexylheptyl, octyl and hexadecyl. In another embodiment of the invention, the alkyl group is optionally substituted with one or more halogens, hydroxides, alkoxides, carboxylic acids, phosphates, phosphonates, sulfates, sulfonates, amidates, cyanates and nitro groups. Each embodiment represents a different embodiment of the present invention.

[0077] In another embodiment, the term “alkenyl” group refers to alkyl groups as described herein having at least one carbon-carbon double bond, including straight and branched chain groups. In one embodiment of the invention, the alkene has one double bond. In another embodiment of the invention, the alkene has more than one double bond. In another embodiment of the invention, the alkene has from 2 to 6 double bonds, each possibility representing a different embodiment of the invention. In one embodiment of the invention, the alkene has 2-20 carbon atoms. Non-limiting examples include ethlenyl, propylenyl, 2-methylpropyl-1-enyl and butenyl, each representing a different embodiment of the present invention.

[0078] In another embodiment of the invention, the term “amino acid” refers to an organic compound containing amine (-NH ₂ ) and carboxyl (-COOH) functional groups along with a side chain specific to each amino acid. In another embodiment of the invention, any amino acid known in the art can be used. In another embodiment, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, tryptophan, tyrosine or valine.

[0079] In another embodiment of the invention, the term “peptide” refers to short chains of amino acids covalently linked through amide (peptide; -C(O)-N(H)-) bonds. In another embodiment of the invention, the peptide contains from 2 to 20 amino acids. In another embodiment of the invention, the peptide is a dipeptide. In another embodiment of the invention, the peptide is a tripeptide. In another embodiment of the invention, the peptide is a tetrapeptide. In another embodiment of the invention, the peptide is a pentapeptide. In another embodiment of the invention, the peptide is a hexapetide.

[0080] In another embodiment, the term “saccharide” refers to the group including sugars, cellulose and starch as described herein.

[0081] In another embodiment, the term “purine” refers to a heterocyclic aromatic organic compound that consists of a pyrimidine ring conjugated to an imidazole ring. Non-limiting examples of purines include: purine, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine.

[0082] In another embodiment of the invention, the term “pyrimidine” refers to a heterocyclic aromatic organic compound similar to pyridine, but which has an additional nitrogen within the aromatic ring, such that the nitrogen atoms are in positions 1, 3 of the ring. Non-limiting examples of purines include: cytosine, thymine and uracil.

[0083] In another embodiment, the term "phosphorylated purine or pyrimidine" refers to a purine or pyrimidine as described herein, wherein the purine or pyrimidine is linked to a phosphoryl group (the chemical compound PO ₃ ^x− ; "x" denotes any possible state protonation).

[0084] In another embodiment of the invention, the sugar is a naturally occurring reducing sugar.

[0085] In another embodiment, the sugar is diose, triose, tetrose, pentose, hexose, septose, octose, nanose or decose. Each embodiment represents a different embodiment of the present invention.

[0086] In another embodiment, the sugar is selected from the group consisting of glycerose (glyceraldehyde), threose, erythrose, lyxose, xylose, arabinose, ribose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and any of these combinations. Each embodiment represents a different embodiment of the present invention.

[0087] In another embodiment of the invention, the sugar is a disaccharide. Each embodiment represents a different embodiment of the present invention.

[0088] In another embodiment of the invention, the disaccharide is selected from the group consisting of maltose, lactose, sucrose, cellobiose, gentiobiose, melibiose, turanose, trehalose, and any combination thereof. Each embodiment represents a different embodiment of the present invention.

[0089] After the steps of crosslinking and washing with the first and second solutions, the composition is lyophilized. In another embodiment of the invention, lyophilization of step (vi) is carried out for a period of time ranging from 24 to 72 hours and a block composition is obtained. In one embodiment of the invention, a collagen block composition is produced using a pre-shaped mold, thereby obtaining a collagen block composition of a specific shape. In another embodiment of the invention, a mold is not used, but a collagen block composition is prepared, which is then cut into the desired block shape.

[0090] In some other embodiments of the invention, the designed mold and die cut are planned, developed and/or designed by a computer-aided design (CAD) and/or computer-aided process control (CAD) system using methods and software known in the art of this invention. Each embodiment represents a different embodiment of the present invention.

[0091] In another embodiment of the invention, die cutting by the method of the invention is performed by any method known in the art. In another embodiment of the invention, die cutting by the method of the invention is performed using a CNC (Computer Numerical Control) machine, laser cutting machine, water jet cutting machine, drilling or abrasive machine. Each embodiment represents a different embodiment of the present invention.

[0092] In some embodiments, the molded block of the invention is offered in a variety of forms. In some embodiments, the blocks are shaped to allow the block to be easily fitted to a dental abutment and to provide at least partial coverage of the dental implant after the abutment is placed into the implant. In another embodiment of the invention, the block is shaped like an O-ring, sleeve-shaped or tube-shaped (Fig. 2a). Each embodiment represents a different embodiment of the present invention.

[0093] The following examples are presented to illustrate in more detail preferred embodiments of the present invention. However, they should not be construed as limiting the broad scope of the present invention.

Examples

Example 1

Collagen cross-linking

[0094] A solution of molecular purified pepsinized porcine collagen type I (1-10 milligrams/milliliter) prepared from porcine tendons (commercially available from Pel-Freez, AR, USA) was dissolved in 0.01 M HCl and kept at 4°C . It was neutralized with 0.1 M NaOH to pH 7.2-7.4, poured into a suitable mold and incubated for 24 hours at a temperature ranging from 20-38°C. The resulting matrix was then pressed with a piston to remove excess solution. The resulting collagen membranes were incubated for 11 days in PBS (phosphate-buffered saline).

[0095] Fibrillated collagen was concentrated by centrifugation at 3000 rpm. All centrifugation operations (unless specifically stated otherwise) were performed using a model RC5C centrifuge with a SORVALL SS-34 rotor, commercially available from SORVALL® Instruments DUPONT, USA. The concentration of fibrillated collagen after centrifugation was adjusted to approximately 35 mg/ml using 10 millimolar phosphate buffer solution (PBS pH 7.36). The mixture was poured into a stainless steel tray. The tray was transferred to a lyophilizer (freeze dryer model FD 8, commercially available from Heto Lab Equipment DK-3450 Allerød, Denmark), pre-frozen for eight hours, and lyophilized for 24 hours. The condenser temperature was -80°C. The shelf temperature during pre-freezing was -40°C. The rack temperature during the lyophilization process was + 35°C and the vacuum during the lyophilization process was approximately 0.01 bar.

[0096] 200 ml of a solution containing 120 ml of absolute ethanol (commercially available from Merck, Germany), 80 ml of PBS buffer solution (10 mM, pH 7.36) and 3 grams of D(-) ribose (commercially available under catalog number R7500 from Sigma, USA) was added to dried (lyophilized) fibrillated collagen and incubated at 37°C for 11 days to perform ribose cross-linking of the collagen structure. The ribose cross-linked collagen products were washed thoroughly with deionized water and lyophilized under the same conditions as described above.

Example 2

Collagen-hydroxyapatite cross-linking

[0097] A solution containing purified collagen consisting of atelocollagen monomers [pepsinized type I collagen (~3 mg/ml)] dissolved in 0.05 M acetic acid and maintained at 4°C was mixed with a suspension of 0.1 M NaOH , containing hydroxyapatite (collagen/HA ratio: 95:5 - 70:30) and adjusted to neutral pH. The solution was then incubated with constant stirring for 24 hours at a temperature in the range of 20-37°C. The fibrillated collagen/HA mixture was concentrated by centrifugation at 3000 rpm for 15 minutes. The concentration of fibrillated collagen after centrifugation was adjusted to approximately 35 mg/ml using 10 millimolar phosphate buffer solution (PBS, pH 7.36). The mixture was homogenized for 10 min at 100 rpm using a planetary centrifugal mixer (“THINKY MIXER” ARE-500; THINKY CORPORATION, Japan) and poured into a stainless steel tray. The tray was transferred to a lyophilizer (freeze dryer model FD 8, commercially available from Heto Lab Equipment DK-3450 Allerød, Denmark), pre-frozen for eight hours and lyophilized for 24 hours. The condenser temperature was -80°C. The shelf temperature during pre-freezing was -40°C. The rack temperature during the lyophilization process was + 35°C and the vacuum during the lyophilization process was approximately 0.01 bar.

[0098] A 200 ml solution containing 120 ml absolute ethanol (commercially available from Merck, Germany), 80 ml PBS buffer solution (10 mM, pH 7.36) and 3 grams DL-glyceraldehyde (commercially available from Biosynth, Switzerland) added to dried (lyophilized) fibrillated collagen and incubated at 37°C for 11 days to perform ribose cross-linking of the collagen structure. The ribose cross-linked collagen products were washed thoroughly with deionized water and lyophilized under the same conditions as described above.

Example 3

Die cutting collagen blocks

[0099] Blocks of dried collagen matrix were used to die-cut the desired shapes. These shapes were O-ring, sleeve-shaped or tube-shaped (Fig. 2b). These structures are easily installed on the abutment and partially or completely cover the implant after the abutment is installed on the implant.

[00100] The soft but conformable nature of the material provides a tight seal to the surface of the abutment and implant, as well as to the surrounding soft and bone tissue.

This proximity, combined with the conductive properties of bone and soft tissue, will allow rapid and efficient insertion of the abutment.

[00101] Although certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents can now be made by those of ordinary skill in the art. Thus, it is to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true scope of the present invention.

Claims (80)

1. A dental implant comprising an implant, an abutment and a molded block containing a dried cross-linked collagen matrix, wherein said molded block is positioned between the abutment and the implant such that it is at least partially in direct contact with the implant and the abutment, wherein the molded block is shaped such that, after implantation, the abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the abutment. 2. A dental implant for use in stimulating bone or soft tissue growth, wherein said dental implant comprises an implant, an abutment and a molded block containing a dried cross-linked collagen matrix; said molded block is positioned between the abutment and the implant such that it is at least partially in direct contact with the implant and the abutment; the molded block of the dental implant is shaped such that, after implantation, the abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the dental implant; and once implanted, the dental implant provides space and environment for cell growth. 3. A dental implant according to claim 1, characterized in that said molded block additionally contains hydroxyapatite. 4. A dental implant according to claim 1, characterized in that said molded block additionally contains titanium. 5. Dental implant according to any one of paragraphs. 1 and 3-4, characterized in that said molded block has an O-shape, a sleeve shape or a tube shape. 6. Dental implant according to any one of paragraphs. 1 and 3-5, characterized in that the molded block additionally contains a pharmaceutically active agent. 7. The dental implant of claim 6, wherein said agent includes antibacterial agents, antifungal agents, anti-inflammatory agents, antibiotic agents, vitamins, or any combination thereof. 8. A dental implant comprising an implant, an abutment and a molded block containing a dried cross-linked collagen matrix, wherein said molded block is positioned around the abutment and implant such that it is at least partially in direct contact with the implant and the abutment, wherein the molded block is shaped such that, after implantation, the abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the abutment. 9. A dental implant for use in stimulating bone or soft tissue growth, wherein said dental implant comprises an implant, an abutment and a molded block containing a dried cross-linked collagen matrix; said molded block is positioned around the abutment and the implant such that it is at least partially in direct contact with the implant and the abutment; the molded block is shaped such that after implantation the abutment is in partial and/or complete contact with the bone and/or soft tissue surrounding the dental implant; and once implanted, the dental implant provides space and environment for cell growth. 10. The dental implant according to claim 8, characterized in that said molded block additionally contains hydroxyapatite. 11. The dental implant according to claim 8, characterized in that said molded block additionally contains titanium. 12. Dental implant according to any one of paragraphs. 8 and 10-11, characterized in that said molded block is O-shaped, sleeve-shaped or tube-shaped. 13. Dental implant according to any one of paragraphs. 8 and 10-12, characterized in that the molded block additionally contains a pharmaceutically active agent. 14. The dental implant of claim 13, wherein said agent includes antibacterial agents, antifungal agents, anti-inflammatory agents, antibiotic agents, vitamins, or any combination thereof. 15. A method for manufacturing a molded block of a dental implant according to any one of claims. 1 and 3-7, characterized in that the specified method includes: a. obtaining a dried cross-linked collagen matrix; And b. cutting a molded block from said dried matrix. 16. The method according to claim 15, characterized in that the dried cross-linked collagen matrix is obtained by a method including: (i) obtaining an acidic collagen solution followed by neutralization of the solution; (ii) concentrating the solution of step (i); (iii) lyophilizing the concentrated mixture of step (ii), thereby obtaining a dried collagen composition; (iv) incubating the composition with the crosslinking agent and the first solvent; (v) washing the incubated composition of step (iv) with a second solvent; And (vi) lyophilizing the washed composition of step (v); thereby obtaining a dried cross-linked collagen matrix. 17. A method for manufacturing a molded block of a dental implant according to any one of claims. 1 and 4-7, characterized in that the specified method includes: (i) obtaining an acidic collagen solution followed by neutralization of the solution; (ii) concentrating the solution of step (i); and pouring it into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition; (iv) incubating said composition with a cross-linking agent and a first solvent; (v) washing the incubated composition of step (iv) with a second solvent; And (vi) lyophilizing the washed composition of step (v); thereby obtaining a molded block of a dental implant according to any one of claims. 1 and 4-7. 18. A method for manufacturing a molded block of a dental implant according to claim 3, characterized in that said method includes: (i) preparing an acidic collagen solution followed by neutralizing the solution using a solution containing hydroxyapatite; (ii) concentrating the solution of step (i); and pouring it into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, which further contains hydroxyapatite; (iv) incubating said composition with a cross-linking agent and a first solvent; (v) washing the incubated composition of step (iv) with a second solvent; And (vi) lyophilizing the washed composition of step (v); thereby obtaining a molded dental implant block according to claim 3. 19. The method according to claim 17 or 18, wherein the incubation in step (iv) is the incubation of said composition with a cross-linking agent, a first solvent and a pharmaceutically active agent. 20. A method for manufacturing a molded block of a dental implant according to any one of claims. 1 and 4-7, characterized in that the specified method includes: (i) obtaining an acidic solution of collagen and a cross-linking agent, followed by neutralizing the solution; (ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition; (iv) incubating the composition obtained in step (iii), c, with a first solvent; (v) washing the incubated composition of step (iv) with a second solvent; And (vi) lyophilizing the washed composition of step (v); thereby obtaining a molded block of a dental implant according to any one of claims. 1 and 4-7. 21. A method for manufacturing a molded block of a dental implant according to claim 3, characterized in that said method includes: (i) obtaining an acidic solution of collagen and a cross-linking agent, followed by neutralizing the solution using a solution containing hydroxyapatite; (ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, which further contains hydroxyapatite; (iv) incubating the composition obtained in step (iii) with the first solvent; (v) washing the incubated composition of step (iv) with a second solvent; And (vi) lyophilizing the washed composition of step (v); thereby obtaining a molded dental implant block according to claim 3. 22. The method of claim 20 or 21, wherein the incubation in step (iv) is the incubation of said composition with a first solvent and a pharmaceutically active agent. 23. A method for manufacturing a molded block of a dental implant according to any one of claims. 1 and 4-7, characterized in that the specified method includes: (i) obtaining an acidic collagen solution followed by neutralization of the solution; (ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition; (iv) incubating the composition with the crosslinking agent and the first solvent; (v) adding a pharmaceutically active agent to the incubated composition from step (iv); (vi) washing the solution obtained in step (v) with a second solvent; And (vii) lyophilizing the washed composition from step (vi); thereby obtaining a molded block of a dental implant according to any one of claims. 1 and 4-7. 24. A method for manufacturing a molded block of a dental implant according to claim 3, characterized in that said method includes: (i) obtaining an acidic collagen solution followed by neutralizing the solution using a solution containing hydroxyapatite; (ii) concentrating the solution of step (i); and pouring into a mold with a pre-designed block shape; (iii) lyophilizing the concentrated mixture obtained in step (ii), thereby obtaining a dried collagen composition, which further contains hydroxyapatite; (iv) incubating the composition with the crosslinking agent and the first solvent; (v) adding a pharmaceutically active agent to the incubated composition from step (iv); (vi) washing the solution obtained in step (v) with a second solvent; And (vii) lyophilizing the washed composition from step (v); thus obtaining a molded block of the dental implant of claim 3. 25. Method according to any one of paragraphs. 15-24, characterized in that said resulting molded block has an O-shape, a sleeve shape or a tube shape. 26. Method according to any one of paragraphs. 15-16, characterized in that said die cutting is performed during a manufacturing process using a CNC machine, a laser cutting machine, a water jet cutting machine, a drilling machine, an abrasive device, or using casting molds or a 3D printer. 27. Method according to any one of paragraphs. 17-24, characterized in that said shape is shaped using a method including 3D printing, casting, or any combination thereof.