CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This, application expressly claims, all Paris Convention and. related priority from U.S. Provisional Application for U.S. Patent Ser. No, 62/431,481, filed December 8, 2016, which is incorporated by references as if set forth, iri its. entirety.

FIELD OF THE INVENTION

[0002] The present invention generally relates, to a bone graft plug with integrated collagen shell and. methods thereof. Although the invention will be illustrated, explained and exemplified, by dental bone graft, plug, it should be appreciated that the present invention can also be applied to other fields.

BACKGROUND OF THE INVENTION

[0003] When . a tooth is extracted by a dentist, an opening, or socket, is left in the. bone. If this socket is left to heal without any preservation techniques or attempts to regenerate the bone, the bone will tend to shrink and the alveolar may become thinner. As a result, bone defects are likely to arise potentially causing one or more health concerns for the patient. When the dentist has removed the tooth so that an implant can be placed,, then the lack of preservation can provide difficulties in placing the. implant with the potential of negatively the. potential advantages of the implant and. associated restoration. As a result, many dentists attempt to preserve the socket, through a. variety of bone grafting methods that are available. In many cases, the bone of the alveolar surrounding an extraction socket has holes, or defects that expose the interior of the socket to soft ti ssue or expose the socket directly to the oral cavity.

[0004] In order to preserve the socket, dentists place bone graft in the cavity to. regenerate bone and prevent bone loss. The bone graft can come in a number of forms. For example, granular bone graft may be mixed with the patient's blood. A separate membrane is used for holding the bone graft, granules in place during healing.. After the graft is placed into the. socket, the dentist, must sew the membrane to the surrounding tissue at the top of the socket to cover the bone graft material and prevent it from escaping the socket at the crestal area of the bone. The membrane may be absorbable into the bone. A separate absorbable membrane can also be used to cover areas of defects in the bone so that the bone graft granules do not escape the socket, For bone graft putty, the bone graft material (putty) is. provided in paste form so that the dentist, can pick.it up out of its container and directly place it in the socket. However, the membrane is still needed to cover the graft, and sewing the membrane to the tissue may be necessary.

[0005] Current bone graft plug is a. mixture of bone graft granules or other bone graft materials within a collagen framework, other framework or no framework. This, approach has the advantage of not necessarily requiring sewing a membrane to surrounding tissue, which can. reduce chair time compared to the granular bone graft, and the bone graft, putty as described above. This approach also reduces the surgical invasiveness by eliminating the procedure of sewing to the tissue. However* there will by necessity be times when a membrane is required and sewing the membrane to the tissue is required. In this approach, the membrane, can also be used to cover areas of bone defect so that the bone graft granules do not escape the socket while the membrane itself will be absorbed into the bone.

[0006] Therefore, there exists a need to overcome the aforementioned problems. Advantageously, the present invention provides an improved means of preserving the socket, particularly when defects, exist in the. bone.

SUMMARY OF THE INVENTION

[0007] One aspect of the present invention provides a bone graft plug for regenerating bone inside a dental socket and having a. shape configured for inserting into the dental socket. The plug includes a bone graft collagen core, and a collagen shell optionally including a bone grafting material. The shell is integrated with the bone, graft collagen core, and the collagen shell covers at least a part of the core's surface. An example of "integrated" is that the collagen shell is chemically crosslinked to a collagen component in the bone graft collagen core.

[0008] Another aspect of the invention provides a process of preparing the above bone graft plug, comprising, providing a bone graft collagen core,, and integrating a collagen shell with the core, wherein the collagen shell covers at least a part of the core's surface.

[0009] The above features and advantages and other features and advantages of the present invention are readily apparent from the following detailed description of the best modes for carrying out the invention when taken in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[001.0] The present invention, is illustrated, by way of example, and not. by way of limitation, in. the figures of the accompanying drawings and in which like reference numerals, refer to similar elements. All the figures are schematic and generally only show parts which are necessary in order to elucidate the invention. For simplicity and clarity of illustration, elements shown in the figures and discussed below have not necessarily been drawn to scale. Well-known structures and devices are shown in simplified form, omitted, or merely suggested, in order to avoid unnecessarily obscuring the present invention.

[0011] Figure 1 schematically shows a bone graft plug designed for inserting into a dental socket in accordance with an exemplary embodiment of the present invention.

[0012] Figure 2 depicts a bone graft plug with a substantially cylindrical shape in accordance with an exemplary embodiment of the present invention.

[0013] Figure 3 illustrates a bone graft plug with different configurations of top shell and. side. shell in accordance with an exemplary embodiment of the present invention.

[0014] Figure 4 demonstrates a bone grafting material being injected into a bone graft collagen core in accordance with an exemplary embodiment of the present invention.

[0015] Figure. 5 depicts a bone graft injection device in accordance with an exemplary embodiment of the present invention.

[0016] Figure 6 schematically shows different microstructures of collagen material used for the plug in accordance with an exemplary embodiment of the present invention.

[0017] Figure 7 demonstrates different methods of preparing the bone graft plug in accordance with an exemplary embodiment of the present, invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[001.8] In the following, description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It is apparent, however, to one skilled in the art that the present invention may be practiced without these specific details or with an equivalent, arrangement.

[001.9] Where a numerical range is disclosed herein, unless, otherwise specified, such range is continuous,, inclusive of both the minimum and maximum values of the range as well as every value between such minimum and maximum values. Still further, where a range refers to integers,, only the integers from the minimum value to and including the maximum value of such range are included. In addition,, where multiple ranges are provided to describe a feature or characteristic, such ranges can be. combined.

[0020] Generally speaking, the present invention provides methods and designs, for improvement of bone healing and soft tissue healing in general surgery, where an opening is created in bone and soft tissue covers the bone as part of the healing process. Referring to Figure 1, when a tooth is removed, a socket 102 is created within the alveolar. The invention may be employed for the improvement of bone and soft, tissue healing after a dentist extracts, a tooth and surgically repairs the bone and the soft tissue contiguous with the tooth extraction region around socket 102. Said socket 102 will typically be exposed to soft tissue at the point where the tooth was interfaced with the crestal ridge. In some cases, defects 102d occur where other regions of the interior of the socket 102 are exposed to soft tissue through defects 102d in the alveolar.

[0021] A bone graft plug 101 is designed for regenerating bone inside dental socket 102. Bone graft plug 101 may have any shape and size suitable for inserting into the dental socket 102. Bone graft plug 101 includes a bone graft collagen core 103, and a collagen shell 104 integrated with the core 103. The collagen shell 104 comprises a bone grafting material, or comprises no bone grafting material at all. Typically, core 103 includes a bone graft component and a collagen component. The term "blank bone graft collagen core" means core 103 has not been loaded or infused or mixed with a bone grafting material yet. When collagen shell 104 is integrated with the core 103, it is typically integrated with the. collagen component in core 103. The invention improves the borie and soft tissue healing process by integrating, a collagen, shell 104 such as a collagen wall 104W into a bone graft core 103 comprising commonly available bone regenerating materials and compositions. The bone regenerating materials and compositions will remain within the socket 102 during the healing process, both improving the healing process, and reducing the. time taken by the dentist, in the bone grafting and soft tissue, suturing process.

[0022] One embodiment of the present, invention can. make the socket preservation easier for a dentist by creating a single plug product 101 from mass-production that includes both the bone graft material in core 103 and the membrane/shell 104 in a single form.. The dentist can remove the plug product 101 from its packaging and place the plug product 101 into the socket 102 in such a way that that a pre-Iocated membrane/shell 104W is appropriately located to cover the bone defect 102d, or at other locations as appropriate. In another embodiment, the top of the core 103 will also be covered, by an integrated membrane/shell 104T so as to reduce the need, or perhaps eliminate the need, to sew the membrane to the tissue in most cases where it is applicable.

[0023] In some embodiments, the collagen shell/membrane 104 of different size, is integrated with the. surface, of the bone graft, collagen core 103 in a variety of locations, so that the dentist can choose the form of the plug product 101 that is optimum given the location of the thin bone or alveolar crest. The collagen shell 104 may cover at least a part of the core 103 's surface, such as 10%-90% percent of the core's total external surface. The density of the collagen shell 104 is at least 5% (e.g. 10%, 20%, 35%, 50%, 100%, or 200%) higher than the density of the bone graft collagen core 103. In other embodiments, the tensile strength of the collagen shell 104 is at least 5% (e.g. 10%, 20%, 35%, 50%, 100%, or 200%) higher than the tensile strength of the bone graft collagen core 103.

[0024] The entire bone: graft plug 101 may have any shape and size suitable for inserting into the dental socket 102, For example, it may have a. substantially cylindrical shape as shown in. Figure 2, with a. total height.H in the range of from 5 mm to 30 mm such as 8 mm to 15 mm, and a diameter D in the range of from 2 mm to 10 mm. The bone grafting core includes a flat top surface configured for placing near the socket's mouth 102m, and a core body 103 extending from the flat top surface. The core body 103 is configured for inserting into the dental socket 102. Collagen shell 104 may include a top shell 104T, a side shell or wall shell 104W, or any combination thereof. The top shell 104T covers at least a part of the (preferably the entire) flat top surface, and the side shell 104W covers at least a part of side surface of the core, body 103. The top shell 1.04T may have a thickness TT in the range of from.0.5 mm to 3 mm. The side shell 104W may have a thickness TW in the range of from 0.5 mm to 3 mm, or 5-20% of diameter D. The side shell 104W may have a height Hw in the range of from 1 mm to 25 mm. Hw may be equal to (H - TT), or less than (H - TT) such as 20% - 50% of (H - TT). The side shell 104W may surround or wrap the core .103 with a span angle Θ in the range of 30° to 360°.

[0025] In a preferred, embodiment, the collagen shell 104 covers the entire flat top surface and a portion of the core body 103's side surface, such as 1-50%, 5-50%, and 10-50% of the body's side surface. In other embodiments, the collagen shell 104 does not cover any part of the flat top surface, but covers at least a part of the body 103 's side surface or wall surface.

[0026] Referring now to Figure 3, panel (a) shows a plug 101, wherein top. shell 104T covers 100% of core 103's flat top surface, but there is no side shell 104W to cover any part of the body 103's side surface or wall surface. Panel (b) shows, a plug 101,,. wherein top shell. 1.04T covers. 100% of core 103's flat top surface, and there is a side shell 104W to cover a part of the body 103's side surface or wall surface. Panel (c) shows a plug 101, wherein side shell 104W covers a part of the body 103 's side surface or wall surface, but there is no top shell 104T, Panel (d) shows a plug 101, wherein side shell 104W covers the body 103's entire side surface or wall surface, but there is no top shell 104T. [0027] Any suitable bone graft materials may be employed, in the. present invention. For example, the bone graft collagen core may comprise a bone graft material selected from xenograft, autograft, allograft, and artificial graft, such as calcium phosphate,, hydroxyapatite, ground collagen, ground bones, blood, or any combination thereof, in a semi-liquefied form, a putty form, or a granular form. Optionally, ground collagen matrix can be mixed outside the. patient with patient, blood to create the regenerative growth material in a semi-liquefied form. The bone graft collagen core 103 may be made of any known bone graft materials or a mix of different materials, either in a putty form, a granular form, or other form, with or without a collagen matrix structure supporting the bone graft material, The bone graft collagen core 103 can consist of any mix of collagen and bone graft materials. In some embodiments, the core may include two components in any suitable weight ratio such as 1 :1. The first component may be calcium-phosphate based ceramic, such as Medtronic Mastergraft with 85% ceramic; or B-TCP (Hydroxyapatite and bioactive glass) such as Medtronic Mastergraft with 15% ceramic. The second component may be ground up collagen. Collagen shell/sheet 104 may be located on core's surface in. any suitable locations, in any suitable form, at any suitable, thickness (e.g. 2 mm thick).

[0028] A bone grafting material may be pre-loaded, or infused into a blank bone graft collagen core 103 in a manufacture facility, or in mass production, A dentist can apply the mass produced bone graft plugs, with, identical mechanical structure and chemical/biochemical composition to two or more patients with different symptoms. Alternatively, the bone grafting material may be injected into a blank bone graft collagen core 103 by a dentist on site. For example, when there is no bone wall existing in the. socket 102, an embodiment involves injecting the bone graft material through the collagen shell 104 after the collagen shell 104 has been placed in the patient's socket 102. As shown in Figure 4, the collagen shell 104 may completely cover the entire, surface of the core. 103. Or, at least, the collagen shell 104 should cover the entire surface of the core 103 except, its bottom surface. A bone grafting material may be injected into the bone graft collagen core 103 by a dentist using a needle 201. As shown in Figure 5, the collagen shell 104 may completely cover the. entire surface of the core 103. Or, at least, the collagen shell 104 should cover the entire surface of the core 103 except its bottom surface. A bone grafting material 401 may be injected into the bone graft collagen core 103 by a dentist using a bone graft injection device 300. Injection device 300 includes a curved pipe 301 , and multiple needles 201 extend from pipe 301 pointing toward a plug 101. Under pressure, a bone grafting material 401 is pumped into pipe 301, and injected into plug 101 through multiple needles.201.

[0029] The collagen material used for the plug 101 (particularly the core 103) is preferably a porous material with voids for receiving bone grafting material 401, as shown in Figure 6. The void may occupy 20-80% of the volume of plug 101 or core 103, and is filled with air before bone grafting material 401 is. pumped or injected or infused, into the voids. The. voids may take any known mierostructures such, as bubbles, layers, random,, or irregular shapes, as shown in Figure 6.

[0030] In an embodiment, a composition of hydrpxyapatite and calcium phosphate is mixed with crushed collagen to create the bone graft collagen core 103 that has. an integrated shell/wall of collagen sheet 104 covering all. or part of the bone graft collagen core 103, thus creating a bone graft plug 101 with an integrated collagen wall 104. The collagen wall 104 may be exposed to soft tissue external to the socket 102 that is created when a tooth is removed. The integrated collagen wall 104, when located between the bone graft collagen core 103 and any surgically repaired soft tissue external to the socket 102, may reduce the effects of the bone graft collagen core 103 liquefying and escaping from the. socket. 102, which would be a detriment to the healing process. The bone graft collagen core 103 may be made from a composition of hydroxyapatite and calcium, phosphate, or other commonly available, bone grafting materials which, in. combination have a proven capability to regenerate bone.

[0031] After placing the plug 101 in the socket 102, the dentist would not need, to suture the soft tissue over the defect 102d. It would not be necessary that a collagen sheet is cut to near the shape of the. socket area that remains open on. the top of the alveolar, and the dentist would not need to place sutures holding the soft tissue together Over the crestal top. During the healing. process, the collagen shell 104 keeps the semi -liquefied (or as paste arid putty) bone graft mix in the core: 103 from leaking out as it solidifies during healing. The invention eliminates the need in the prior art for the dentist to apply collagen sheets separately to cover bone defects and the alveolar at the top of the socket .

[0032] In an embodiment, side shell 104W in Figure 1 is flattened, so that the bone, graft, plug 101 does not extrude through a defect 102d in the side of the crestal bone. As a result, the defect 102d is repaired in a shape closer to its original shape prior to the creation of the defect 102d.

[0033] The invention provides a process of manufacturing the bone plug component mix, including e.g. calcium carbonate and hydroxyapatite in manners which can improve the. bone healing process. One example is to create a collagen scaffold with the shape of the bone graft and insert the mix of calcium carbonate and hydroxyapatite into the pores, as previously shown in Figure 5. In another embodiment as shown in panel (a) of Figure 7, one can take a lengthy collagen sheet, and wrap it around itself until it forms the shape of the bone graft plug 101 or core 103 and then insert the mix of calcium carbonate and hydroxyapatite, leaving a collagen wall 104 surrounding the entire, bone graft collagen core 103 and thereby covering any and all exposures of soft tissue resulting when a tooth is extracted. In still another embodiment as shown in panel (b) of Figure 7, a sheet Or multiple sheets 501 of collagen are formed, in the shape of the bone graft plug 101 or core 103. One can crush the collagen sheet and mix it with the calcium carbonate and hydroxyapatite to form the bone graft plug 101 or core 103. In still another embodiment as shown in panel (c) of Figure 7, one can create tubes 601 of collagen sheet and mix the calcium carbonate and hydroxyapatite. within the center of the tubes 601, then accumulate the collagen tubes in the shape of the bone graft plug 101 or core 103. Multiple tubes 601 are assembled in the shape of the bone graft plug 101 or core 103.

[0034] In some embodiments, a process of manufacturing the plug 101 include (1). making molds of stainless, steel that are a negative of the bone graft plug 101, for example* the bottom of the mold is the rounded part; (2) placing a collagen wall in its. location on the side of the molds; for example, collagen sheet may be wetted so it temporarily sticks to the cylindrical wall of the mold; (3) poring the bone graft composition in the mold; and (4) putting a collagen sheet on the flat surface of the bone graft composition in the mold; and (5) thermally heating or chemically solidifying the bone graft composition within the mold, A cover may be put over the mold,

[0035] In some embodiments, one can spray ground-up collagen to the exterior of the core 103 so that it. sticks to the exterior surface, and forms shell 104.

[0036] As described above, the density and the tensile strength of the collagen shell 104 are higher than those of the bone graft collagen core 103. In a process, the step of integrating a collagen shell with the core includes chemically erosslinking the collagen shell with the collagen component, in the core* wherein the collagen shell and the collagen in the core are formed using different reaction conditions. Collagen is typically isolated, from natural, sources, such as bovine hide, cartilage, or bones. Bones are usually dried, defatted, crushed, and demineralized to extract collagen, while hide and cartilage ore usually minced and digested with proteolytic enzymes (other than collagenase). Collagen in its native form is typically a rigid, rod-shaped molecule approximately 300 nra long and 1,5 nm in diameter. It is composed of three collagen polypeptides which form, a tight triple helix. The collagen polypeptides are characterized by a long midsection having the repeating sequence -Gly-X-Y- where X and Y are often proline or hydroxyproline, bounded at each end by the "telopeptide" regions, which constitute less than about 5% of the molecule. The telopeptide regions of the collagen chains are typically responsible for the cross-linking between chains, and for the immunogenieity of the protein.

[0037] In an embodiment, a collagen in solution (CIS) may be precipitated to produce collagen fibers which resemble native collagen fibers. The. precipitated, reconstituted fibers may additionally be cross-linked using a chemical agent (for example aldehydes such as formaldehyde and glutaraldehyde), or using heat or radiation. Collagen shell 104 and collagen within core 103 may be crosslinked to each other for the purpose of "integration", but. collagen shell 104 and collagen within core 103 themselves may be internally crosslinked at different, conditions, to achieve, different density and tensile strength as desired. Suitable erosslinking agents include difunctional polymers prepared by reacting a dicarboxylic anhydride (e.g., glutarie or succinic anhydride) with a diol such as polyethylene or polypropylene glycol having a molecular weight of about 400 to 10,000 daltons, preferably from about 500: to 5,000 daltons, to form a polymer derivative (e.g., succinate), which may then be activated by esterification with a convenient leaving group, e.g., N-hydroxysuccinirnide, N,N'-disuccinimidyl oxalate, N,N'-disuccininiidyl carbonate and the like. Preferred dicarboxylic anhydrides used to form the crosslinking compositions include glutarie anhydride,, adipic anhydride, succinic anhydride, 1,8 -naphthalene: dicarboxylic anhydride and the like:. Other suitable crosslinking agents include the more conventional materials such as aldehydes. Suitable aldehydes are formaldehyde, glutaraldehyde, acid aldehyde, glyoxalj glyoxal pyruvic, aldehyde, and aldehyde starch.

[0038] For example, a process may include forming a mixture of a. calcium phosphate mineral powder and a reconstituted fibrillar atelopeptide collagen,, shaping the mixture, drying, the mixture under dry flowing air at 35-45° C to a moisture content of less than 1%, rehydrating the dried structure until a moisture content of 1-6% is achieved, and subjecting the rehydrated structure to sterilizing radiation. Collagen, shell 104. and collagen within core 103 may be controlled to have different, moisture content,

[0039] In the foregoing specification, embodiments of the present invention have been described with reference to numerous specific details that may vary from implementation to implementation. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. The sole and exclusive indicator of the scope of the invention,, and what is intended by the applicant to be the scope of the. invention, is the literal and equivalent, scope of the set of claims that issue from this application, in the. specific form in which such claims issue, including any subsequent correction.