Compositions and methods for adhesion to surfaces

Abstract

The present disclosure is characterized by adhesive compositions and methods of using them in relation to the medical, veterinary and dental fields.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: May 27, 2016; application number: 2016800443933).

[0002] Related applications

[0003] This application claims priority to U.S. Patent Application No. 62 / 168,630, filed May 29, 2015, which is incorporated herein by reference in its entirety. Technical Field

[0004] Embodiments of this disclosure relate to adhesive compositions and methods of using them. Background Technology

[0005] This application generally relates to adhesive compositions and methods of attaching to structures (e.g., bones, grafts, and devices), as well as methods of forming barriers or seals. More specifically, it is applicable to medical, veterinary, and dental procedures aimed at attaching skeletal parts to each other or attempting to attach artificial devices to the skeleton or calcified tissue of any animal (including humans) or attempting to prevent leakage or connection of fluids through the skeleton.

[0006] Current methods utilize various hardware metal fixation devices (such as screws, needles, anchors, plates, and rods) securely inserted into drilled or reamed cavities to secure bony portions (including fracture fragments). These devices may also be artificial devices or prosthetic elements attached to the bone. In the dental market, such devices can be dental implants anchored to the bone by their attached supports and crowns or prosthetic prostheses. As the primary means of fixation, all these devices utilize their mechanical shape features and friction rather than adhesive forces. Alternatively, bone bonding agents, typically non-resorbable organic materials structurally associated with acrylics, are used to seal prostheses by engaging surface features or another device (usually metal) to attach them to the bone. Resorbable devices (such as screws, needles, anchors, and plates) are also used to mechanically attach articles (such as tendon grafts and bone fragments) to the host bone structure.

[0007] The methods described above rely on the existing volume and density of bone to serve as a medium for accommodating and retaining attachment elements. Because bone volume and density can be limited by anatomical factors, trauma, and / or disease-related processes, fixation methods are often limited and subject to compromise due to a lack of suitable bone material in terms of volume and strength for fixation. In the long term, fixation and retardation further depend on a balance of natural regulatory processes of bone formation and growth (e.g., modeling, remodeling, osseointegration, and resorption) to attach bone tissue to the surfaces of various devices that provide this function. Resorbable devices are gradually replaced by bone, allowing tendon grafts to heal together with the host bone to become a mechanosynthetic unit. Summary of the Invention

[0008] On one hand, this disclosure features a composition having adhesive properties, conforming to a surface, capable of being clay-sealed, and becoming a solid that can be adhesively applied to the surface of a bone or device. In some embodiments, the shape of the coated composition can be shaped and sized by any other kind of flow, molding, shaping, or plastic deformation before becoming substantially rigid and solid.

[0009] In some embodiments, the composition may have a reabsorption feature that allows the body to replace the material with natural bone over time through biological processes, while substantially maintaining the original volume of the material during application. In some embodiments, this feature is referred to as space or volume retention.

[0010] In some embodiments, the formulation of the adhesive composition may be varied. It may vary in the ratio of the basic reactants, or it may be altered by adding materials intended to modify the characteristics of the material. Including these modifiers may modify (but is not limited to) the rheological properties, setting kinetics, soft tissue interactions, hard tissue interactions, interactions with abiotic materials, interactions with the microbiome, adhesion properties, reabsorption kinetics, porosity ratio, optical properties, and mechanical properties of the composition. In some embodiments, including these modifiers may modify the size and number of internal pores.

[0011] In some embodiments, the composition may be coated in layers or volume segments to construct a desired structure, fill voids, or adhere a structure to a surface. These layers or volume segments may vary based on the components of the composition and the ratio of said components.

[0012] In some embodiments, the composition may be applied to layers or volume segments to construct a desired structure, fill voids, or adhere a structure to a surface. These layers or volume segments may vary based on the components of the composition and the ratio of said components. These layers or volume segments may be applied simultaneously or at various delays (e.g., between about 5 to 10 seconds, between about 10 to 20 seconds, between about 20 to 60 seconds, between about 1 minute to 3 minutes, between about 3 minutes to 10 minutes, between about 10 minutes to 30 minutes, between about 0.5 hours to 2 hours, between about 2 hours to 24 hours, between about 1 day to 7 days, between about 1 week to 1 month, between about 1 month to 1 year or more).

[0013] In some embodiments, the interaction between the adhesive composition and the tissue may produce a solid comprising bone and the composition coated onto the bone, the volume of which is larger than the volume of the bone alone prior to the coating composition. The solid comprising bone and the composition adhered to the bone may also be larger in any dimension.

[0014] In some embodiments, the interaction between the adhesive composition and the tissue may produce a solid comprising bone and a composition adhered to the bone. Such a solid comprising bone and composition may be drilled, ground, reamed, scraped, or otherwise shaped.

[0015] In some embodiments, the interaction between the adhesive composition and the tissue may produce a solid comprising bone and a composition adhered to the bone. This solid, comprising bone and composition, may be drilled, ground, reamed, scraped, or otherwise shaped to accept the attachment of the structure. Such attachment may be regulated by (but not limited to) adhesion, gluing, clay sealing, shape interlocking, or friction. Shape alteration may involve two components: bone tissue or hardened material, or a solid comprising both said bone tissue and said hardened material. The structure may also be attached only to the bone, only to the composition, or to both. Before the material becomes rigid, the placement of the structure may be spatially guided to its desired location and orientation by mechanical components, thus allowing the structure to be precisely placed and attached according to its desired relationship with its surroundings by solidifying the material.

[0016] On one hand, this disclosure is characterized by an adhesive composition comprising a polyvalent metal compound and a compound of formula (I) or a salt thereof:

[0017]

[0018] (I)

[0019] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0020] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1bEach of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5 In some embodiments, R 2 For NR 4a R 4b In some embodiments, R 2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0021] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (I) includes an organophosphate compound (e.g., a small amount of an organophosphate compound). In some embodiments, the compound of formula (I) is phosphoserine.

[0022] On the other hand, this disclosure features a method for increasing bone volume, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to an extraction socket; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to the extraction socket; and c) allowing the composition to remain undisturbed until the composition hardens, cures, or is reabsorbed and replaced by bone.

[0023] On the other hand, this disclosure features a method for filling bone voids resulting from the removal of bone cysts, granulomas, abscesses, or similar bone defects, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to the bone void; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to the bone void; and c) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is reabsorbed and replaced by bone. In some embodiments, the bone void is caused by the loss of natural bone or the removal of bone fragments.

[0024] On the other hand, this disclosure features a method for increasing bone volume, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to a substantially flat or convex surface of bone to build volume; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to a substantially flat or convex surface of bone to build volume; and c) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is reabsorbed and replaced by bone. In some embodiments, hardening, solidification, and / or reabsorption occur with substantially no loss of increased bone volume. The bony surface that serves as the attachment site of the composition may be treated by removing the periosteum, by surface scoring, by peeling, or may be altered by mechanical or chemical means, by laser, or by another method. In some embodiments, another method includes perforation.

[0025] On the other hand, this disclosure features a method for adhesively bonding two or more bones, bone fragments, or bone segments using load-bearing capacity, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to the bony surface of the adjacent bones, bone fragments, or bone segments to be bonded in an amount sufficient to make the adhesive composition integrally continuous; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to the bony surface of the adjacent bones, bone fragments, or bone segments to be bonded in an amount sufficient to make the adhesive composition integrally continuous; and c) allowing the composition to remain undisturbed until the composition hardens, cures, or is reabsorbed and replaced by bone. In some embodiments, the composition may be kept undisturbed with or without compressive force (e.g., splints, tweezers, fingers) or with or without the use of a fixation implant (e.g., membrane, mesh, suture, K-line, screw, nail).

[0026] In some embodiments, the gaps between bones or bone fragments may be caused by congenital defects (e.g., cleft palate), trauma (e.g., jawbone or other fractures), disease (e.g., osteosarcoma), bone removal (e.g., due to removal of vesicles or sequestra), surgical treatment (e.g., orthognathic procedures or correction of long bone deformities), or the loss of small segments that have lost their mechanical integrity. In some embodiments, the gaps between bones or bone fragments may be caused by osteochondral fractures or by the knots of corrective or reconstructive procedures.

[0027] In some embodiments, this disclosure features a method of applying an adhesive composition to bone that allows the composition to remain undisturbed until it hardens, solidifies, or is reabsorbed, with or without compressive forces (e.g., splints, tweezers, fingers) or with or without fixation implants (e.g., membranes, meshes, sutures, k-threads, screws, nails). In some embodiments, the adhesive composition remains firmly attached to the bone and does not migrate from its application site.

[0028] On the other hand, this disclosure features a method for repairing defects in bone, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to or onto the bone defect; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the composition to or onto the bone defect in an adhesive manner; and c) allowing the composition to remain undisturbed until the composition hardens, cures, or is reabsorbed and replaced by bone. In some embodiments, the bone defect is located at the root of a tooth.

[0029] On the other hand, this disclosure features a method for repairing defects in teeth, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to or onto the tooth defect; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the composition to or onto the tooth defect in an adhesive manner; c) allowing the composition to remain undisturbed until the composition hardens or cures; and d) completing the restoration to obtain the desired shape, contour, and surface features.

[0030] On the other hand, this disclosure features a method for adhesively repairing defects in teeth, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., in an aqueous solution or suspension); and b) applying the composition to or on the tooth defect in close proximity to or in contact with the dental pulp tissue; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method of this disclosure comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the composition adhesively to or on the tooth defect in close proximity to or in contact with the dental pulp tissue; and c) allowing the composition to remain undisturbed until the composition hardens or cures.

[0031] On the other hand, this disclosure features a method for attaching a dental device to a tooth, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) applying the composition to the tooth or a prepared surface of a device to be attached to the tooth; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method comprises: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the composition adhesively to the tooth or a prepared surface of a device to be adhesively attached to the tooth; c) orienting the device in a desired specific relationship with the tooth; and d) allowing the composition to remain undisturbed until the composition hardens or cures. The dental device may be a post, crown restoration, fixed partial prosthesis, or similar device.

[0032] On the other hand, the present invention is characterized by an adhesive method for attaching a device (e.g., a prosthetic support, implanted crown restoration, fixed partial denture, or prosthesis) to a retention device (e.g., an intraosseous implant, implanted tooth, or amputation stump implant) in an adhesive manner, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) coating the composition onto the preparation surface of the retention device or the device to which the retention device is to be attached; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the method includes: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively coating the composition onto or onto a surface of the retaining device or a device to be adhesively attached to the retaining device; c) orienting the device to a desired specific relationship with the retaining device; and d) allowing the composition to remain undisturbed until the composition hardens or cures. The device may be a post, crown restoration, fixed partial prosthesis, prosthetic element, or similar device.

[0033] On the other hand, the present invention is characterized by an adhesive method for sealing the gap between a device (e.g., a prosthesis, implanted crown restoration, fixed partial denture, prosthesis) and a retaining device (e.g., an intraosseous implant, implanted tooth, amputation stump implant) in an adhesive manner, the method comprising: a) (e.g., in an aqueous solution or suspension) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I); and b) coating the composition onto the retaining device or a surface of a device to be adhesively attached to the retaining device; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the method includes: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively coating the composition onto or onto a surface of the retaining device or a device to be adhesively attached to the retaining device; c) orienting the device to a desired specific relationship with the retaining device; and d) allowing the composition to remain undisturbed until the composition hardens or cures. The device may be a post, crown restoration, fixed partial prosthesis, prosthetic element, or similar device.

[0034] In any embodiment, the method may further include placing a structure (e.g., an implant, graft, or device) in the composition before hardening or curing the composition or before the composition is resorbed or replaced by bone, for example, as described in step c). In any embodiment, the method may further include placing a structure (e.g., an implant, graft, or device) in the composition after applying the composition (e.g., for about 5 seconds, about 10 seconds, about 30 seconds, about 60 seconds, about 2 minutes, about 5 minutes, about 10 minutes, or longer) as described in step b), but before hardening or curing the composition or before the composition is resorbed or replaced by bone (e.g., as described in step c).

[0035] In some embodiments, this disclosure is characterized by a method of implanting a bone implant or device, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) applying the composition to an extraction socket in bone and / or to the surface of the implant or device; and c) implanting the implant or device into the composition; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less).

[0036] In some embodiments, this disclosure is characterized by a method of installing a bone implant or device, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) placing the implant or device in an extraction socket in the bone; and c) applying the composition to the installation site (e.g., to secure the implant or device to the bone); wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, this disclosure features a method for closing a wound, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) injecting the composition into, on top of, or near the wound site; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the method prevents microorganisms (e.g., bacteria, fungi, viruses, or combinations thereof) from moving into the wound.

[0037] In some embodiments, this disclosure is characterized by a method for sealing a site or fistula to prevent the inflow or communication of fluids (e.g., cerebrospinal fluid or blood) or materials, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) injecting the composition into, on top of, or near the site; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the fluid or material comprises microorganisms (e.g., bacteria, fungi, viruses, or combinations thereof).

[0038] In some embodiments, this disclosure features a method for controlling excessive bleeding from wounds involving bone injuries or fractures, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) applying or injecting the composition into, onto, or near the site of the bone injury; and c) proximal bone grafts to reduce the gaps between the grafts, thereby blocking blood flow from the injury site to the bone; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, such application of the adhesive composition may be performed in emergency environments (e.g., battlefields, injury sites, ambulances, rescue helicopters) or at the trauma center. In some embodiments, such application may be performed as part of a routine surgical procedure. In some embodiments, such application of the composition may be performed as a temporary bandage. In some embodiments, such application of the composition may be performed as a definitive treatment.

[0039] In some embodiments, this disclosure features a method for controlling excessive bleeding from wounds involving bone injuries or fractures, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) applying or injecting the composition into, on top of, or near the site of the bone injury; and c) applying a solid material to the composition applied to the bone to prevent blood from flowing from the injured surface of the bone; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, such a solid material may comprise a reabsorbable material (e.g., collagen or polyglycolic acid) or a non-reabsorbable material (e.g., titanium). In some embodiments, such a solid material may be in the form of a plate, a plug, or a flexible, bendable material (e.g., woven or nonwoven fabric or mesh). In some embodiments, this application of the composition may be performed in emergency environments (e.g., battlefields, injury sites) or at the trauma center. In some embodiments, such application may be performed as part of a routine surgical procedure. In some embodiments, such application of the composition may be performed as a temporary bandage. In some embodiments, such application of the composition may be performed as a definitive treatment.

[0040] In some embodiments, this disclosure features a method for controlling excessive bleeding from wounds involving bone injuries or fractures, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) coating the composition onto a solid material; and c) coating the solid material with the coated composition applied to the injured bone to prevent blood from flowing from the injured surface of the bone; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, such a solid material may comprise a reabsorbable material (e.g., collagen or polyglycolic acid) or a non-reabsorbable material (e.g., titanium). In some embodiments, such a solid material may be in the form of a plate, a plug, or a flexible, bendable material (e.g., woven or nonwoven fabric or mesh). In some embodiments, this application of the composition may be performed in emergency environments (e.g., battlefields, injury sites) or at the trauma center. In some embodiments, such application may be performed as part of a routine surgical procedure. In some embodiments, such application of the composition may be performed as a temporary bandage. In some embodiments, such application of the composition may be performed as a definitive treatment.

[0041] In some embodiments, this disclosure features a method for controlling excessive bleeding from a wound involving an artery injury near or around the vertebral foramen, which marks the exposure of the artery from within the bone mass, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) injecting the composition into the artery generally through the vertebral foramen from which it is exposed from the bone or onto its top, or into its outlet or near the site of the bone injury; and c) applying pressure to impede blood flow; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, such application of the composition may be performed in emergency environments (e.g., battlefields, injury sites) or at the center of trauma. In some embodiments, such application may be performed as part of a routine surgical procedure. In some embodiments, such application of the composition may be performed as a temporary bandage. In some embodiments, such application of the composition may be performed as a definitive treatment.

[0042] In some embodiments, this disclosure features a method for controlling excessive bleeding from a wound involving an artery injury caused by a transverse cut, fracture, or other septation of the bone as the artery passes through its passage in the bone, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) injecting the composition into the passage through which the artery normally passes but from which bleeding now flows, or onto the top of the passage opening; and c) impeding blood flow by applying pressure (e.g., directly or by using the composition applied under hydrostatic pressure via a tip such as a cannula or a specialized syringe); wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, such application of the composition may be performed in emergency environments (e.g., battlefields, injury sites) or at the trauma center. In some embodiments, such application may be performed as part of a routine surgical procedure. In some embodiments, this application of the composition may be performed as a temporary bandage. In some embodiments, this application of the composition may be performed as a definitive treatment.

[0043] In some embodiments, this disclosure is characterized by a method for restoring a skeletal deformity to its original palate, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to, on top of, or near the skeletal deformity or bone defect; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less).

[0044] In some embodiments, this disclosure is characterized by a method for restoring the load-bearing capacity of segmented bone as part of an orthognathic procedure (e.g., fixing the condyle to the mandibular body after a sagittal split osteotomy, oblique osteotomy, LaForte osteotomy, or genioplasty procedure), the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) applying the composition to, on top of, or near the surface of the bone; and c) placing the bone fragments in an advantageous specific relationship; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). The application of the composition may occur once or more. Reapplication of the composition may occur during steps b) and c) or during the hardening and / or curing of the composition as described above.

[0045] In some embodiments, this disclosure is characterized by a method of superimposed reshaping, molding, or contouring of the outer surface of bone (e.g., in a facial region, forehead, mandible, or any joint bone surface), the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to the desired area of ​​the bone; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, most of the composition may be modified in size or shape prior to its hardening. In some embodiments, most of the composition may be modified in size or shape after its hardening. In some embodiments, the procedure may be performed in conjunction with other reducing bone contouring processes.

[0046] In some embodiments, this disclosure is characterized by a method of superimposed reshaping, molding, or contouring the outer surface of bone in a facial region of an individual undergoing cosmetic treatment, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) adhesively applying the composition to the desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less). In some embodiments, the facial region includes the nose, chin, cheek, midface, or forehead.

[0047] In some embodiments, this disclosure is characterized by a method of treating an individual suffering from a disease or condition, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the disease or condition includes cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, osteonecrosis, or other genetic or developmental disorders. In some embodiments, the disease or condition includes fibrous dysplasia or nerve compression. In some embodiments, the individual has another cause of bone deterioration, fracture, bone abrasion, bone erosion, bone wear, or internal bone fragmentation or bone loss. In some embodiments, the skeleton includes teeth. In some embodiments, the individual has suffered from or has been diagnosed with another cause of tooth decay, tooth fracture, tooth wear, tooth erosion, tooth abrasion, internal tooth fragmentation, or loss of tooth material. In some embodiments, the loss of calcified tissue is caused by cutting the tissue during surgery or dental procedures.

[0048] In some embodiments, this disclosure is characterized by a method for repairing bone or other calcified tissue defects in an individual suffering from a disease or condition, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the disease or condition includes cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, osteonecrosis, or other genetic or developmental disorders. In some embodiments, the individual suffers from or is diagnosed with another cause of tooth decay, tooth fracture, tooth wear, tooth erosion, tooth abrasion, internal tooth fragmentation, or loss of tooth material. In some embodiments, the loss of calcified tissue is caused by cutting the tissue during surgery or dental procedures.

[0049] In some embodiments, this disclosure features a method for strengthening bones in an individual suffering from a disease or condition, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less). In some embodiments, the disease or condition includes cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infections, osteonecrosis, or other genetic or developmental disorders. In some embodiments, the disease or condition includes fibrous dysplasia or nerve compression. In some embodiments, the individual suffers from or is diagnosed with tooth decay, tooth fracture, internal tooth cracking, tooth abrasion, or tooth erosion.

[0050] In some embodiments, this disclosure is characterized by a method for repairing bone defects caused by trauma in an individual, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less).

[0051] In some embodiments, this disclosure is characterized by a method for preparing a graft of bone tissue or a complex of bone and a hardening composition, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) applying the composition to a desired area; c) shaping the composition into a desired shape and size, wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less); and d) collecting the graft by removing the composition of the form consisting of bone or a complex of bone and a hardening composition.

[0052] In some embodiments, this disclosure features a method for preparing a graft of bone tissue or a complex of bone and a hardening composition, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; b) shaping the composition into a desired shape and size; c) applying the form to a desired bone region, wherein the composition hardens and / or solidifies in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less); and d) collecting the graft by removing the form comprising bone or a complex of bone and a hardening composition. In some embodiments, the form applied adhesively may be shaped to conform to a plan based on observations and measurements of radiographic images or data.

[0053] In some embodiments, this disclosure features a method for preparing a graft of bone tissue or a complex of bone and a sclerotic composition, the method comprising: a) preparing a binder composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension, wherein the composition is sclerotic and / or cured in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less); b) forming the composition into a desired shape and size; c) exposing the formed composition to a tissue culture medium capable of reconstructing the formation into bone tissue; and d) collecting the graft form consisting of bone or a complex of bone and a sclerotic composition. In some embodiments, the form may be shaped to conform to a plan based on observation and measurement of radiographic images or data.

[0054] In some embodiments, this disclosure is characterized by a method for adhesively repairing defects and fractures and adhesively joining bony fragments in non-human vertebrates, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less).

[0055] In some embodiments, this disclosure is characterized by an adhesive method for repairing defects and fractures and for adhesively joining fragments in invertebrate structures (e.g., corals), the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to a desired area; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes or less).

[0056] In some embodiments, this disclosure is characterized by a method for repairing gaps or spaces between joint bone surfaces (e.g., intervertebral joints), or a method for bridging gaps or spaces between bone surfaces (e.g., between vertebral bodies, between transverse processes, or between spinous processes) to prevent relative displacement of bone surfaces (e.g., spinal fusion procedures) and to provide a load-bearing support with or without a supporting implant (e.g., screws, plates, intervertebral cages). These coatings can be applied individually or used to provide multi-point fixation when applied to several or other locations. In some embodiments, the method includes: a) preparing an adhesive composition comprising a polyvalent metal salt and a compound of formula (I) (e.g., a small amount of an organophosphate compound) in an aqueous solution or suspension; and b) applying the composition to the desired area with or without a supporting implant; wherein the composition hardens and / or cures in less than about 30 minutes (e.g., less than about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, or less).

[0057] In some embodiments, the polyvalent metal salt includes calcium. In some embodiments, the polyvalent metal salt includes calcium and / or phosphate. In some embodiments, the polyvalent metal salt includes hydroxyapatite. In some embodiments, the polyvalent metal salt includes tricalcium phosphate. In some embodiments, tricalcium phosphate includes α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, the polyvalent metal salt includes oxides. In some embodiments, the polyvalent metal salt includes calcium oxide. In some embodiments, the polyvalent metal salt includes tricalcium phosphate and calcium oxide. In some embodiments, the polyvalent metal salt does not include tetracalcium phosphate.

[0058] In some embodiments, the polyvalent metal salt is a polyvalent calcium compound. In some embodiments, the polyvalent calcium compound includes tetracalcium phosphate. In some embodiments, the composition includes a plurality of polyvalent calcium compounds. In some embodiments, the plurality includes tetracalcium phosphate and at least one other polyvalent calcium compound. In some embodiments, the polyvalent calcium compound does not include tetracalcium phosphate.

[0059] The amount of a polyvalent metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) in the composition may vary from, for example, from about 10% to about 90% by weight (w / w) of the total composition. In some embodiments, the amount of the polyvalent metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) ranges from about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 30% to about 75%, about 40% to about 70%, or about 50% to about 65% w / w of the total composition. In other embodiments, the amount of the metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) ranges from about 5% to about 95%, about 10% to about 85%, about 15% to about 75%, about 20% to about 65%, about 25% to about 55%, or about 35% to about 50% w / w of the total composition.

[0060] In any and all aspects and embodiments herein, a small amount of organophosphate may be a compound of formula (Ia) or a salt thereof:

[0061]

[0062] Formula (Ia)

[0063] Where L represents O, S, or NH; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 Independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0064] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1b Each of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5In some embodiments, R 2 For NR 4a R 4b In some embodiments, R 2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0065] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (Ia) is phosphoserine.

[0066] On the other hand, this disclosure is characterized by an adhesive composition comprising a mixture of at least two polyvalent metal salts and a compound of formula (I) or a salt thereof in an aqueous solution or suspension:

[0067]

[0068] (I)

[0069] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R4b C(O)R 5 or C(O)OR 5 ;R 3 Independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0070] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1b Each of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5 In some embodiments, R 2 For NR 4a R 4b In some embodiments, R 2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0071] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (I) is phosphoserine.

[0072] In some embodiments, the polyvalent metal salt comprises calcium. In some embodiments, at least one of the polyvalent metal salts comprises calcium and a phosphate. In some embodiments, at least one of the polyvalent metal salts comprises hydroxyapatite. In some embodiments, at least one of the polyvalent metal salts comprises tricalcium phosphate. In some embodiments, tricalcium phosphate comprises α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, at least one of the polyvalent metal salts comprises an oxide. In some embodiments, at least one of the polyvalent metal salts is calcium oxide. In some embodiments, the composition comprises tricalcium phosphate and calcium oxide. In some embodiments, the composition does not contain tetracalcium phosphate.

[0073] In some embodiments, each of at least two polyvalent metal salts is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises hydroxyapatite, and the hydroxyapatite is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises tricalcium phosphate, and the tricalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises calcium oxide, and the calcium oxide is present at about 1% to about 30% by weight (w / w) of the total composition (e.g., about 1% to about 30%, about 1% to about 10%, about 1% to about 5%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 20%, about 10% to about 15%).

[0074] In some embodiments, the aqueous solution or suspension includes water, saliva, saline, serum, plasma, or blood.

[0075] In some embodiments, the polyvalent metal salt is initially provided in granular or powder form. In some embodiments, the composition further includes additives.

[0076] On the other hand, this disclosure features a method for attaching a structure to bone, the method comprising preparing and using an adhesive composition comprising at least two polyvalent metal salts and a compound of formula (I) or a salt thereof in an aqueous solution or suspension, thereby attaching the structure to bone:

[0077]

[0078] (I)

[0079] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0080] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1b Each of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5 In some embodiments, R 2 For NR 4a R 4b In some embodiments, R2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0081] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (I) is phosphoserine.

[0082] In some embodiments, the polyvalent metal salt includes calcium. In some embodiments, at least one of the polyvalent metal salts includes calcium and phosphate. In some embodiments, at least one of the polyvalent metal salts includes tricalcium phosphate. In some embodiments, tricalcium phosphate includes α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, at least one of the polyvalent metal salts includes an oxide. In some embodiments, at least one of the polyvalent metal salts includes calcium oxide. In some embodiments, the composition includes tricalcium phosphate and calcium oxide. In some embodiments, the composition does not contain tetracalcium phosphate.

[0083] In some embodiments, each of at least two polyvalent metal salts is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises tricalcium phosphate, and the tricalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition includes calcium oxide, and the calcium oxide is present at about 1% to about 30% by weight (w / w) of the total composition (e.g., about 1% to about 30%, about 1% to about 10%, about 1% to about 5%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 20%, about 10% to about 15%).

[0084] In some embodiments, the aqueous solution or suspension includes water, saliva, saline, serum, plasma, or blood.

[0085] In some embodiments, the polyvalent metal salt is initially provided in granular or powder form. In some embodiments, the composition further includes additives.

[0086] In another aspect, this disclosure is characterized by a method for filling voids or gaps in bone, the method comprising preparing and using in an aqueous solution or suspension a binder composition comprising at least two polyvalent metal salts and a compound of formula (I) or a salt thereof, thereby filling voids or gaps in bone:

[0087]

[0088] (I)

[0089] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4aEach of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0090] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1b Each of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5 In some embodiments, R 2 For NR 4a R 4b In some embodiments, R 2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0091] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4bEach of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (I) is phosphoserine.

[0092] In some embodiments, the polyvalent metal salt includes calcium. In some embodiments, at least one of the polyvalent metal salts includes calcium and phosphate. In some embodiments, at least one of the polyvalent metal salts includes tricalcium phosphate. In some embodiments, tricalcium phosphate includes α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, at least one of the polyvalent metal salts includes an oxide. In some embodiments, at least one of the polyvalent metal salts is calcium oxide. In some embodiments, the composition includes tricalcium phosphate and calcium oxide. In some embodiments, the composition does not contain tetracalcium phosphate.

[0093] In some embodiments, each of at least two polyvalent metal salts is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises tricalcium phosphate, and the tricalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises hydroxyapatite, and the tricalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the total composition (e.g., about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, about 35% to about 60%). In some embodiments, the composition comprises calcium oxide, and the calcium oxide is present at about 1% to about 30% by weight (w / w) of the total composition (e.g., about 1% to about 30%, about 1% to about 10%, about 1% to about 5%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 15%).

[0094] In some embodiments, the aqueous solution or suspension includes water, saliva, saline, serum, plasma, or blood.

[0095] In some embodiments, the polyvalent metal salt is initially provided in granular or powder form. In some embodiments, the composition further includes additives.

[0096] On the other hand, this disclosure features a kit for attaching structures to bone, the kit comprising a container (e.g., a first container) containing a composition comprising at least one polyvalent metal salt (e.g., at least two polyvalent metal salts) and a compound of formula (I) or a salt thereof:

[0097]

[0098] (I)

[0099] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 The alkyl or aryl groups are optionally substituted; and each of x and y is independently 0, 1, 2, or 3. In some embodiments, the kit further includes a second container containing an aqueous medium.

[0100] On the other hand, this disclosure features a kit for filling voids or gaps in bone, the kit comprising a container (e.g., a first container) containing a composition comprising at least one polyvalent metal salt (e.g., at least two polyvalent metal salts) and a compound of formula (I) or a salt thereof:

[0101]

[0102] (I)

[0103] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 The alkyl or aryl groups are optionally substituted; and each of x and y is independently 0, 1, 2, or 3. In some embodiments, the kit further includes a second container containing an aqueous medium.

[0104] On the other hand, this disclosure features a kit for increasing bone volume, the kit comprising a container (e.g., a first container) containing a composition comprising at least one polyvalent metal salt (e.g., at least two polyvalent metal salts) and a compound of formula (I) or a salt thereof:

[0105]

[0106] (I)

[0107] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 The alkyl or aryl groups are optionally substituted; and each of x and y is independently 0, 1, 2, or 3. In some embodiments, the kit further includes a second container containing an aqueous medium.

[0108] In some embodiments of the above aspects, the polyvalent salt includes calcium. In some embodiments, the polyvalent metal salt includes calcium and phosphate. In some embodiments, the polyvalent salt includes tetracalcium phosphate. In some embodiments, the polyvalent salt does not include tetracalcium phosphate. In some embodiments, the polyvalent salt includes tricalcium phosphate. In some embodiments, tricalcium phosphate includes α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, the polyvalent metal salt includes oxides. In some embodiments, the polyvalent metal salt includes calcium oxide. In some embodiments, the polyvalent salt includes hydroxyapatite.

[0109] In some embodiments, the compound of formula (I) is phosphoserine.

[0110] In some embodiments, the aqueous medium includes water or saline solution (e.g., phosphate-buffered saline). In some embodiments, the aqueous medium includes water, saliva, saline solution, serum, plasma, or blood. In some embodiments, the aqueous solution or suspension includes saliva, serum, or blood. In some embodiments, the aqueous medium is not provided as part of the kit. In some embodiments, the aqueous medium is present at the application site of the composition.

[0111] In some embodiments, the first container further includes an additive.

[0112] In some embodiments, the kit comprises a single container (e.g., a first container, such as comprising at least one polyvalent metal salt and a compound of formula (I) or a salt thereof). In some embodiments, the kit comprises a first container (e.g., comprising at least one polyvalent metal salt and a compound of formula (I) or a salt thereof) and a second container (e.g., comprising an aqueous medium).

[0113] In some embodiments, after the contents of the first container are mixed with the contents of the second container, the resulting composition exhibits an adhesive strength greater than about 1 MPa (e.g., greater than about 1.5 MPa, about 2.0 MPa, about 2.5 MPa, or about 3 MPa) upon hardening or curing. In some embodiments, the hardening or curing occurs within at least about 30 minutes after the contents of the first container are mixed with the contents of the second container (e.g., within at least about 25 minutes, about 20 minutes, about 15 minutes, about 12 minutes, about 10 minutes, about 8 minutes, or about 5 minutes). Attached Figure Description

[0114] Figure 1 This diagram illustrates a demonstrative extraction site in the mandible, highlighting the alveolar ridge and the split lateral bone. It shows the alveolar ridge in its clinical presentation state or after preparation (e.g., grinding, drilling, reaming) of the site, ready to receive the adhesive composition.

[0115] Figure 2 A diagram of an implanted tooth placed in the alveolar bone with insufficient bone contact to provide initial stability.

[0116] Figure 3 This diagram illustrates an alveolar fossa filled with an exemplary adhesive composition that surrounds the implanted tooth, thereby providing initial stability of the implant after the composition hardens. In this depiction, the exemplary adhesive composition further acts as a seal to prevent fibrous tissue from growing inwards from the overlying gingiva and also to prevent microorganisms from invading the bone tissue from the forming oral cavity.

[0117] Figure 4This diagram illustrates a mandibular alveolar ridge lacking sufficient height to maintain the implanted tooth. It shows the alveolar ridge in its clinical presentation state or before preparation (e.g., by grinding, drilling, or reaming) to receive the adhesive composition.

[0118] Figure 5 The image shows an external graft in which an exemplary adhesive composition has been applied to provide vertical ridge amplification and add sufficient ridge volume.

[0119] Figure 6 This image shows an implant placed in an exemplary bonding composition and an expanded alveolar ridge. In this example, the implant achieves initial stability after the composition has hardened. During the composition's flexible working period or at some point after hardening, the implant may be placed alone in the composition or in the composition-bone complex, at which point the implant may be ground, drilled, or reamed to accommodate the implant.

[0120] Figure 7 This diagram illustrates a defective mandibular alveolar ridge (e.g., not wide enough) lacking sufficient bone volume for predictable bone maintenance after implant placement. The diagram shows the alveolar ridge in its clinical presentation state or prior to site preparation (e.g., by grinding, drilling, or reaming) to receive the adhesive composition.

[0121] Figure 8 The image shows a lateral external graft in which an exemplary adhesive composition has been applied to provide lateral crest amplification and generate sufficient crest volume.

[0122] Figure 9 This is a diagram of an implant placed in an exemplary adhesive composition and in a laterally expanded alveolar ridge. In this example, the implant achieves initial stability after the composition has hardened. During the flexible working period of the composition or at some point after hardening, the implant is placed either alone in the composition or in the composition-bone complex, at which time the implant may be ground, drilled, or reamed to accommodate the implant.

[0123] Figure 10 A diagram illustrating a mandibular alveolar ridge (e.g., a knife-edge ridge) that severely lacks the volume for dental implant placement due to insufficient width. The diagram shows the alveolar ridge in its clinical presentation state or before preparation (e.g., by grinding, drilling, or reaming) to prepare it for receiving the bonding composition.

[0124] Figure 11 The diagram shows a lateral external graft in which an exemplary adhesive composition has been applied to provide sufficient ridge volume.

[0125] Figure 12This is a diagram of an implant tooth placed in a composite of an exemplary adhesive composition and laterally expanded alveolar ridge bone. In this example, the implant achieves initial stability after the adhesive composition has hardened. During the flexible working period of the composition or at some point after hardening, the implant tooth is placed either alone in the composition or in the composite of the composition and bone, at which time the implant tooth may be ground, drilled, or reamed to accommodate the implant.

[0126] Figure 13 A cross-section of the maxillary alveolar ridge is presented for cases where there is insufficient volume for dental implant placement.

[0127] Figure 14 For from Figure 13 The key feature is the presentation of the maxillary alveolar ridge cross-section after applying a demonstrative adhesive composition during the sinus floor elevation procedure to increase the ridge height and thus obtain sufficient volume for implant placement.

[0128] Figure 15 This is a cross-sectional view of the maxillary alveolar ridge, showing a dental implant placed in a demonstrative bonding composition and alveolar ridge bone complex after a sinus floor lift procedure. In this example, initial implant stability is achieved after the composition hardens. During the composition's flexible working period or at some point after hardening, the implant is placed either alone in the composition or in the composition-bone complex, at which time the implant may be ground, drilled, or reamed to accommodate the implant.

[0129] Figure 16 This illustration depicts posterolateral fixation of adjacent vertebral bodies, wherein an exemplary adhesive composition is applied to bridge the gap between transverse processes to provide primary fixation after the composition has hardened. Bilateral fixation is shown here.

[0130] Figure 17 Representation of intervertebral body fixation for adjacent vertebral bodies, wherein an exemplary adhesive composition is applied to provide fixation of the intervertebral body cage device after the composition has hardened.

[0131] Figure 18 Representation of intervertebral body fixation for adjacent vertebral bodies, wherein an exemplary adhesive composition is applied to bridge the gap to provide primary fixation after the composition has hardened.

[0132] Figure 19 The following is an illustration: preparing an intervertebral joint to form a hole between adjacent vertebral bodies (shown on the left), then applying an intervertebral joint needle device into the hole and stabilizing it with an exemplary adhesive composition to provide primary fixation of the intervertebral joint (shown on the right) after the composition has hardened.

[0133] Figure 20The diagram illustrates the preparation of the intervertebral joint using an exemplary tool (e.g., bone forceps) and the subsequent application of an exemplary adhesive composition to provide primary fixation of the intervertebral joint (shown on the right) after the composition has hardened. The exemplary tool is used to remove articular cartilage and decortical surfaces from the intervertebral joint between adjacent vertebral bodies (shown on the left).

[0134] Figure 21 This is a schematic representation of attaching a prosthetic element to an osteotomy stump using an exemplary adhesive composition. A portion of the structure shown is inserted into the medullary space of a long bone (e.g., the femur) and stabilized as a weight-bearing support. The adhesive composition is applied to fill the space between the device surface and the adjacent surface of the supporting bone, thereby creating primary fixation of the device after the composition hardens. Note that the bone surface is not drawn to show the details of the intramedullary space.

[0135] Figure 22 A cross-sectional view of a prosthesis attached to an osteotomy stump by applying an exemplary adhesive composition to fill the space between the surface of the prosthesis attachment device and the adjacent surface of the bone. The osteotomy stump is inserted into the medullary space of a long bone (e.g., the femur) and stabilized for load-bearing support. The seal provided by the adhesive composition is highlighted in the figure.

[0136] Figure 23 shows two images depicting the response of exemplary adhesive composition A in the alveolar bone 3 weeks post-procedure. Figure 23A 20x magnification; details are presented in Figure 23B In the middle, 100× magnification.

[0137] Figure 24 shows three images depicting the response of the exemplary adhesive composition C in the alveolar bone at 21 weeks post-procedure. Figure 24A 25× magnification; Figure 24B 100× magnification; Figure 24C 400× magnification.

[0138] Figure 25 illustrates a depiction of direct surgery ( Figure 25A From then until 1 week after surgery ( Figure 25B ), 2 weeks ( Figure 25C ), 3 weeks ( Figure 25D ), 5 weeks ( Figure 25E ) and 8 weeks ( Figure 25F A series of images showing the response of the exemplary adhesive composition F.

[0139] Figure 26 A graph showing implant stability (Ostell readings) of mandibular implants provided by exemplary adhesive composition F from 3 to 10 weeks post-operation.

[0140] Figures 27A to 27BImages (50× magnification) of the adhesive implant and its response to the exemplary adhesive composition C in a large osteotomy.

[0141] Figure 28 depicts the surgical procedure ( Figure 28A After 1 week Figure 28B ), 2 weeks (28C), 3 weeks ( Figure 28D ), 4 weeks ( Figure 28E ), 8 weeks ( Figure 28F ) and 10 weeks ( Figure 28G A series of CBCT images showing the response of the exemplary adhesive composition F as an external graft near the canine tooth.

[0142] Figure 29 is a series of images depicting the response of the exemplary adhesive composition F as an external graft near the canine tooth at 9 weeks post-operation. Clinical images are shown in... Figure 29A In the middle, 3D CBCT images are shown. Figure 29B The CBCT image of the parapalatal plane is shown in the middle. Figure 29C middle.

[0143] Figure 30 Image of explanted spinal cord tissue from a rabbit spine mounted on an Instron tensile testing machine. Adjacent rabbit vertebral bodies (L5 / L6) are secured with exemplary adhesive composition G to bridge the gap between transverse processes (bilaterally).

[0144] Figure 31 To show as Figure 30 The graph shown represents the mechanical tensile test results obtained after 10 weeks from adjacent rabbit vertebrae (L5 / L6) fixed with exemplary adhesive composition G to bridge the gap between transverse processes (both sides).

[0145] Figure 32 shows three time-course radiographic images of spinal fusion obtained from adjacent rabbit vertebral bodies (L5 / L6) fixed with exemplary adhesive composition G to bridge the gap between transverse processes (bilaterally). Figure 32A These are postoperative CBCT images, and Figure 32B These are CBCT images taken at 3 weeks, and Figure 32C to this end Figure 32B 3D rendering. Detailed Implementation

[0146] The embodiments of this disclosure are characterized by adhesive compositions comprising metal salts and small amounts of organophosphate compounds, and methods of using them. More specifically, this disclosure applies to adhesive compositions and their use in attaching structures to skeletons, wherein the structures include bones, calcified tissue, grafts, inserts, and devices.

[0147] Components of the adhesive composition

[0148] It has been shown that polyvalent metal salts (e.g., tetracalcium phosphate) react with small amounts of organophosphate compounds in an aqueous environment to form compositions with strong adhesive properties. Without being bound by theory, it is assumed that these polyvalent metal salts and organophosphate compounds form ionic interactions, and that the polyvalent metal salts and organophosphate compounds react in a heated manner at a specific ratio upon merging to provide adhesive materials. Exemplary polyvalent metal salts can be organic or inorganic in nature and include calcium phosphate (e.g., hydroxyapatite, octacalcium phosphate, tetracalcium phosphate, tricalcium phosphate), calcium nitrate, calcium citrate, calcium carbonate, magnesium phosphate, sodium silicate, lithium phosphate, titanium phosphate, strontium phosphate, barium phosphate, zinc phosphate, calcium oxide, magnesium oxide, and combinations thereof.

[0149] The amount of a polyvalent metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) may vary from about 10% to about 90% w / w of the total composition. In some embodiments, the amount of the polyvalent metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) ranges from about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 30% to about 75%, about 40% to about 70%, or about 50% to about 65% w / w of the total composition. In other embodiments, the amount of the metal salt (e.g., calcium phosphate or calcium oxide, or combinations thereof) ranges from about 5% to about 95%, about 10% to about 85%, about 15% to about 75%, about 20% to about 65%, about 25% to about 55%, or about 35% to about 50% w / w of the total composition. In some embodiments, the total combined amount of each polyvalent salt (e.g., calcium phosphate or calcium oxide or combinations thereof) may vary between, for example, about 10% to about 90 wt% of the total composition.

[0150] In some embodiments, the polyvalent metal salt includes calcium. In some embodiments, the polyvalent metal salt includes calcium and phosphate. In some embodiments, the polyvalent metal salt includes tetracalcium phosphate. In some embodiments, the composition includes a plurality of polyvalent metal salt compounds. In some embodiments, the plurality includes tetracalcium phosphate and at least one other polyvalent metal salt compound. In some embodiments, the polyvalent metal salt includes hydroxyapatite. In some embodiments, the polyvalent metal salt includes tricalcium phosphate. In some embodiments, tricalcium phosphate includes α-tricalcium phosphate or β-tricalcium phosphate. In some embodiments, the polyvalent metal salt includes an oxide. In some embodiments, the polyvalent metal salt is calcium oxide. In some embodiments, the polyvalent metal salt compound does not include tetracalcium phosphate. In some embodiments, the composition includes tricalcium phosphate and calcium oxide.

[0151] The present disclosure is characterized by an adhesive composition comprising a multivalent metal salt and a compound of formula (I) or a salt thereof:

[0152]

[0153] (I)

[0154] Where L is O, S, NH or CH2; R 1a and R 1b Each of these is independently H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 2 For H, NR 4a R 4b C(O)R 5 or C(O)OR 5 ;R 3 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 4a and R 4a Each of them is independently H, C(O)R 6 Or optionally substituted alkyl groups; R 5 H, an optionally substituted alkyl group, or an optionally substituted aryl group; R 6 It is an alkyl group or an aryl group that is optionally substituted; and each of x and y is independently 0, 1, 2 or 3.

[0155] In some embodiments, L is O or S. In some embodiments, L is O. In some embodiments, R 1a and R 1b Each of them is independently H. In some embodiments, L is O and R is... 1a and R 1b Each of them is independently H. In some embodiments, R 2 For H, NR 4a R 4b or C(O)R 5 In some embodiments ， R 2 For NR 4a R 4b In some embodiments, R 2 For NR 4a R 4b And R 4a and R 4b Each of these is independently H. In some embodiments, L is O, R is... 1a and R 1b Each of them is H, R 2 For NR 4a R 4b And R 4a and R 4b Each of them is independently H. In some embodiments, R 3 For H. In some embodiments, L is O, R 1a and R 1b Each of them is independently H, R2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, and R 3 H is a variable. In some embodiments, each of x and y is 0 or 1. In some embodiments, each of x and y is 1.

[0156] In some embodiments, L is O, R 1a and R 1b Each of them is H, R 2 For NR 4a R 4b R 4a and R 4b Each of them is independently H, R 3 H is a constant, and each of x and y is 1. In some embodiments, the compound of formula (I) comprises an organophosphate compound (e.g., a small amount of organophosphate). In some embodiments, the compound of formula (I) is phosphoserine.

[0157] As used herein, the term "optionally substituted" is intended to encompass all permissible substituents of an organic compound. More broadly, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds (e.g., alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be further substituted), as well as halogens, carbonyl groups (e.g., aldehydes, ketones, esters, carboxyl groups, or formyl groups), thiocarbonyl groups (e.g., thioesters, thiocarboxylic esters, or thiocarboxylate esters), amino groups, -N(R) groups, and other substituents. b (R) c ), where each R b and R c Independently H or C1-C6 alkyl, cyano, nitro, -SO2N(R) b (R) c -SOR d and S(O)2R d , where each R b R c and R d Independently, it is an H or C1-C6 alkyl group. Illustrative substituents include, for example, those described above herein. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. This disclosure is not intended to be limited in any way by permissible substituents of organic compounds. It should be further understood that “substituted” or “substituted” includes implied limitations: such substitution is based on the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc.

[0158] In some embodiments, the molecular weight of the compound of formula (I) is less than about 1000 g / mol. In some embodiments, the molecular weight of the compound of formula (I) is between 150 g / mol and about 1000 g / mol, for example, between about 155 g / mol and about 750 g / mol, between about 160 g / mol and about 500 g / mol, between about 165 g / mol and about 250 g / mol, between about 170 g / mol and about 200 g / mol, or between about 175 g / mol and about 190 g / mol. In some embodiments, the molecular weight of the compound of formula (I) is between about 180 g / mol and about 190 g / mol.

[0159] Compound (I) may be in any stereoisomer form or a mixture containing stereoisomers. For example, compound (I) may be a mixture of D,L-phosphoserine, or contain substantially pure D-phosphoserine or substantially pure L-phosphoserine. In many embodiments, the stereochemistry of compound (I) does not significantly affect the adhesive properties of the composition. In some embodiments, the specific stereochemistry of compound (I) or the ratio of stereoisomers of compound (I) has a significant effect on the adhesive properties of the composition.

[0160] The amount of compound (I) may vary from about 5% to about 95% w / w of the total composition, for example. In some embodiments, the amount of compound (I) may range from about 5% to about 80%, about 5% to about 50%, about 5% to about 30%, about 10% to about 80%, about 10% to about 50%, about 15% to about 40%, or about 20% to about 35% w / w of the total composition. In some embodiments, compound (I) is a small amount of an organophosphate (e.g., phosphoserine) and is present in the range of about 5% to about 80%, about 5% to about 50%, about 5% to about 30%, about 10% to about 80%, about 10% to about 50%, about 15% to about 40%, or about 20% to about 35% w / w of the total composition.

[0161] In other embodiments, the amount of compound (I) may vary from about 5% to about 95% w / w of the combined polyvalent metal salt and a small amount of organophosphate compound. In some embodiments, the amount of compound (I) is in the range of about 5% to about 80%, about 5% to about 50%, about 5% to about 30%, about 10% to about 80%, about 10% to about 50%, about 15% to about 40%, or about 20% to about 35% w / w of the combined polyvalent metal salt of compound (I). In some embodiments, compound (I) is a small amount of organophosphate (e.g., phosphoserine) and is present in the range of about 5% to about 80%, about 5% to about 50%, about 5% to about 30%, about 10% to about 80%, about 10% to about 50%, about 15% to about 40%, or about 20% to about 35% w / w of the combined polyvalent metal salt of compound (I).

[0162] In some embodiments, the polyvalent metal salt is present in the composition at about 10% to about 90% by weight (w / w) of the incorporated polyvalent metal salt and the compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine). In some embodiments, the polyvalent metal salt is present in the composition at about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, or about 45% to about 60%. In some embodiments, the composition comprises tetracalcium phosphate, and the tetracalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the incorporated polyvalent metal salt and the compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine), for example, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, or about 45% to about 60%. In some embodiments, the composition comprises tricalcium phosphate, and the tricalcium phosphate is present in the composition at about 10% to about 90% by weight (w / w) of the incorporated polyvalent metal salt and the compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine), for example, about 10% to about 90%, about 15% to about 85%, about 20% to about 80%, about 25% to about 75%, about 30% to about 70%, about 30% to about 65%, or about 45% to about 60%. In some embodiments, the composition comprises hydroxyapatite, and the hydroxyapatite is present at about 1% to about 50% by weight (w / w) of the incorporated polyvalent metal salt and the compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine), for example, about 1% to about 30%, about 1% to about 15%, about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 10% to about 20%, about 15% to about 25%. In some embodiments, the composition comprises calcium oxide, and the calcium oxide is present at about 1% to about 30% by weight (w / w) of the incorporated polyvalent metal salt and the compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine), for example, about 1% to about 30%, about 1% to about 10%, about 1% to about 5%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 20%, about 10% to about 15%. Each additive may also include phases and ingredients not specifically listed.

[0163] In some embodiments, the polyvalent metal salt is initially provided in powder or granule form. These powders may exhibit the following average particle sizes: about 0.001 to about 0.250 mm, about 0.005 to about 0.150 mm, about 0.25005 to about 0.75075 mm, 0.25 to about 0.5010 to about 0.050 mm, about 0.015 to about 0.025 mm, about 0.020 to about 0.060 mm, about 0.020 to about 0.040 mm, about 0.040 to about 0.100 mm, about 0.040 to about 0.060 mm, about 0.060 to about 0.150 mm, or about 0.060 to about 0.125 mm. The average particle size may be bimodal to include any combination of average particle sizes as previously described. These particles can exhibit the following particle sizes: about 0.050 mm to about 5 mm, about 0.100 to about 1.500 mm, about 0.125 to 1.000 mm, 0.125 to 0.500 mm, about 0.125 to 0.250 mm, about 0.250 to 0.750 mm, about 0.250 to 0.500 mm, about 0.500 to 1.00 mm, and about 0.500 to 0.750 mm. The average particle size can be multimodal, encompassing any combination of average particle sizes as previously described. The particles can have various proportions of porosity and various sizes of internal pores. In some embodiments, the powder or particles of varying sizes can be used in adhesive compositions.

[0164] In this disclosure, polyvalent metal salts (e.g., calcium phosphate, calcium oxide, or combinations thereof) react with organophosphate compounds to form an adhesive composition when combined with an aqueous medium. In some embodiments, the aqueous medium includes water (e.g., sterile water), saliva, buffers (e.g., sodium phosphate, potassium phosphate, or saline solutions (e.g., phosphate-buffered saline)), bone-enhancing agents, blood-based solutions (e.g., plasma, serum, bone marrow), cerebrospinal fluid, dental pulp, cell-based solutions (e.g., solutions comprising fibroblasts, platelets, odontoblasts, stem cells (e.g., mesenchymal stem cells), tissue cells, macrophages, mast cells, or plasma cells), or combinations thereof in aqueous, suspension, or colloidal form. In some embodiments, the aqueous medium includes sterile water, distilled water, deionized water, seawater, or fresh water.

[0165] In some embodiments, the aqueous medium includes water from the environment, such as freshwater, saltwater, or brackish water from the ocean, sea, bay, river, stream, pond, or other moving or stagnant water sources.

[0166] The amount of aqueous medium mixed with the adhesive composition may vary, for example, from about 5% to about 50% w / w of the total composition. In some embodiments, the amount of aqueous medium is in the range of about 5% to about 50%, about 10% to about 35%, or about 15% to about 25% w / w of the total composition.

[0167] In some embodiments, the temperature of the aqueous medium can be controlled to affect the viscosity and solidification (e.g., working time, solidification time) of the adhesive composition. Typically, the temperature can be selected within the room temperature range (e.g., 15°C to 25°C, 18°C ​​to 22°C); however, the temperature can be selected within a range from refrigeration temperatures that slow down solidification kinetics (e.g., 2°C to 6°C) to body temperatures that accelerate solidification kinetics (e.g., 37°C).

[0168] In some embodiments, the method of applying the composition to a surface occurs in a dry or wet environment. If a wet environment is present, the adhesive composition can be applied without first removing aqueous fluids (e.g., water, saline, cerebrospinal fluid, blood) from the surface. The adhesive composition can be applied in a wet environment where it is subjected to fluid pressure originating from the surface (e.g., blood seeping from an injury site into the bone, or cerebrospinal fluid flowing under pressure from a ruptured dura mater or skull fracture) or fluid flow above the surface, provided the initial adhesive strength is strong enough to resist loss of contact. Initial adhesive strength is established by making face-to-face contact between the applied adhesive composition and the intended surface to which it adheres. This can be achieved by applying compressive stress to the surface via hydrostatic pressure or by direct pressure of the material. In some embodiments, if the adhesive composition is to be used in an environment where an aqueous medium is already present at the site of application, it is possible to use the component without first combining it with the aqueous medium. In this case, the composition can be applied, sprayed, or additionally applied to the site of application and combined with the aqueous medium already present at the site.

[0169] In some embodiments, the composition may further include additives. Additives may be used to impart additional functionality to the compositions disclosed herein, such as improving or influencing the handling, texture, durability, strength, or reabsorption rate of a material, or to provide additional cosmetic or medical properties. Exemplary additives may comprise salts (e.g., calcium carbonate, calcium bicarbonate, sodium carbonate, sodium bicarbonate, sodium chloride, potassium chloride), fillers, formulation bases, viscosity modifiers (e.g., polyols (e.g., glycerol, mannitol, sorbitol, trehalose, lactose, glucose, fructose, or sucrose)), abrasives (e.g., bone flakes), colorants (e.g., dyes, pigments, or opacifiers), flavoring agents (e.g., sweeteners), locally acting drugs (e.g., anesthetics, coagulants, clotting factors, chemotactic agents, and agents that induce phenotypic changes in local cells or tissues), systemically acting drugs (e.g., analgesics, anticoagulants, hormones, vitamins, pain relievers, anti-inflammatory agents, chemotactic agents, or agents that induce phenotypic changes in local cells or tissues), antimicrobial agents (e.g., antibacterial agents, antiviral agents, or antifungal agents), or combinations thereof. In some embodiments, the additive comprises a polymer. Bioactive substances (e.g., pharmaceutical products) in the above categories may comprise active substances or precursors that become bioactive after interaction with the surrounding environment and subsequent modification. The substance may be synthetic, semi-synthetic, or biologically derived (e.g., peptides, proteins, or small molecules). The substance may contain (but is not limited to) anti-inflammatory drugs (e.g., steroids, non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors), complement proteins, osteogenic factors and proteins, locally or systemically effective hormones (e.g., parathyroid hormone, calcitonin), or other small molecules (e.g., calciferol).

[0170] In some embodiments, the additive is a polymer. Suitable polymers incorporated into the adhesive composition as additives may contain functional groups containing anionic atoms as bonding sites from the polymer surface to usable metal ions, such as anionic carbonyl oxygen atoms of ester groups or anionic nitrogen atoms of amino groups as bonding sites from the polymer surface to usable metal ions. These functional groups may be in the polymer backbone or in groups attached to the polymer chain. These polymeric compounds may include (but are not limited to) one or more of the following: poly(L-lactide), poly(D,L-lactide), polyglycolic acid, poly(ε-caprolactone), poly(tetramethylglycolic acid), poly(dioxanone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(lactide-co-glycolic acid), poly(glycolic acid-co-trimethylene carbonate), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone-co-glycolic acid ... Poly(tetramethylglycolic acid-co-dioxane-co-trimethylene carbonate), poly(glycolic acid-co-caprolactone-co-lactide-co-trimethylene carbonate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(methyl methacrylate), poly(acrylate), polyamines, polyamides, polyimide, poly(vinylpyrrolidone), collagen, silk, polyglucosamine, hyaluronic acid, gelatin, and / or mixtures thereof. In addition, copolymers of the above homopolymers may also be used.

[0171] The bulk structural properties of the polymer (e.g., the polymer used as an additive in the adhesive compositions described herein) may include linear homopolymers and copolymers, crosslinked polymers, block polymers, branched polymers, hyperbranched polymers, or star polymers. The polymer can be added to formulations in the form of solutions, powders, fibers, resins, liquid crystals, hydrogels, fragments, sheets, etc. The polymeric material may be included directly in the adhesive composition or may be an adjuvant applied in situ when applying a binder to bone.

[0172] In some embodiments, the composition comprises a plurality of the additives described herein. In some embodiments, certain additives may be provided in the form of powders or granules or solutes or any combination thereof. These powders may exhibit the following average particle sizes: about 0.001 to about 0.250 mm, about 0.005 to about 0.150 mm, about 0.25005 to about 0.75075 mm, 0.25 to about 0.5010 to about 0.050 mm, about 0.015 to about 0.025 mm, about 0.020 to about 0.060 mm, about 0.020 to about 0.040 mm, about 0.040 to about 0.100 mm, about 0.040 to about 0.060 mm, about 0.060 to about 0.150 mm, or about 0.060 to about 0.125 mm. The average particle size may be bimodal to include any combination of average particle sizes as previously described. These particles can exhibit the following particle sizes: about 0.050 mm to about 5 mm, about 0.100 to about 1.500 mm, about 0.125 to 1.000 mm, 0.125 to 0.500 mm, about 0.125 to 0.250 mm, about 0.250 to 0.750 mm, about 0.250 to 0.500 mm, about 0.500 to 1.00 mm, and about 0.500 to 0.750 mm. The average particle size can be multimodal, encompassing any combination of average particle sizes as previously described. In some embodiments, the size-varying powders or particles can be used in adhesive compositions.

[0173] In some embodiments, certain additives may be provided in the form of fibers. In some embodiments, the fibers may exhibit the following average fiber diameters: about 0.010 mm to about 2 mm, about 0.010 mm to about 0.50 mm, or about 0.025 mm to about 0.075 mm. These fibers may exhibit the following average fiber lengths: about 0.025 mm to about 50.0 mm, about 0.50 mm to 10 mm, or about 1.00 mm to about 3.50 mm. The average fiber diameter or length may be multimodal to include any combination of average fiber diameters or lengths as previously described.

[0174] As used herein, the term adhesion can include a reference to molecular attraction in contact areas between identical or dissimilar bodies that holds the bodies together. In some embodiments, adhesion includes molecular and atomic-level attraction and does not include macroscopic-level interlocking structures. Exemplary molecular forces include covalent bonding, ionic bonding (e.g., cation and anion interactions), chelation, van der Waals interactions, dipole forces, and other interactions between molecules and submolecular elements. In some embodiments, the adhesion process provides resistance to the displacement of interacting macro-elements. These micro-elements may comprise a coagulated composition in contact with other surfaces (e.g., bone, teeth, or other materials such as metallic, ceramic, polymeric, or glass structures).

[0175] As used herein, the term "adhesive" can refer to the formation of molecular bonds in the contact area between the coated material and its coated surface. In some embodiments, the coating of the composition includes adhesive coating.

[0176] As used herein, the term "mud seal" can encompass securing or bonding objects into a fixed, specific relationship by means of mechanical interlocking with surface irregularities and providing frictional resistance to displacement. Mud seals can also encompass securing or bonding objects into a fixed, specific relationship by means of mechanical interlocking with surface irregularities and providing frictional resistance to displacement. Generally, an adhesive can be applied as a fluid material to the voids between non-protruding solid surfaces, one surface generally surrounding another, and the adhesive hardens into a solid that fills the space and rigidly interlocks the object surfaces and resists relative displacement of the objects.

[0177] In some embodiments, the term "structure" as used herein refers to a solid object. Solid objects may include artificial devices or biological tissues, such as synthetic graft materials (e.g., bone void fillers, bone bonding agents, hardened adhesive compositions), implantable devices (e.g., orthopedic devices, dental devices), percutaneous support devices, or prosthetic devices. Implantable devices may take several forms, including rods, needles, posts, handles, screws, anchors, plates, cages, or other implantable devices designed for attachment to bone (e.g., cochlear implants, maxillofacial implants). Prosthetic devices may include dental crowns, limb replacement devices, and joint replacement devices. Percutaneous or transmucosal support devices may include dental abutments, prosthetic attachment devices, or other devices designed for attaching implants to prosthetic devices. Biological tissues may include tissue grafts (e.g., autografts, allogeneic grafts, or xenografts), tendons, ligaments, bone, bone fragments, or bone blocks.

[0178] Artificial devices may essentially comprise a bioresorbable surface for adhesion to an adhesive composition. In some embodiments, the bioresorbable component includes inorganic materials (e.g., calcium phosphate, calcium carbonate, calcium sulfate, calcium oxide, bioglass, or mixtures thereof). In other embodiments, the bioresorbable component includes polymeric materials (e.g., poly(lactide), poly(glycolic acid), poly(ε-caprolactone), poly(tetramethylglycolic acid), poly(dioxanone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(lactide-co-glycolic acid), poly(glycolic acid-co-trimethylene carbonate), poly(glycolic acid-co-dioxanone-co-trimethylene carbonate), poly(tetramethylglycolic acid-co-dioxanone-co-trimethylene carbonate), poly(glycolic acid-co-caprolactone-co-lactide-co-trimethylene carbonate), poly(hydroxybutyrate-co-hydroxyvalerate), polyamines, polyamides, polyimide, poly(vinylpyrrolidone), polyglucosamine, hyaluronic acid, gelatin, or copolymers, derivatives, or mixtures thereof). In some embodiments, a permanent surface is treated to facilitate a hydrophilic surface.

[0179] Artificial devices may essentially comprise a permanent surface for adhesion to an adhesive composition. In some embodiments, the permanent surface includes silk, nylon, polyamide, glass, carbon, aromatic polymers (e.g., polyphenylene oxide) and conjugated polymers (e.g., polyacetylene), inherently conductive polymers (e.g., polyaniline, polypyrrole, polythiophene), metals (e.g., calcium, silicon, copper, silver, gold, zinc, iron, titanium, aluminum, cobalt, chromium, tantalum, molybdenum), metal alloys (e.g., bronze, brass, steel (e.g., stainless steel), cobalt-chromium), poly(etherketone), poly(ethylene), poly(urethane), poly(methyl methacrylate), poly(carbonate), or poly(acrylic acid) polymers, or copolymers, derivatives, or mixtures thereof. In some embodiments, the permanent surface is treated to facilitate a hydrophilic surface.

[0180] Use of adhesive compositions

[0181] The adhesive composition is suitable for a wide range of applications. In some embodiments, the adhesive composition can be used to adhere a structure to a surface (e.g., bone) or another structure, such as... Figures 1 to 20(As shown in the diagram). In some embodiments, the structure includes an implant, anchor, graft, device, biological tissue, or another bone or bone fragment. In some embodiments, the surface is the inner surface of bone or the subperiosteal surface. In some embodiments, the adhesion of the structure is temporary, such that the structure can be removed after a period of time (e.g., greater than about 1 hour, about 2 hours, about 12 hours, about 24 hours, about 1 week, about 1 month, about 6 months, about 1 year, about 5 years). In other embodiments, the adhesion of the structure is permanent, or intended to be permanent, or until the material is reabsorbed or replaced with bone.

[0182] In other embodiments, the adhesive composition can be used to bond structures (e.g., bones or other structures, such as...) Figures 4 to 15 (As shown) is placed on a surface (e.g., an implant, anchor, graft, device, biological tissue, or another bone or bone fragment, such as... Figures 1 to 3 This refers to filling gaps, cavities, or voids in the surface before or after (as shown in the diagram). This particular application could be useful, for example, when the core diameter of the gap, cavity, or void is larger than the size of the structure during placement of the implant tooth into the alveolar ridge (e.g., as shown in the diagram). Figures 1 to 3 (As shown in the illustration). In this example, the adhesive composition can impart additional strength, fixation, stability, durability, or other advantageous properties to the attachment structure at the attachment site. In other embodiments, the adhesive composition can impart fixed strength to the attachment structure at the attachment site (e.g., as shown in the illustration). Figure 17 As shown in the illustration. In some embodiments, the adhesive composition may, for example, support new bone growth at the attachment site by increasing or stimulating bone resorption, deposition, or remodeling rates. In additional embodiments, the adhesive composition may be used to fill gaps created in or at the attachment site to produce a seal (e.g., as shown in the illustration). Figures 1 to 3 and Figure 22 As shown in the diagram), to prevent leakage, or to prevent microbial growth (e.g., interference) or to prevent fibrous tissue invasion. In some embodiments, the adhesive composition may be used to prevent microbial invasion, for example, to prevent infection, or to prevent fibrous tissue invasion (e.g., as shown in the diagram). Figures 1 to 3 and Figure 22 (as shown in the image).

[0183] In some embodiments, the adhesive composition is used during a medical procedure. In some embodiments, the adhesive composition is used during a surgical or dental procedure. In some embodiments, the medical procedure includes surgery (e.g., dental surgery, sinus surgery, facial surgery, or other surgery on a skeletal region). In other embodiments, the medical procedure includes spinal fusion, prosthetic attachment, bone cosmetic enhancement, or other surgery on the musculoskeletal system. Surgical procedures may expose or approach the coating site through open tissue procedures. Similarly, surgical procedures may be performed through small incisions or minimally invasive methods to minimize tissue damage (e.g., using a needle to approach the coating site or inject an exemplary composition, such as...) during a spinal fusion procedure. Figures 16 to 20 (As shown in the diagram). Such surgical procedures can be performed in a sterile operating room or in a non-sterile environment, such as in a clinical, office setting, or in a remote location outside the hospital setting (e.g., surgical site, battlefield, ocean, ambulance).

[0184] In some embodiments, the composition can be used in dental applications (e.g., ridge-preserving grafts after tooth extraction, filling cavities or defects caused by caries, tooth fractures, tooth wear, tooth abrasion, tooth decay, internal tooth fragmentation, placement of implants or devices, periosteal grafts, pulp remodeling, or others). In some embodiments, the composition is used as an external graft to increase bone volume (e.g., as...). Figures 4 to 16 and Figure 18 (As shown in the diagram). In some embodiments, the composition is used for cutting teeth. In other embodiments, the adhesive composition can be used in ossicular chain reconstruction or for attaching structures (e.g., hearing aids) to the inner or middle ear. In other embodiments, the adhesive composition can be used to provide contouring in surgical applications, such as for facial bone enhancement applications. In some embodiments, the adhesive composition can be used in cosmetic applications.

[0185] In other embodiments, the composition is placed into the extraction socket by injection and allowed to solidify. The solid material is allowed to remain undisturbed until the composition hardens, solidifies, or reabsorption of the material continues, thereby resulting in an increase in bone volume through alveolar filling and ridge preservation.

[0186] In other embodiments, the adhesive composition is placed or injected into bone voids created by the removal of bone cysts, granulomas, or similar bone defects at the top, center, or side of a ridge (e.g., bone), and the adhesive composition is allowed to solidify. The solid material is allowed to remain undisturbed until reabsorption continues, resulting in increased bone strength and remodeling of the bone contour.

[0187] In other embodiments, the adhesive composition is placed or injected into bone voids partially or entirely surrounding the exterior of the structure (e.g., an implant) because the bone voids are exposed from the bone, thereby providing a continuous profile to the bone surface, enhancing the stability of the structure (e.g., the implant) in the bone when needed, and allowing fibrous tissue cells to drain from the voids. In some embodiments, the adhesive is placed or injected into bone voids partially or entirely surrounding the exterior of the structure to seal the gaps, thereby allowing fibrous tissue to drain or preventing microbial invasion (e.g., preventing infection, such as...). Figures 1 to 3 and Figure 22 (As shown in the illustration). In some embodiments, this may be performed during the initial medical visit after implantation. In other embodiments, this may be performed during emergency procedures for the implant.

[0188] In other embodiments, the adhesive composition is placed or injected into a refined extraction socket or similar bone cavity, and the structure (e.g., an implant) is positioned in a desired relationship to the surrounding environment during this preparation before the composition solidifies. Once the composition solidifies, the structure (e.g., the implant) has initial stability, which in some embodiments may mean that the implant is clinically immobile relative to the bone host site under lateral and axial loads and under torsional loads of at least 10 N / cm in a clockwise rotation. In some embodiments, initial stability may mean that the implant is clinically immobile relative to the bone host site when using an Ostell instrument that analyzes resonant frequencies with measured ISQ values, where the ISQ scale is normalized from 0 to 100, where a higher ISQ indicates greater implant stability, and / or where an ISQ value >50 has been clinically accepted to indicate that the implant is sufficiently stable to account for loads. In other embodiments, initial stability refers to the relative immobility of the adhesive surface when the adhesive bond is subjected to a load-bearing stress of at least 250 kPa.

[0189] Placement of intraosseous structures may be performed through open procedures involving partial or full-thickness flaps, or through non-flap procedures with minimal periosteal reflection (e.g., perforated access, laser, electrocautery, etc.).

[0190] Placing the adhesive composition into contact with the bone may be done through an open procedure involving partial or full-thickness flap reflection, or through a non-flap procedure with minimal soft tissue cutting or interruption (e.g., access via cannulation or needle injection after a tunneling method).

[0191] The adhesive composition may be applied to the surface of a structure in its fluid or semi-solid state by means of an injection delivery device or by application using a tool such as a spatula. The viscosity of the adhesive composition in its fluid state may be as low as about 100 cP to about 10,000 cP, and in its semi-solid state, it may be from about 10,000 cP to about 250,000 cP. The viscosity and cohesiveness of the adhesive composition, when the viscosity is in the low range of its fluid state, will facilitate the ability to extrude the material through needles or cannulas as small as 18 wire diameters. Regarding the viscosity in the semi-solid state, the shape and amount of material can be varied by spreading or removal techniques without substantially affecting the strength of the solidified material. In some embodiments, the working time of the adhesive composition is when the viscosity is between about 100 cP and about 250,000 cP.

[0192] Before the adhesive composition hardens into a solid, it may be coated onto the surface of the host structure in its fluid or semi-solid state and remain in these states during subsequent placement of another structure in contact with the adhesive composition, thus giving the structure initial stability.

[0193] Structure-to-host structure adhesion may occur to a bed, film, or layer of adhesive composition that surrounds, contacts, or embeds the structure, while the adhesive composition is in its fluid or semi-solid state before curing, thus the structure has initial stability (e.g., as...). Figures 1 to 3 , Figures 13 to 15 and Figures 21 to 22 (As shown in the diagram). To do this, the host site of the structure may require formulation before the adhesive composition is applied. The adhesive composition can be applied to the host site, which may have convex or concave surfaces, or a combination of convex and concave surfaces. The adhesive composition, in its fluid or semi-solid state, can have sufficient cohesive and adhesive forces to resist displacement from gravity or fluid flow acting on it. Before the adhesive composition hardens, the structure may be placed in or on the adhesive composition in its fluid or semi-solid state at a desired location relative to the surrounding environment, thus providing initial stability to the structure. Alternatively, the structure may be placed in or on the host site at a desired location relative to the surrounding environment, and thereafter, the adhesive composition may be injected into the surrounding area or through the orifice feature of a cannula insertion or implantation device, which communicates with the surface of the host site before the adhesive composition hardens, thus providing initial stability to the structure. Alternatively, before the fluid adhesive composition hardens, the structure may be first coated with the adhesive composition on some or all of the structural surfaces and then placed on or in the host site, thus providing initial stability to the structure.

[0194] In other embodiments, the alveolar ridge is amplified using an adhesive composition to increase the ridge bone volume, while the implant tooth is placed according to the following technique. First, the alveolar ridge may require an initial step of preparing the bone surface, which may include drilling or reaming the available bone into the desired shape (e.g., as shown in the image). Figure 4 , Figure 7 and Figure 10 (As shown in the diagram). Next, the adhesive composition is applied to the alveolar ridge in an adhesive manner (e.g., as shown in the diagram). Figure 5 , Figure 8 and Figure 11 (As shown in the diagram). Before the adhesive composition hardens to a solid state, the implant tooth is placed in the adhesive composition in the desired position relative to the surrounding environment, thus providing initial stability of the implant. The implant may or may not engage with the bone in the previously prepared alveolar ridge (e.g., as shown in the diagram). Figure 6 , Figure 9 and Figure 12 (As shown in the diagram). Furthermore, during the same procedure, at a subsequent step or at a subsequent step after sufficient time has passed since soft tissue and bone healing has occurred, the healed, temporary, or fixed abutment and temporary or fixed crown are placed on the implant. These intervals may be equal to or less than 24 hours, 24 hours to one week, one week to two weeks, two weeks to one month, one month to three months, three months to six months, six months to one year, or more than one year. The crown, implant, abutment, materials, and surrounding bone are all affected and able to maintain initial stability under patient loads (e.g., chewing forces).

[0195] The structure may be adhered to the hardened adhesive composition at intervals. These intervals may be equal to or less than one hour, more than one hour but less than eight hours, eight to twenty-four hours, twenty-four hours to one week, one week to two weeks, two weeks to one month, one month to three months, three months to six months, six months to one year, or more than one year. To do this, the formulation may be ground (e.g., drilled) into the matrix consisting of the solidified adhesive composition and the surrounding skeleton. The structure can be placed directly into the formulation in the desired position relative to the surrounding environment, thus giving the structure initial stability (e.g., as shown in the image). Figure 3 , Figure 6 , Figure 9 , Figure 12 and Figure 15 (As shown in the diagram). Alternatively, the formulation may first be partially or completely filled with an adhesive composition, and the structure can then be placed in the formulation in the desired position relative to the surrounding environment, while the adhesive composition is in its fluid or semi-solid state. Thus, the structure replaces the adhesive composition during placement before the fluid adhesive composition hardens, thereby giving the structure initial stability (e.g., as shown in the diagram). Figure 3 , Figure 6 , Figure 9 , Figure 12 and Figure 15 (As shown in the diagram). Alternatively, the structure can be placed in a formulation in a desired position relative to its surroundings, and thereafter, an adhesive composition may be injected via a cannula insertion or an orifice feature of an implantation device, the orifice feature being in communication with the surface of the formulation before the adhesive composition hardens, thus giving the structure initial stability. Alternatively, the structure may be first coated with an adhesive composition on some or all of its surfaces before being placed in the formulation, prior to the hardening of the fluid adhesive composition, thus giving the structure initial stability.

[0196] In other embodiments, an adhesive composition is used to amplify the alveolar ridge to create an increase in ridge volume (width or height) while placing the implanted tooth according to the following techniques. In some embodiments, the alveolar ridge may require an initial step of preparing the bone surface, which may include drilling or reaming the available bone to the desired state (e.g., as shown in the image). Figure 4 , Figure 7 and Figure 10 (As shown in the diagram). In some embodiments, the adhesive composition may then be placed or injected into the prepared extraction socket, allowing the adhesive composition to solidify. The formulation may then be ground (e.g., drilled) into a matrix consisting of a coagulating material and surrounding bone. Next, a composition of similar or different compositions in its fluid state (i.e., its working state) is placed into the formulation and / or coated onto the surface of the implant (e.g., the implanted tooth). The implant is placed in the formulation in the desired position relative to the surrounding environment before the fluid material hardens to a solidified adhesive state, thus giving the implant initial stability (e.g., as shown in the diagram). Figure 6 , Figure 9 and Figure 12 (As shown in the diagram). Furthermore, during the same procedure, at subsequent time intervals or at subsequent procedures after sufficient time has passed since soft tissue and bone healing has reached the desired state, a healed, temporary, or fixed abutment, and possibly a temporary or fixed crown, is placed on the implant. These intervals may be equal to or less than 24 hours, 24 hours to one week, one week to two weeks, two weeks to one month, one month to three months, three months to six months, six months to one year, or more than one year. In some embodiments, the crown, implant, abutment, material, and surrounding bone are all affected and able to maintain initial fixation under immediate patient loads (e.g., chewing forces). In other embodiments, the crown, implant, abutment, material, and surrounding bone are all affected and able to maintain initial stability under patient loads (e.g., chewing forces).

[0197] In other embodiments, full-thickness cutting (e.g., distal full-thickness cutting), followed by tunneling subperiosteal dissection and subperiosteal placement or injection of an adhesive composition in contact with the bone, is used to create an expansion of bone volume in the region. This may widen the alveolar ridge where implant placement is required, but the width of the residual ridge of bone is more or less insufficient for implant placement. The ridge thus expanded is wide enough to allow osteotomy to be performed within the original bone volume at the time of the original procedure or after a delay of days, weeks, or months, and to provide resistance to lateral movement of the rotary cutting instrument during bone preparation and to the implant when placed in the planned relationship with the surrounding host bed, either in a hardened state or by host modification.

[0198] In other embodiments, when the width of the residual alveolar ridge is insufficient, thus limiting implant placement options, full-thickness cutting and skin flap reflection are performed, followed by coating with an adhesive composition that contacts the bone to induce bone volume expansion in the region (e.g., as shown in the image). Figure 11 (As shown in the diagram). This may widen the alveolar ridge where implant placement is required, but the width of the residual ridge of bone is initially more or less insufficient for implant placement. Therefore, the ridge thus enlarged is then wide enough to allow osteotomy to be performed within the original bone volume at the time of the original procedure or after a delay of days, weeks, or months, and to provide resistance to lateral movement of the rotary cutting instrument during bone preparation and to the implant when placed in the planned relationship with the surrounding host bed, either in a hardened state or when altered by the host.

[0199] In other embodiments, full-thickness cutting (e.g., long-distance full-thickness cutting) is followed by subperiosteal coating of a tunneling subperiosteal dissection and an adhesive composition in contact with the bone to generate bone volume expansion in the region (e.g., as shown in the image). Figure 8 and Figure 11 (As shown in the diagram). This may increase the height of the alveolar ridge, where implant placement is required, but the width of the residual ridge of bone is initially more or less insufficient for implant placement (e.g., as shown in the diagram). Figure 5 (As shown in the diagram). Therefore, the expanded ridge, consisting of the original bone and the adhesive composition, is then high enough to allow osteotomy to be performed immediately or after a delay of hours, days, weeks, or months, and to provide resistance to the lateral movement of the rotating cutting instrument during bone preparation and to the implant when placed in a planned relationship with the surrounding host bed, either in a hardened state or when altered by the host.

[0200] In other embodiments, when the residual alveolar ridge height is insufficient, thus limiting implant placement options, full-thickness cutting and skin flap reflection are performed, followed by coating with an adhesive composition that contacts the bone to induce bone volume expansion in the region (e.g., as shown in the image). Figure 5(As shown in the diagram). This may increase the total height of the volume available for implant placement. Thus, the ridge thus expanded is then high enough to allow the implant receiving site to grind into the volume immediately or after a delay of hours, days, weeks, or months, and to provide resistance to lateral movement of the rotary cutting instrument during bone preparation and to the implant when placed in the planned relationship with the surrounding host bed, either in a hardened state or when altered by the host.

[0201] In other embodiments, the expanded ridges are wide enough that osteotomy is performed within a wider solid volume consisting of the bone ridges and additional adhesive material in a hardened state or when modified by the host. In some embodiments, the implant host bed, throughout the length of the implant, is a combination of pre-existing bone, the composition, or the composition when modified by the host. In other embodiments, the expanded ridges are high enough that osteotomy is performed within a higher solid volume consisting of the bone ridges and additional adhesive material in a hardened state or when modified by the host. Alternatively, implant placement is delayed until the composition is partially or completely reabsorbed and replaced by bone. In this embodiment, the outermost layer of the implant host bed is the composition or the composition when modified by the host, and the deepest part of the bed is the bone volume present before the composition is placed.

[0202] In some embodiments, in the mucosal periosteum of the facial sinuses or another air chamber (e.g., nasal airway, such as...) Figure 14 Subperiosteal injection or placement of an adhesive composition in contact with bone is performed between the tissues shown in the diagram. In some embodiments, facial sinuses include paranasal sinuses, such as the maxillary sinuses. This may involve an increase in bone volume height where dental implant placement is required, but where the height of the residual bone between the oral cavity and the sinus air chambers is insufficient for implant placement. The bone thus increased is high enough that osteotomy is performed within a higher solid volume consisting of bone and additional adhesive material in a hardened state or when altered by the host. Alternatively, implant placement is delayed until the composition is partially or completely reabsorbed and replaced by bone. In this embodiment, the deepest layer of the implant host site bed is the composition or the composition when altered by the host, and the outermost layer of the bed is the bone volume present prior to material placement.

[0203] In some embodiments, the composition may be adhesively applied to gaps or discontinuous bone walls between bone surfaces designated for closure, since gaps or discontinuities in the bone cause disability, dysfunction, or are otherwise undesirable. In some embodiments, gaps or discontinuities in the bone are undesirable because of the loss of weight-bearing function. These may include gaps or discontinuities that are congenital (e.g., cleft palate), caused by trauma (e.g., fracture), caused by improper healing (e.g., fibrous adhesion), caused by the removal of bone (e.g., vesicle, necrosis, or infection), or caused by procedures involving bone cutting or segmentation to alter its size, shape, or contour (e.g., orthognathic surgery or correction of deformed long bones due to congenital, metabolic, or dietary problems). The composition may be used in conjunction with fixation devices (e.g., microplates, bone pins, and screws) or with associated bone plates spanning gaps or shape and volume retention devices for discharging other tissues (e.g., titanium mesh or titanium cages), or may be used alone or in combination with several formulations of the composition that contain formulations that release substances intended to influence surrounding tissues and the environment. In this embodiment, the composition functions as a bridge relative to existing elements of the skeleton, thereby providing continuity of contour, mechanical connection, and preventing the proliferation of other tissues when bone tissue replaces the coagulation material. In some embodiments, the mechanical connection is a load-bearing connection.

[0204] In some embodiments, this disclosure features a method for strengthening bone (e.g., osteoporosis, osteosclerosis, or osteodystrophy) at the risk of fracture, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to a desired area of ​​the bone and also adhesively applying it to one or more rigid or semi-rigid devices (e.g., plates, rods, strips, bandages) made of a metal or other biocompatible material; c) applying the device of b) adhesively attached to the bone to the desired area of ​​the bone; and d) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is reabsorbed and replaced by the bone. In some embodiments, the bone is osteoporotic, osteopenia-reduced, osteosclerotic, or affected by osteodystrophy.

[0205] In some embodiments, this disclosure is characterized by a method for repairing fractures of broken bones (e.g., osteoporotic femur), the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) adhesively applying the composition to a desired area of ​​the bone and also adhesively applying it to one or more rigid or semi-rigid devices (e.g., plates, rods) made of metal or other biocompatible materials; c) applying the device of b) adhesively attached to the bone to the desired area of ​​the bone; and d) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is reabsorbed and replaced by the bone.

[0206] In some embodiments, the composition is adhesively coated onto bone (e.g., femur, for example, as shown in the image). Figures 21 to 22 As shown; alveolar ridge, for example, as Figure 4 , Figure 7 , Figure 10 and Figure 13 The gaps, discontinuities, or volume defects shown in the diagram, or the gaps, discontinuities, or volume defects coated between bones (e.g., as shown in the diagram). Figure 17 and Figure 18 The spinous process and vertebral body are shown in the diagram. In some embodiments, the gap or interruption results in disability, dysfunction, or is otherwise undesirable. The gap or interruption may be congenital (e.g., cleft palate), caused by trauma (e.g., fracture), caused by the removal of bone (e.g., vesicle, necrosis, or infection), or caused by procedures involving bone cutting or segmentation to alter its size, shape, or contour (e.g., orthognathic surgery or correction of deformed long bones due to congenital, metabolic, or dietary problems). In other embodiments, the gap or interruption may be caused by the removal of soft tissue (e.g., cartilage removal or discectomy, for example, as shown in the diagram). Figure 17 and Figure 18 As shown in the figure. In some embodiments, the composition is used alone. In other embodiments, the composition is used in combination with rigid devices made of metal or other solid materials (e.g., microplates, plates, and other shaped objects of bone), bone plates associated with intervertebral discs, or shape and volume retention devices for discharging other tissues (e.g., titanium mesh), or may be used alone or in combination with several formulations of the composition that contain formulations that release substances intended to affect surrounding tissues and the environment. In some embodiments, the composition may be used with intervertebral body devices (e.g., cages, such as...). Figure 17 (As shown in the diagram) used in combination. In this embodiment, the composition functions as a bridge relative to existing elements of the skeleton, thereby providing continuity of the contour, mechanical connection, and preventing the proliferation of other tissues when bone tissue replaces the coagulation material.

[0207] In some embodiments, the adhesive composition is applied to the surface of the joint bone (e.g., intervertebral joint, for example, as shown in the figure). Figure 19 As shown in the figure, or coated onto adjacent bone surfaces to bridge gaps (e.g., between vertebral bodies, such as...). Figure 18 As shown; between the transverse processes, for example, as Figure 16 As shown; or between the spinous processes), to prevent relative displacement of the bone surface (e.g., spinal fusion procedures) and with or without supporting implants (e.g., screws, plates, intervertebral cages, e.g., as shown). Figure 17 As shown in the diagram, load-bearing supports are provided. These coatings can be applied individually or used to provide multi-point fixation when applied to several or other locations.

[0208] In some embodiments, an adhesive composition in contact with bone is adhesively placed or injected into a space near the bone volume or a gap between bone volumes, where it is desired to attach an implant or other device (e.g., such as...). Figures 21 to 22 (as shown in the diagram). The device may be placed, embedded, or otherwise attached to the composition and host bed each time before the composition is in an adhesive state, during the solidification process, after the composition is solid, or after the composition is partially or completely replaced by bone tissue.

[0209] In some embodiments, an adhesive composition is placed or injected into a bone defect associated with the tooth root (e.g., a periodontal defect) and allowed to solidify. In some embodiments, the bone defect associated with the tooth root is a periodontal or periapical defect. The composition can then be replaced by bone, thereby providing increased mechanical stability to the tooth and also preventing the entry and exit of environmental microbial communities onto the tooth root surface and into the alveolar bone.

[0210] In other embodiments, an adhesive composition is placed or injected into a bone defect associated with the implant (e.g., a periodontitis defect), and the adhesive composition is allowed to solidify. The composition can then be replaced by bone, thereby providing increased mechanical stability to the implant and also preventing the entry and exit of environmental microbiota onto the implant surface and surrounding bone.

[0211] In some embodiments, the adhesive composition may have adhesive properties toward soft tissue. A layer of the composition may be applied as an adhesive to stop soft tissue flaps, fragments, or areas. Attaching the composition to the soft tissue may be durable and strong enough to close the wound. The attachment of the composition may provide a barrier to fluid flow from one side of attachment to the other. The attachment of the composition may provide a barrier to microbial movement from one side of attachment to the other. The surface of the composition may be a barrier to the movement of soft tissue cells (e.g., fibroblasts) into the coagulated material. The surface of the composition may be a barrier to the movement of microorganisms into the coagulated composition.

[0212] In some embodiments, an adhesive composition may be injected or otherwise placed at the percutaneous or healing site where the implant or device is placed to seal the site and prevent fluids, materials, and microorganisms and their products from flowing deeper into the wound. This application may occur concurrently with the initial placement of the implant or another later procedure involving the implant. The implant may be a dental implant, a maxillary prosthesis fixation implant, or any other implant with healing or percutaneous components. In some embodiments, the insert may be a prosthetic element.

[0213] In other embodiments, the adhesive composition may be injected, layered, sprayed, brushed, or otherwise applied, according to one or more variations of the composition, to a surgical wound in which bony tissue is present near the gums, mucosa, skin, or other elements of the covering, thereby securing the soft tissue edges and preventing fluids, materials, and microbial communities and their products from moving deeper into the wound.

[0214] In other embodiments, the adhesive composition can be used to reconstruct and approximate cracks or gaps caused by congenital malformations (such as, but not limited to, cleft lip and cleft palate). The composition can be used to restore bone deformities to the original palate by filling and adhering the maxillary process and medial nasal process with the composition.

[0215] In other embodiments, the adhesive composition can be used as an external graft in the field of plastic surgery, wherein the adhesive composition can be coated and adhered to the outer surface of bone in a facial region. The composition can be applied and contoured or molded into a desired cosmetic profile or contour as a fluid or putty substance before hardening. The composition can be reabsorbed and replaced by the bone over time while maintaining its original volume and shape formed during application. The composition can be applied (but is not limited to) the chin, cheeks, mid-face, or forehead areas.

[0216] In some embodiments, the adhesive composition may be applied adhesively to attach the removed bone fragment, thereby creating a window that allows for the use of the graft in a sinus floor lift procedure or a Caldwell-Luc procedure. The adhesive composition may be injected, sprayed, brushed, or otherwise applied in one or more compositional variations to fill gaps and / or attach bony fragments or flaps formed by surgical instruments, thereby allowing access to the nasal cavity.

[0217] In some embodiments, the composition may be adhesively coated to attach one or more removed bone fragments, thereby establishing access to a procedure within a space enclosed by bone (e.g., an intracranial space for brain surgery procedures). In some embodiments, establishing access to a space enclosed by bone includes providing access to a cranial bone flap within the intracranial space (e.g., for brain surgery procedures). The adhesive composition may be injected, sprayed, brushed, or otherwise coated in one or more compositional variations to attach bony fragments, bone pieces, or bone flaps to the anatomical site from which the adhesive composition is removed during the acquisition of the access using surgical instruments.

[0218] In some embodiments, an adhesive composition may be applied to seal openings in the bone or communications between spaces or potential spaces separated by the bone. This opening may be congenital, pathological, traumatic, or surgically created bone fenestrations, fissures, or communications (e.g., oral-nasal fistulas, Colloche procedure access openings, sinus lift graft access openings) or any other opening. The adhesive composition may be combined with other materials that may act as a carrier or matrix, or, in the absence of said other materials, injected, sprayed, brushed, or otherwise applied in one or more compositional variations to block pathways from one side of the bone to the other via gaps, fistulas, or communicating channels.

[0219] In some embodiments, the adhesive composition may act as a seal to close the communication between an intracranial or spinal space immersed in cerebrospinal fluid and the outside of the body: the method includes: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the adhesive composition to or over the communication (e.g., a crevice, fistula, or tear); and c) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is reabsorbed and replaced by bone.

[0220] In some embodiments, this disclosure is characterized by a method of adhesively repairing defects in a tooth, the method comprising: a) preparing an adhesive composition comprising a polyvalent metal salt and a small amount of an organophosphate compound in an aqueous solution or suspension; b) applying the composition to or on the tooth defect; and c) allowing the composition to remain undisturbed until the composition hardens, solidifies, or is resorbed and replaced by bone.

[0221] In some embodiments, the adhesive composition may be applied to the tooth surface in an adhesive manner. The adhesive composition may be injected, sprayed, brushed, or otherwise applied in one or more compositional variations to fill gaps in tooth material resulting from the removal of caries, or injected, sprayed, brushed, or applied to surfaces exposed by tooth fracture or wear, abrasion, or corrosion of tooth material.

[0222] In some embodiments, the adhesive composition may be adhesively applied to a tooth surface or dental restorative material to seal or adhere the tooth surface or dental restorative material. The adhesive composition may be injected, sprayed, brushed, or otherwise applied in one or more compositional variations to fill gaps in tooth material resulting from the removal of caries, or injected, sprayed, brushed, or applied to surfaces exposed by tooth fracture or wear, abrasion, or corrosion of tooth material.

[0223] In some embodiments, different variations of the components of the adhesive composition may be packaged and sold as kits for specific indication.

[0224] In some embodiments, the kit may include a container containing a polyvalent metal salt (e.g., calcium phosphate or calcium oxide) and a compound of formula (I) (e.g., a small amount of an organophosphate compound, such as phosphoserine), the polyvalent metal salt being present with the compound of formula (I) and sealed under good packaging practices to maintain the shelf life of the individual components. In some embodiments, maintaining the shelf life of the components within the kit includes maintaining sterility. If an additive is included in the kit, the additive may be packaged within this container or in a separate container. An aqueous medium (if included) (e.g., a solution or suspension) may be provided in a separate container. The kit may include additional components for preparing or coating adhesive compositions, such as a mixing bowl or surface, a stirring rod, a spatula, a syringe, a heat gun, or other preparation or delivery device.

[0225] In some embodiments, after mixing with an aqueous solution or suspension and before hardening, the adhesive composition may be in a flexible working state for up to about 30 minutes or less, depending on the components of the composition. In some embodiments, after mixing with an aqueous solution or suspension, the adhesive composition may be in a flexible working state for less than or equal to about 30 minutes, for example, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, less than about 5 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute, less than about 30 seconds, or less than about 5 seconds.

[0226] In some embodiments, after a predetermined time period, the adhesive composition may take on a hard, hardened state. This transition from a flexible working state to a hardened state may be referred to as “hardening,” “curing,” or “solidification.” In some embodiments, depending on the application and specific components and the ratio of the components in the adhesive composition, the adhesive composition may exhibit an adhesive strength in the hardened state ranging from about 100 kPa to about 12,000 kPa. In some embodiments, the adhesive strength of the adhesive composition in the hardened state is between about 100 kPa and, for example, about 10,000 kPa, about 9,000 kPa, about 8,000 kPa, about 7,000 kPa, about 6,000 kPa, about 5,000 kPa, about 4,000 kPa, about 3,000 kPa, about 2,000 kPa, about 1,000 kPa, about 750 kPa, about 500 kPa, about 250 kPa, or about 200 kPa. In some embodiments, the adhesive strength of the adhesive composition in a viscous state is between about 100 kPa, about 200 kPa, about 300 kPa, about 400 kPa, about 500 kPa, about 600 kPa, about 700 kPa, about 800 kPa, about 900 kPa, about 1,000 kPa, about 2,500 kPa, about 5,000 kPa, about 7,500 kPa, about 10,000 kPa, or about 12,000 kPa. In some embodiments, the adhesive strength of the adhesive composition in a viscous state is in the range of about 200 kPa to about 2,500 kPa. In some embodiments, specific components of the adhesive composition can be selected to achieve the desired strength according to the intended use of the adhesive composition. In all embodiments, a skilled practitioner (e.g., a doctor, dentist, surgeon, nurse, or other suitable person) can modify specific components to achieve the desired adhesive properties of the composition based on the intended use or desired results.

[0227] In other embodiments, the adhesive composition is used to treat or cure an individual suffering from a disease or condition, such as cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, severe and obstructive malocclusion, osteonecrosis, or other genetic or developmental disorders. In some embodiments, the adhesive composition is used to repair bone defects caused by a disease or condition, such as cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infection, or other genetic or developmental disorders. In some embodiments, the adhesive composition is used to strengthen the bones of an individual weakened by a disease or condition, such as cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, bone malignancy, bone infection, or other genetic or developmental disorders. In some embodiments, the individual has experienced trauma, such as a broken bone, fracture, or damaged tooth. In some embodiments, the individual has experienced tooth decay. In some embodiments, the individual is undergoing orthopedic surgery. The composition and method can be used to treat an individual suffering from or affected by any disease or condition that affects the structural integrity of the skeleton. In some embodiments, the individual is a child. In some embodiments, the individual is an adult. In some embodiments, the individual is a non-human animal.

[0228] In some embodiments, the adhesive composition comprises at least one of the following: tetracalcium phosphate, phosphoserine, hydroxyapatite, tricalcium alpha-phosphate, tricalcium beta-phosphate, calcium oxide, sorbitol, poly(lactide-co-glycolic acid), or water. In some embodiments, the adhesive composition comprises at least two of the following: tetracalcium phosphate, phosphoserine, hydroxyapatite, tricalcium alpha-phosphate, tricalcium beta-phosphate, calcium oxide, sorbitol, poly(lactide-co-glycolic acid), or water. In some embodiments, the adhesive composition comprises at least three of the following: tetracalcium phosphate, phosphoserine, hydroxyapatite, tricalcium alpha-phosphate, tricalcium beta-phosphate, calcium oxide, sorbitol, poly(lactide-co-glycolic acid), or water.

[0229] In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, and water (e.g., as exemplified by composition A in Table 1). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, α-tricalcium phosphate, and water (e.g., as exemplified by composition B in Table 1). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, β-tricalcium phosphate, and water (e.g., as exemplified by composition C in Table 1). In some embodiments, the adhesive composition comprises phosphoserine, α-tricalcium phosphate, calcium oxide, and water (e.g., as exemplified by composition D in Table 1). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, sorbitol, and water (e.g., as exemplified by composition E in Table 1). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, hydroxyapatite, and water (e.g., as exemplified by composition F in Table 1). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, hydroxyapatite, poly(lactide-co-glycolic acid), and water (e.g., as exemplified by composition G in Table 1).

[0230] In some embodiments, the adhesive composition has an adhesive strength (e.g., mean shear stress strength) greater than 0.5 MPa (e.g., greater than about 0.75 MPa, about 1.0 MPa, about 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, and water (e.g., as exemplified by composition A in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, tricalcium α-phosphate, and water (e.g., as exemplified by composition B in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, β-tricalcium phosphate, and water (e.g., as exemplified by composition C in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises phosphoserine, α-tricalcium phosphate, calcium oxide, and water (e.g., as exemplified by composition D in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, sorbitol, and water (e.g., as exemplified by composition E in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa). In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, hydroxyapatite, and water (e.g., as exemplified by composition F in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, or about 3.0 MPa).In some embodiments, the adhesive composition comprises tetracalcium phosphate, phosphoserine, hydroxyapatite, poly(lactide-co-glycolic acid) and water (e.g., as exemplified by composition G in Table 1) and has an adhesive strength (e.g., mean shear stress strength) greater than 1 MPa (e.g., greater than 1.25 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa or about 3.0 MPa).

[0231] Example

[0232] Some embodiments presented herein are described in further detail with reference to the following examples. Unless otherwise stated, these examples are provided for illustrative purposes only and are not intended to be limiting. This disclosure should be construed as covering any or all variations that become apparent as a result of the teachings provided herein.

[0233] Without further description, it is believed that those skilled in the art can use the foregoing description and the following illustrative examples to manufacture and utilize the said compound and practice the claimed method. The following examples specifically illustrate various aspects of this disclosure and should not be construed as limiting the remainder of this disclosure in any way.

[0234] Example 1:

[0235] Exemplary adhesive compositions are summarized in Table 1. The solid components listed in the table are combined in a suitable container and mixed with water to achieve the desired consistency. When water is used in the compositions summarized in the table, the aqueous medium for the compositions of this disclosure can actually be blood, saliva, serum, or a blood-based solution. The solid components listed in the table can be supplied in particulate, granular, or fibrous form, and the size of each component listed in Table 1 can be within the range described in the embodiments. In some embodiments, the resulting properties (e.g., working and setting times) will be affected by these variations. The specific uniform particle size, granular, or fibrous size of each solid component is selected to meet the usage requirements described in each embodiment.

[0236] The quantity of each listed component may be varied or adjusted with respect to other components in the composition. After mixing, the described composition is applied to the desired area, and adhesive properties are checked, for example, for tensile strength and durability. Each component may further include phases and ingredients not specified in the table.

[0237] Table 1: Components of the exemplary adhesive composition

[0238]

[0239] Example 2:

[0240] In this example, the bone-bone or bone-titanium adhesion shear strength of the compositions described in Table 1 was tested. Bone cubes for shear testing were prepared from bovine femoral cortex, and the metal cubes used for shear testing were highly corrosion-resistant Grade 2 titanium with an alumina-blasted finish. Each cube used for testing was rectangular, measuring 8.5 mm × 8.5 mm × 20 mm. The adhered surfaces were the 8.5 mm × 8.5 mm faces from both cubes. The bone cubes were stored at -20°C prior to testing to maintain their structure. Prior to testing, the bone cubes were removed from the refrigerator and preconditioned by immersing them in a phosphate-buffered saline (PBS) bath at 37°C for at least one hour. Immediately before testing, the bone cubes were removed from the bath without removing excess aqueous solution from the surface (i.e., the surface was wet). The titanium cubes were also preconditioned by immersing them in a phosphate-buffered saline (PBS) bath at 37°C for at least one hour prior to testing.

[0241] Using a stainless steel spatula, mix each composition in Table 1 in a 25 mL silicone mixing bowl for t=20 seconds. After mixing, load the composition into a 3 cc slip-tipped syringe. Immediately at t=1.5 minutes after the start of mixing, inject the composition onto one end of each of the 8.5 mm × 8.5 mm surfaces of two cubes. Immediately thereafter, the cube surfaces covered with the adhesive composition are placed side-by-side, and excess material extruded around the perimeter of the joint is removed with a spatula. From the start of mixing, place adjacent cubes into a fixture that applies a slight compressive force (3 to 5 N) for 4 minutes corresponding to the working period of the composition. Thereafter, remove the cubes from the fixture and immerse them in a 37°C PBS bath to allow the composition to cure until the specified time. Test the adhesion of the cube sets at t=10 minutes, t=1 hour, or t=24 hours from the start of mixing. After the specified curing time, remove the cubes from the PBS bath for shear force testing. The proximal cube of the attached cube assembly is secured in a stable manner to prevent movement within the sample clamping device up to 1.0 mm of the adhesion joint within the Instron 5969 axial load frame. The distal cube of the attached cube assembly is cantilevered from the sample clamping device. In testing the bone-titanium cube assembly, the titanium cube is the distal cube. The Instron crosshead with the attached incus fixation device is lowered until the distal surface of the incus is within 0.5 mm of the top surface of the distal bone cube and within 1.0 mm of the adhesion joint. The test is performed at a crosshead speed of 2 mm / min.

[0242] Table 2 shows the results of bone-to-bone mean shear stress (MPa) and standard deviation, along with the number of repetitions for each test group. Table 3 shows the results of bone-to-bone titanium mean shear stress (MPa) and standard deviation, along with the number of repetitions for each test group. NT means that no specific test group was tested. The results indicate that the compositions have adhesive strength, with the mean shear stress of the adhered bone-to-bone and bone-to-titanium cubes exceeding 1 MPa for each of the tested compositions.

[0243] Table 2: Bone-to-bone adhesion shear force test of adhesive compositions

[0244]

[0245] Table 3: Bone-Titanium Adhesion Shear Strength Test of Adhesive Compositions

[0246]

[0247] Example 3:

[0248] In this example, the compositions described in Table 1 can be used in any of the embodiments described herein, but specifically, for filling alveolar bone in extraction alveoli, filling periodontal defects, filling cystic defects, performing sinus floor elevation, and / or for augmenting alveolar bone ridges before, during, or after implant placement. Similarly, the compositions can be used to fix adjacent vertebrae in spinal fusion surgery with or without instruments. The compositions can be used with or without internal metal fixation and can be mixed with autologous or allogeneic grafts as bone graft augmentants.

[0249] Example 4:

[0250] In this example, the adhesive composition described in Table 1 is used to fill voids or gaps in the bone, as bone cysts, granulomas, or similar bone defects on the top or side of the alveolar ridge are removed. After preparing the composition, the material is applied to the voids or gaps and allowed to solidify. After solidification, the tensile strength and durability of the material are tested.

[0251] Example 5:

[0252] In this example, the adhesive composition described in Table 1 is used to repair bone defects in individuals suffering from conditions such as cancer (e.g., osteosarcoma), osteoporosis, rickets, osteogenesis imperfecta, fibrous dysplasia, Paget's disease, hearing loss, renal osteodystrophy, malignant bone tumors, bone infections, osteonecrosis, or other genetic or developmental disorders. After preparing the composition, the material is coated onto the voids or gaps, allowing the material to solidify. The solidification process can be accelerated by using a hot air gun or other heating element.

[0253] Individuals may require one or more applications of the adhesive composition to fully repair bone defects. Furthermore, the application site may be weakened due to the condition, allowing additives to be used in the adhesive composition to enhance its functional properties. Exemplary additives include pharmaceuticals, antimicrobial agents, flavoring agents, etc.

[0254] Example 6: Bone void filler (jawbone) – alveolar ridge preservation in the maxilla – bone regeneration at t=3 weeks (canines)

[0255] Composition A, as outlined in Table 1, was implanted into the alveolar bone of a freshly extracted tooth as a ridge-retaining graft in the canine maxilla. No dental membrane was used for repair to prevent microbial invasion, composition migration, or fibrous tissue invasion, and no sutures were employed to close the wound; i.e., secondary healing continued via composition A. Figure 23A and Figure 23B Description of the graft (decalcified segment, hematoxylin and eosin (H&E)) at t=3 weeks postoperatively. As shown, it is filled with living osteocytes and osteoblasts, and new bone surrounds composition A (TA). Figure 23A This indicates the presence of the graft site, tooth root (R), new woven bone (NWB), absence of excessive acute inflammatory cells, or soft tissue inward growth. Figure 23B This is a high-magnification image of the framed area. Note the presence of osteocytes (black arrows) in the lacunae of the pre-existing alveolar bone (AB); the presence of osteoblasts (blue arrows) and osteoid is direct evidence of new bone juxtaposition. As shown, the adhesive composition (composition A) does not migrate from the graft site and acts as a barrier against the invasion of microorganisms that could cause infection, and prevents fibrous tissue from invading the graft site.

[0256] Example 7: Bone Void Filler (Jawbone) -- Alveolar Ridge Preservation in the Mandible -- Bone Regeneration at t=21 Weeks (Canines)

[0257] Composition C, as outlined in Table 1, was implanted into the alveolar bone of a freshly extracted tooth as a ridge-retaining graft in the canine mandible. No dental membrane was used for repair to prevent microbial invasion, composition migration, or fibrous tissue invasion, and no sutures were employed to close the wound; i.e., secondary healing continued via composition C. Figures 24A to 24C Explanation of graft at t=21 weeks post-surgery (ground section, H&E). Low-power image of embedded deposits in composition C ( Figure 24A The image shows the old cortical lamellar bone (lb), mucosa (mu), and newly laid bone (nb). Figure 24B The frame details are shown at a higher magnification. The new bone is a mixture of woven and lamellar bone at this point, revealing a low bone deposition rate. The highest magnification image (24C) shows... Figure 24BDetails of the framed segment. Note the presence of residual particulate material of composition C (white arrow) within the bone tissue, indicating that this composition enables bone regeneration when the material as a whole is reabsorbed at t=21 weeks. As shown, the adhesive composition does not migrate from the transplant site and acts as a barrier against the invasion of microorganisms that may cause infection, and prevents fibrous tissue from entering the transplant site.

[0258] Example 8: Bone void filling and implant stabilization (jawbone) – Alveolar ridge preservation and implant fixation in the mandible – Bone regeneration after t=8 weeks (canines)

[0259] Composition F, as outlined in Table 1, was implanted into the freshly extracted alveoli of premolars P2 and P3 in the canine mandible. Composition F was implanted adhesively as an internal graft for ridge retention in the distal alveolar region of premolar P3. Composition F was also adhesively coated to provide initial fixation of the implant following osteotomy of the centric alveolar region at P2 and P3, creating an oversized defect relative to the implant. Artificial models of the implant were constructed to demonstrate the use of the adhesive composition for stabilizing the implant. After the composition hardened, healing screws were attached to the implant. No dental ligament was used for repair to prevent microbial invasion, composition migration, or fibrous tissue invasion, and no sutures were used to close the wound; secondary healing continued via composition F.

[0260] use Figures 25A to 25F Cone-beam computed tomography (CBCT) and clinical examinations depicted in the images were used to assess implantation site healing at t=8 weeks post-surgery. The top row of images illustrates the following CBCT findings: a) the deposition composition F as a ridge-retaining site for the implanted graft in site P3; and b) the deposition composition F as a site for stabilizing the implant in ultra-large osteotomies at sites P2 and P3. The bottom row of images shows the clinical findings at the same time points. It should be noted that the healthy appearance of the tissue with a persistently low level of inflammation surrounding the deposited composition was present upon removal of the healing screw. The adhesive composition did not migrate from the graft site and acted as a barrier against the invasion of potentially infectious microorganisms and fibrous tissue into the graft site. Note that the unfilled extraction alveolar bone serves as a control site (c).

[0261] The stability of implanted teeth bonded to the P3 and P4 osteotomy sites using composition F was assessed weekly using the Osstell instrument at t=10 weeks. Figure 26The average readings for each implant shown were taken from the buccal, centric, and lingual sides. The stability of the implants adhered to Composition F indicates that the implants are stable, as the average ISQ value was above 65 at each assessment time point, with ISQ values ​​above 50 being clinically significant to indicate that the implants are stable enough to account for loads.

[0262] Example 9: Implant Stabilization (Jawbone) -- Alveolar Ridge Implant Fixation in the Mandible -- Bone Regeneration at t=9 Weeks (Canines)

[0263] Composition C, as outlined in Table 1, was adhesively applied to provide initial fixation of the implant following tooth extraction and centric alveolar osteotomy at the P2 site of the canine mandible, to create an oversized defect relative to the implant, and an artificial model of the implant was constructed to demonstrate the use of the adhesive composition for stabilizing the implant. Once composition C hardened, a transmucosal support and crown were attached to the implant during the same surgical visit. No ligament was used for repair to prevent microbial invasion, composition migration, or fibrous tissue invasion, and no sutures were used to close the wound; i.e., secondary healing continued with composition F. At t=45 days post-operation, after loading with the implant and adhesive composition, the dogs transitioned from a soft to a hard diet. Histological examination (ground sections, H&E) of the implant and composition C used for attaching the implant to the oversized osteotomy site in the canine mandible at t=9 weeks post-operation produced in… Figures 27A to 27B The photomicrograph shown. Two views presenting the field of view: bright field (…). Figure 27A ) and UV fluorescence ( Figure 27B Tetracycline IV was administered 3 days prior to euthanasia (t=). The images show concentrated new bone juxtaposition (nb) on the surface of composition C (TN) and the primary bone spur (B). The newly laid bone fluoresces as brightly as in the image on the right. Note the adjacent tooth roots (R) lacking fluorescent dye uptake and the mononuclear phagocytes removing TN material. It should also be noted that the implanted tooth (IM) under the TN is more clearly visible in the UV fluorescence image. As shown, the adhesive composition does not migrate from the graft site and acts as a barrier against the invasion of microorganisms that may cause infection and prevents fibrous tissue from invading the graft site. This study demonstrates that adhesive compositions (such as those described herein) can be applied to stabilize implanted teeth that fully revert to alveolar sites with insufficient bone volume and withstand postoperative loading.

[0264] Example 10: External graft (jawbone) – alveolar ridge expansion – bone volume expansion and maintenance after t=10 weeks (canines)

[0265] Composition F, as outlined in Table 1, is applied as an external deposit to the buccal surface of the alveolar bone near the maxillary canines in hounds via subperiosteal injection to promote ridge expansion and increase bone volume. No dental membrane or fixation is used to repair or stabilize the composition. Animals are monitored weekly by cone-beam computed tomography (CBCT) and clinical examination. Figures 28A to 28G The results of the investigation, including radiographic examinations at 10 weeks post-operation, are shown. The images are coronal CBCT images. This study demonstrates the ability of the adhesive composition (e.g., the adhesive composition described herein) to adhere to the cortical surface of the chin without being assessed as mobile by palpation during weekly clinical examinations, while maintaining the expanded volume and being replaced by bone without the use of a ligament or fixation. The adhesive composition acts as a barrier against the invasion of microorganisms that could lead to infection and prevents fibrous tissue from invading the graft site. Note the remodeling of the graft mass accompanied by its decalcification.

[0266] Example 11: External graft (jawbone) -- alveolar ridge expansion -- bone volume expansion at t=9 weeks (canines)

[0267] Composition C, as outlined in Table 1, is applied as an external deposit to the buccal surface of the alveolar bone near the maxillary canines via subperiosteal injection to promote ridge expansion and increase bone volume. No dental membrane or fixation is used to repair or stabilize the composition. Animals are monitored weekly via CBCT and clinical examination. Figures 29A to 29C The results of clinical and radiographic examinations at t=9 weeks post-surgery are presented. Figure 29A Clinical photographs of the area of ​​interest. Figure 29B The image shows overlapping 3D CT reconstructions before and at t=9 weeks postoperatively, bone mineral density filtering of the adhesive composition deposits, and the surrounding environment. Figure 29C Cone-beam computed tomography (CBCT) images of the parapalatal plane segment traversing the transplant area (TN) of composition C. Note the cross-section of the canine root (C) overlying the continuous volume of the graft deposit in the cheekbone. This study demonstrates the ability of the adhesive composition (e.g., the adhesive composition described herein) to adhere to the cortical surface of the chin without being assessed as mobile by palpation during clinical examination, while maintaining the expanded volume and allowing for bone replacement without the use of a ligament or fixation. The adhesive composition acts as a barrier against the invasion of microorganisms that could lead to infection and prevents fibrous tissue from entering the transplant site.

[0268] Example 12: Adhesive bridging – Posterolateral fusion of the lumbar spine without instruments at t=3 weeks (rabbit)

[0269] Composition G was used to perform two types of spinal fixation without instruments using a load-bearing model of New Zealand white rabbits, similar to the Boden study (Boden, SD et al., *Spine* (1995) 20:412-420). Composition G was injected bilaterally at the L5 / L6 vertebral segments between the transverse processes, followed by injection along the interarticular portion, allowing the composition to solidify, thereby forming a solid-phase bridging. At t=3 weeks (n=1), t=6 weeks (n=2), and t=10 weeks (n=2) postoperatively, these vertebral segments bridged by composition G were detached and withdrawn for use as follows: Figure 30 The in vitro tests shown are used to assess fixation tensile strength. Adjacent non-fused joints (L4 / L5) are tested to provide an internal control. Graphs of these results are shown in [the diagram / image / etc.]. Figure 31 In the study, at t=3 weeks, t=6 weeks, and t=10 weeks, the spine treated with composition G showed a significant increase in relative load-bearing strength compared to controls of 3.25x, 3.59x, and 3.65x, respectively, indicating the load-bearing capacity of the adhesive composition to maintain spinal fixation without the use of instruments.

[0270] In addition, CBCT scans were performed post-surgery and on a weekly schedule until each rabbit was euthanized in this study. A collection of examples of CBCT images acquired from rabbits euthanized at t=3 weeks is shown below. Figures 32A to 32C middle. Figure 32A Showing the spine after surgery, Figure 32B The spine is shown at t=3 weeks postoperatively, and Figure 32C A 3D rendering of the spine is shown at t=3 weeks post-surgery. The CBCT images show that the adhesive composition does not migrate from the transplant site, achieving spinal fixation and maintaining stability without breaking over time.

[0271] Equivalent content

[0272] Every patent, patent application, and disclosure cited herein is hereby incorporated in its entirety. While this disclosure has been described with reference to specific aspects, it will be apparent to those skilled in the art that other aspects and variations may be devised without departing from the true spirit and scope of this disclosure. The appended claims are intended to be construed as encompassing all such aspects and equivalent variations. Any patent, publication, or other disclosure material claimed to be incorporated herein by reference, in whole or in part, is incorporated only to the extent that the incorporated material does not conflict with the existing definitions, statements, or other disclosures set forth in this disclosure. Therefore, and where necessary, the disclosure expressly set forth herein supersedes any conflicting material incorporated herein by reference.

[0273] While the present disclosure has been specifically shown and described with reference to preferred embodiments thereof, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the disclosure as covered by the appended claims.

Claims

1. A method for increasing bone volume, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition to the tooth extraction socket; The composition is cured and / or hardened in less than about 30 minutes.

2. A method for filling bone voids resulting from the removal of bone cysts, granulomas, abscesses, or similar bone defects, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition to the bone cavity; The composition is cured and / or hardened in less than about 30 minutes.

3. A method for increasing bone volume, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition to a substantially flat or convex surface of the bone to build volume; The composition is cured and / or hardened in less than about 30 minutes.

4. A method for joining two or more bones, bone plates, or bone segments using load-bearing capacity, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition to the bony surface to be joined (e.g., adjacent bone, bone plate, or bone segment) in an amount sufficient to make the adhesive composition continuous throughout; The composition is cured and / or hardened in less than about 30 minutes.

5. The method of claim 4, wherein the gaps between the bones, bone fragments or bone segments can be caused by congenital defects (e.g., cleft palate), trauma (e.g., jawbone or other fractures), disease (e.g., osteosarcoma), or by bone removal (e.g., due to removal of sarcomas or sequestra), or by surgical treatment (e.g., orthognathic surgery or correction of long bone deformities), or by the loss of small segments that have lost their mechanical integrity.

6. A method for repairing defects in bone, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Applying the composition to or onto the bone defect; The composition is cured and / or hardened in less than about 30 minutes.

7. A method for repairing gaps or spaces between joint bone surfaces (e.g., intervertebral joints) by utilizing the ability to bear loads and prevent relative movement, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition to the gap or space to be joined in an amount sufficient to make the adhesive composition continuous throughout; The composition is cured and / or hardened in less than about 30 minutes.

8. A method for bridging the gaps between bone surfaces (e.g., between vertebral bodies, between transverse processes, or between spinous processes) by utilizing the ability to bear loads and / or prevent relative movement, the method comprising: a) Prepare an adhesive composition comprising a multivalent metal salt and a small amount of organophosphate compound; and b) Apply the composition in an amount sufficient to make the adhesive composition continuous throughout to bridge the gaps or spaces to be joined; The composition is cured and / or hardened in less than about 30 minutes.

9. The method according to any one of claims 1 to 8, wherein the bone comprises cortical bone or cancellous bone.

10. The method according to any one of claims 1 to 8, wherein the bone comprises teeth.

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