Abstract:
There is disclosed a composition formed by a reaction of at least one component A and at least one component B, wherein component A is selected from among a compound comprising having at least two thiol-groups and a disulfide derivative of a compound having at least two thiol groups, and wherein component B is a compound having at least two vinyl reactive groups, for the manufacture of an implant for the treatment of a bone fracture. Advantages include that the adhesive patch formed by the composition will be solid in body fluid upon curing and will exhibit excellent mechanical strength. Advantages include that the composition is biocompatible, the material can be applied in small and inaccessible areas, the process requires less surgeon training, it solves drawback with open surgery, and it is possible to use cost effective materials and methods in the process.

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to compositions and their use for the treatment and stabilisation of bone fractures. The invention further relates to a method of treating and stabilizing bone fractures. 
       BACKGROUND 
       [0002]    Orthopaedic healthcare costs are increasing worldwide. With a growing elderly population and an increasing demand for advanced healthcare globally, new efficient treatments are needed. Bone fractures are often stabilized using conventional screws and plates such as described in Miller D, L Goswami T in  Clinical Biomechanics  2007; 22:1049-1062. 
         [0003]    However, these implants pose a number of drawbacks due to their inflexible forms. Insertion of screws and plates requires open surgery, thus limiting the accessibility to proximate fractures. For fractures that cannot be reached during open surgery, stabilization with screws and plates cannot be performed. An important drawback is also that plates demand drilling and screws to be fixated. Since it may be unsuitable to screw into thin and sensitive bone structures, for example found in cervical spine-, cranio-maxillofacial- and hand-surgery, it may be difficult to place plate implants in-vivo. It is also not always possible to fit a small number of predefined plates on a large number of different fractures. For those fractures located in the cervical spine that cannot be treated with conventional implants, a Halo vest is often used such as described in (Vieweg U, Schulteiss R in  Archives of Orthopaedic and trauma surgery  2001; 121:50-55). Although conventional methods are effective, problems with small fracture areas, dislocations and patient discomfort are still persistent. 
         [0004]    For compression fractures on vertebral bodies, vertebroplasty or kyphoplasty is often used. By inflating the vertebrae with bone filler, e.g. bone cement or a balloon, the fracture is stabilized. The technique is widely used and can be performed with minimally invasive surgery. The need for minimally invasive surgery for vertebral fractures is constantly increasing as they can curb complications such as excessive blood loss, extended recovery period and post-operative trauma caused by conventional screw and plate methods. 
         [0005]    Bone fillers have been developed and manufactured by a number of companies, among them Doxa AB and Bone Support AB, both of Sweden. Contrary to positive reports regarding their mechanical stability and flexibility, concerns about infection or cement leakage into the spinal canal or into the perivertebral venous system have surfaced (M. E. Jensen, A. J. Evans, J. M. Mathis, D. F. Kallmes, H. J. Cloft and J. E. Dion in  Am. J. Neuroradiol.  18 (1997), pp. 1897-1904). Furthermore, grave complications, such as fatal pulmonary failure in the immediate postoperative period, have been reported on. They were commonly due to thrombotic tissue embolism while embolism caused by the cement itself remained asymptomatic (F. Monticelli, H. J. Meyer, E. Tutsch-Bauer in  Forensic Science International, Vol  149, 1, (2005) pp 35-38). Reports have also suggested adjacent vertebra fracture caused by imbalance of load distribution after vertebroplasty procedures. 
         [0006]    In dental applications various glues have been used as fissure sealants, tissue adhesives, dentine seals and as denture reparative agents(Peter A. LEGGAT, Ureporn KEDJARUNE and Derek Richard SMITH Industrial Health 2004, 42, 207-211). For these purposes, traditionally, acrylic adhesives have been used with acceptable strength for its purpose but with regular reports on toxic response both on cell culture and in-vivo studies. Many experimental adhesives found in literature either possess good biocompatibility or good strength. (Ciapetti G, Stea S, Cenni E, Sudanese A, Marraro D, Toni A, Pizzoferrato A Biomaterials. 1994 January; 15(1):63-7). 
         [0007]    Other commercially available adhesives/fillers for similar bone fracture problems have been described such as chronOS® for Spine fractures by Synthes North America. ChronOS® is a non synthetic, biocompatible bone void filler, and is ideal for many bone void filler applications. The material is a radiopaque β-tricalcium phosphate which contains two of the main mineral constituents of bone, calcium and phosphorus. ChronOS® is resorbed and replaced by bone in 6-18 months during the healing process. 
         [0008]    Cryolife&#39;s BioGlue® is a surgical adhesive and is composed of purified bovine serum albumin (BSA) and glutaraldehyde. The two glue components are dispensed by a controlled delivery system comprising a double-chambered syringe, applicator tips, and optional extender applicator tips. Once dispensed, the adhesive components are mixed within the applicator tip where the cross-linking begins. 
         [0009]    Glutaraldehyde molecules bond with the BSA molecules and, upon application to the tissue proteins at the repair site, create a flexible mechanical seal. It begins to polymerize within 20 to 30 seconds and reaches its bonding strength within two minutes. It also adheres to synthetic graft materials through mechanical bonding within the interstices of the graft material. 
         [0010]    Cohera Medical is developing a small bone adhesive that chemically bonds with adjacent bone and resorbs in a timely fashion to allow normal bone healing. Testing of the strength of glued lap joints in porcine bones revealed that the adhesive under development exhibits significant strength and adherence to bone, suggesting that it could be quite useful for fixation of small bones where mechanical fixation is problematic or impossible. 
         [0011]    Maurer P, Bekes K, Gernhardt C R, Schaller H-G, Schubert J in  International Journal of Oral  &amp;  Maxillofacial Surgery  2004; 33:377-381 Compares a number of dental adhesives to cortical bone with various results. 
         [0012]    Szep S, Kunkel A, Ronge K, Heidemann D in Journal od  Biomedical Materials Research: Applied Materials  2002: 53-60 finds a high rate of cell apoptosis in a number of dental adhesives. 
         [0013]    Previous studies have showed that reinforcing adhesives with fibres increases mechanical strength on bonded bone fractures. They have shown better fracture stability when compared to using only conventional biomaterial adhesive fillers. 
         [0014]    Nordberg A, von Holst H, Brolin K, Beckman A in  Bio - Medical Materials and Engineering  2007; 17(5):299-308 discloses fibre reinforced adhesives for fixating vertebral fractures. 
         [0015]    PCT publication “WO 03/080144 A1” describes a polymeric cement for augmentation of bone fractures. The cement is either applied in a fracture or as filler, in e.g. in a vertebra. However, this method is limited to fractures with even/smooth surfaces, or to voids, such as an osteoporotic vertebra. 
         [0016]    PCT publication “WO 2005/027988 A2” describes a calcium salt composition alternatively demineralised bone reinforced with discrete fibres as a bone cement. Although this innovation increases the mechanical properties of calcium salt cements the method is limited to be used as filler of voids e.g. osteoporotic vertebrae and mainly for compressive loads. 
         [0017]    PCT publication WO 2009/029734 A2 describes a polymeric bone cement with a several alternative compositions including thiol-ene chemistry. The invention includes a filler that can be chosen to promote bone formation. However, regardless of composition the bone cement and its related method of application is limited to be injected in bone voids e.g. vertebrae and dental applications. 
         [0018]    Problems with the presently available adhesives include too low strength, too low adhesion and too high toxicity. It would be thus desirable to use a biocompatible and mechanical robust adhesive when stabilizing bone fractures. Since adhesives do not demand drilling and can be distributed via minimally invasive surgery it also possesses long term advantages. It is also possible with adhesive fixation to use degradable substances that are naturally resorbed during the natural bone healing process. 
       SUMMARY 
       [0019]    It is an object of the present invention to obviate at least some of the disadvantages in the prior art and provide a composition, use of the composition, a method, an implant and a kit for the treatment of a bone fracture. 
         [0020]    In a first aspect there is provided a composition formed by a reaction of at least one component A and at least one component B, wherein component A is selected from the group consisting of a compound comprising at least two thiol-groups and a disulfide derivative of a compound comprising at least two thiol groups, and wherein component B is a compound comprising at least two vinyl groups,for the manufacture of an implant for the treatment of a bone fracture. 
         [0021]    In a second aspect there is provided use of the composition for the manufacture of an implant for the treatment of at least one selected from a bone fracture and a bone cavity. 
         [0022]    In a third aspect there is provided a method of treating at least one selected from a bone fracture and a bone cavity, said method comprising the steps applying the composition at the site of the fracture in the body. 
         [0023]    In a fourth aspect there is provided an implant comprising a fibre and the composition as described above for the treatment of a bone fracture. 
         [0024]    In a fifth aspect there is provided a kit for the treatment of at least one selected from a bone fracture and a bone cavity, said kit comprising the composition above and a primer. 
         [0025]    Further aspects and embodiments are defined in the appended claims, which are specifically incorporated herein by reference. 
         [0026]    Advantages include that the adhesive patch formed by the composition will be solid in body fluid upon curing and will exhibit excellent mechanical strength. 
         [0027]    Another advantage is that the material can be applied in small and inaccessible areas. It is an advantage that minimal invasive surgery can be used. 
         [0028]    Yet another advantage is that the process is comparable to the application of regular bone fillers and thus requires less surgeon retraining. 
         [0029]    Since there is provided the possibility of a minimal invasive surgical procedure, it will further solve drawbacks with open surgery involving drilling and screwing. This would reduce operational time, post operational trauma and recovery and hospitalization costs. 
         [0030]    Yet another advantage is that it is possible to use cost effective materials and methods in the process. 
         [0031]    Further objects and advantages of the invention will be apparent from the figures and descriptions that follow. 
       DETAILED DESCRIPTION 
       [0032]    Before the invention is disclosed and described in detail, it is to be understood that this invention is not limited to particular compounds, configurations, method steps, substrates, and materials disclosed herein as such compounds, configurations, method steps, substrates, and materials may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention is limited only by the appended claims and equivalents thereof. 
         [0033]    It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. 
         [0034]    If nothing else is defined, any terms and scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. 
         [0035]    The term “about” as used in connection with a numerical value throughout the description and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. Said interval is ±10%. 
         [0036]    “Compacted fracture” is used herein to denote a fracture caused when bone fragments are driven into each other. 
         [0037]    “Complete fracture” is used herein to denote a fracture in which bone fragments separate completely. 
         [0038]    “Compression fracture” is used herein to denote a fracture in which bone is compressed. 
         [0039]    “Fibre” is used herein to denote a class of material which comprises continuous filaments and/or discrete elongated pieces. 
         [0040]    “Incomplete fracture” is used herein to denote a fracture in which the bone fragments are still partially joined. 
         [0041]    “Linear fracture” is used herein to denote a fracture that is parallel to the bone&#39;s long axis. 
         [0042]    “Oblique fracture” is used herein to denote a fracture that is diagonal to a bone&#39;s long axis. 
         [0043]    “Spiral fracture” is used herein to denote a fracture where at least one part of the bone has been twisted. 
         [0044]    “Transverse fracture” is used herein to denote a fracture that is at a right angle to the bone&#39;s long axis. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0045]    The invention is described in greater detail with reference to the drawings in which: 
           [0046]      FIG. 1A  and  FIG. 1B  show alternative embodiments of component A. 
           [0047]      FIG. 2A  and  FIG. 2B  show alternative embodiments of component B. 
           [0048]      FIG. 3A  and  FIG. 3B  show alternative embodiments of a primer. 
           [0049]      FIG. 4  shows an exploded view of a bone fracture which is repaired according to the present invention. 
           [0050]      FIG. 5A  and  FIG. 5B  show NMR characterization of the compounds poly(maleic anhydride alt methyl vinyl ether)and allyl functionalized hydrophilic poly(maleic anhydride alt methyl vinyl ether), respectively. 
           [0051]      FIG. 6A  and  FIG. 6B  show Raman spectroscopy of component A, tris[2-mercaptopropionyloxy)ethyl]isocyanurate, component B, 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione and cured composition from component A and component B, respectively. 
           [0052]      FIG. 7  shows the cytotoxicity of bone adhesives and primers. 
           [0053]      FIG. 8  shows shear strength of adhesives. 
       
    
    
       [0054]    There is provided a composition formed by a reaction of at least one component A and at least one component B, wherein component A is selected from the group consisting of a compound comprising at least two thiol-groups and a disulfide derivative of a compound comprising at least two thiol groups, and wherein component B is a compound comprising at least two vinyl groups, for the manufacture of an implant for the treatment of a bone fracture. 
         [0055]    Component A and B can be used in varying molar ratios for optimization purposes, such as adhesion, mechanical strength and crosslinking efficiency. A skilled person can in the light of this description perform routine experiments to optimize the ratio of A and B to obtain the properties. Preferably the ratio of A and B are optimised starting with an equimolar ratio with respect to functionality. 
         [0056]    The composition becomes cross-linked after curing. The composition is cured via various methods. These methods include but are not limited to, spontaneous curing, heat induced curing and ultra-violet light induced curing. 
         [0057]    Any number of different components A and components B can be used together, such as A1+A2+A3+B1+B2, to form the composition. 
         [0058]    In one embodiment component A and component B are mixed without the addition of any solvents. In an alternative embodiment component A and component B are mixed with at least one solvent. Examples of solvents include but are not limited to water and ethanol. 
         [0059]    In one embodiment the compound in component A further comprises at least one group selected from the group consisting of a hydroxyl group, a carboxyl group, a dopamine group, and a phenol group. 
         [0060]    In one embodiment the component A is a polymer. In such cases the polymer molecular weight is from 1 to 100 kDa. In case of a polymer the substitution degree of thiol groups or disulfide groups on the polymer is from 1% to 100% of all possible substitution sites. 
         [0061]    Component A is described further with reference to  FIG. 1A  showing an embodiment of component A with two thiol groups R1 and one other substituent R2, wherein R2 is selected from the group consisting of a hydroxyl, a carboxyl, a dopamine and a phenol group. In an alternative embodiment illustrated in  FIG. 1B  component A is a polymer with several thiol groups and/or disulfide groups R1, and optionally at least one group R2 which is selected from the group consisting of a hydroxyl, a carboxyl, a dopamine and a phenol group. 
         [0062]    In one embodiment component A is selected from Pentaerythritol tetrakis(3-mercaptopropionate), trimethylolpropane tris(3-mercaptopropionate), tris[2-mercaptopropionyloxy)ethyl]isocyanurate, Mercaptopropyl methylsiloxane-dimethylsiloxane copolymer, poly(mercaptopropyl)methylsiloxane, 2,2′-(Ethylenedioxy)diethanethiol, Ditiotreitol, tetraethyleneglycol-bis(3-mercaptopropionate), Ethyleneglycol-bis(3-mercaptopropionate), trimethylolpropane diallylether, Dipentaerytritolhexakis(3-merkaptopropionate), tetradecane-1,14-dithiol, (+/−)-trans-1,2-bis(2-mercaptoacetamido)cyclohexane, (E)-S,S′-bis(10-mercaptodecyl)-4,4′-(diazene-1,2-diyl)bis(4-cyanopentanethioate), bis(2-mercaptoethyl)sulfone, 2,5-dimercaptomethyl-1,4-dithiane, 1,4-butanediol-bis(3-mercaptopropionate), 1,16-hexadecanedithiol, undecane-1,11-dithiol, heptane-1,7-dithiol, 1,12-dimercaptododecane, octadecane-1,18-dithiol, (5-mercaptomethyl-2,4-dimethyl-phenyl)-methanethiol, (3-mercaptomethyl-5-methyl-phenyl)-methanethiol, 1,2-benzenedimethanethiol, (4R,5R)-4,5-bis(mercaptomethyl)-2,2-dimethyl-1,3-dioxolane, 3-bis(2-mercaptoethylthio)propane, ethanethiol, aceticacid-mercapto-1,2,6-hexanetriyl ester, L-1,4-dithiothretol, glycerylthioglycolate, 3,6-dioxa-1,8-octanedithiol, trimethylolpropane-tris(mercaptoacetate), 2,3-butanediol-1,4-dimercapto-pentaerythritol-tetrakis(3-mercaptopropionate), ethanethiol-2,2′,2″-nitrilotris, 2,2′-thiodiethanethiol, 1,9-nonanedithiol, 2,2′-oxydiethanethiol, and 10-decanedithiol. 
         [0063]    In another embodiment component A is synthesized from compounds, including linear and dendritic polymers, with a minimum functionality of two or more. Such as compounds include but are not limited to compounds with reactive groups of isocyanates, alcohols, amines, epoxides, methacrylates, acrylates, carboxylic acids, anhydrides, and allyls. 
         [0064]    In another embodiment, component A is obtained by reacting hydrophilic linear polymers, such as PVAl, PHEMA, dendritic materials and maleic anhydride substituted polymers with thiol-groups, or a disulfide derivative thereof, components to give thiol substituted polymers. 
         [0065]    In one embodiment component A is selected from the group consisting of
       poly(maleic anhydride-methyl vinyl ether) substituted with 50% cysteamin,   tris(2-mercaptopropionlyloxy)ethyl isocyanurate, and   tetraethyleneglycol bis (3-mercaptopropionate).       
 
         [0069]    Component B is described referring to  FIG. 2B  which shows an embodiment where component B is a molecule comprising two vinylic functional groups R3 and one group R4 selected from a hydroxyl, a carboxyl, a dopamine, and a phenol group. In an alternative embodiment depicted in  FIG. 2B  component B is a polymer comprising at least two vinylic functional groups R3 and optionally at least one group R4 selected from a hydroxyl, a carboxyl, a dopamine, and a phenol group. 
         [0070]    In one embodiment component B is a triazine. 
         [0071]    In one embodiment component B comprises vinyl reactive groups selected from vinyl, acrylates, methacrylates, allyls and unstaturated cyclic vinyls including norbornenes and N-maleinimides. 
         [0072]    In yet one embodiment component B is selected from the group consisting of trimethylolpropane diallyl ether, 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione, trimethylolpropane diallyl ether, poly(ethylene glycol)diacrylate, poly(ethylene glycol)dimethacrylate and poly(ethylene glycol)dimaleinimide. 
         [0073]    In another embodiment component B is synthesized from compounds, with a minimum functionality of two or more, such as compounds with reactive groups of isocyanates, alcohols, amines, epoxides, carboxylic acids and anhydrides. 
         [0074]    In another embodiment other linear or dendritic polymers are used for functionalization with vinyl-groups of component B. Examples include but are not limited to polycaprolactone with di-, tri, and tetra hydroxyl functionality and 2,2-bis(hydroxymethyl)propanoic acid based dendritic materials. 
         [0075]    In yet one embodiment, component B is obtained by reacting hydrophilic linear polymers, examples include but are not limited to PVAl, PHEMA, dendritic materials and maleic anhydride substituted polymers with vinyl components to give vinyl substituted polymers including acrylate, methacrylate, allyl and maleinimide functionalities. The obtained component B based on polyfunctional polymer is defined between 1-100 kDa. The substitution degree is 1-100% of available functionality. Obtained linear polymers include poly (PVAl-co-Allyl)Alyllic functionalized, poly (PVAl-co-acrylate) Acrylic functionalized, poly (PVAl-co-methacrylate) Methacrylic functionalized, poly (PVAl-co-4-Maleimidobutyric) Maleinimido functionalized, poly (HEMA-co-Allyl) Allyl functionalized and poly (HEMA-co-Maleimido) Maleimido functionalized. 
         [0076]    In one embodiment component B is selected from the group consisting of
       1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione,   tetra(ethylene glycol)diacrylate,   poly(maleic anhydride-methyl vinyl ether) substituted with 10% 2-allyloxy ethanol, and   poly(maleic anhydride-methyl vinyl ether) substituted with 50% 2-allyloxy ethanol.       
 
         [0081]    In another embodiment the side group R3 in  FIGS. 2A and 2B  is a vinyl substituent including, acrylates, methaacrylate, vinyl, allyl, unsaturated cyclic compounds, N-substituted maleimide and combinations thereof. 
         [0082]    In another embodiment the side group R4 in  FIGS. 2A and 2B  is selected from aliphatic hydroxyl, aliphatic carboxyl and aromatic hydroxyl substituents including dopamine and p-hydroxy derivatives. 
         [0083]    If the component B is based on a polymer the molecular weight is from 1 k to 100 kDa. The substitution degree ranges between 1-100% of available functionality. 
         [0084]    In one embodiment the composition further comprises fibres. Fibres are added to the composition to enhance the mechanical properties. The composition including fibres forms a fibre-reinforced adhesive patch. 
         [0085]      FIG. 4  shows an exploded view of one embodiment with fibres in the shape of a mesh  1 , surrounded on both sides by the composition  2 , and applied to a fracture  3 . A primer  4  is applied to the bone. 
         [0086]    In one embodiment the fibre is a commercially available fibre, examples include but are not limited to E-glass-, S-glass-, Carbon-, UHMWPE-, Cellulose based-, collagen-, and polypropylene fibres. 
         [0087]    In another embodiment the fibres comprise wood derived cellulose or bacterial cellulose. 
         [0088]    In another embodiment the fibre is formed as uni-directional-, random-oriented-, 90/0 degree woven-, 45/45 degree woven-fibres. Preferably the fibres are chosen to be compliable/thin enough to follow the topology of the substrate. Number of fibres are chosen according to fracture load and surgical circumstances. 
         [0089]    In yet one embodiment the fibre is used neat or grafted with at least one vinylic group, examples include but are not limited to acrylates, methacryaltes, allyls and unsaturated cyclic substituents including norbornenes and N-maleinimides. 
         [0090]    There is further provided use of the composition for the manufacture of an implant for the treatment of at least one selected from a bone fracture and a bone cavity. 
         [0091]    Many different types of bone fractures can be cured using the present invention. In one embodiment the bone fracture to be cured is a bone fracture selected from the group consisting of a compression fracture, a complete fracture, an incomplete fracture, a linear fracture, a transverse fracture, an oblique fracture, a spiral fracture, and a compacted fracture. 
         [0092]    There is provided a method of treating a bone fracture comprising the steps applying the composition described above at the site of the fracture in the body. 
         [0093]    The compositions according to the present invention are used for the treatment of a bone fracture of type I-III as detailed below. 
         [0094]    Type I—Bone Fractures 
         [0095]    The stabilization of bone defects with the present crosslinked system through minimal invasive treatments. The cross linked system gives support to the defected bones, acting as artificial compact bones, and allowing for bone regeneration and degradation within a set timeframe. Fractures of the vertebrate bone systems are examples of Type I treatment. 
         [0096]    In one preferred embodiment the compositions according to the present invention are used together with a fibre reinforcement, examples include but are not limited to polymethylmethacrylate mesh, polypropylene mesh, fibre mesh, carbon fibre, glass fibre, biological fibres including cellulose fibres and collagen fibres. Plastic meshes examples include but are not limited to polypropylene, ethylene tetrafluoroethylene and polymethamethacylate have been used in vascular, cardiac tissue repair and cranioplasty. These meshes have been available for conventional surgical procedures. 
         [0097]    In one embodiment fibres impregnated with the composition are applied to the fracture. This pre-impregnation of the reinforcement fibre makes the handling and application easier. A pre-impregnated fibre is abbreviated a prepreg fibre. 
         [0098]    When using the compositions according to the present invention, a reinforcement fibre and the composition are applied to the bone where it is desired to stabilize a fracture. The composition comprising component A and B is applied, where after the composition is cured. In one embodiment, during UV curing, accelerators such as photoactivators are added. It is assumed that these additives shorten the time frame needed for the fibre reinforced patch adhesive to cure. 
         [0099]    In one embodiment a pre-impregnated reinforcement fibre, is applied through an in-vivo delivery device such as a surgical endoscope, insertable catheter or a novel applicator device as is presently available (Method and apparatus for preparing a self-curing two component powder/liquid cement, U.S. Pat. No. 4,808,184). 
         [0100]    In another embodiment, component A and B premix is injected and cured in-vivo followed by the addition of impregnated fibre mesh using the above said insertable devices. 
         [0101]    In yet another embodiment, component A and B premix is injected and impregnated with fibre mesh followed by curing, upon which each step is repeated to form multiple fibre reinforced adhesive layers. 
         [0102]    In one embodiment the crosslinked system, the cured composition, according to the present invention and/or the reinforcement fibre, is resorbed by the body. In this embodiment the fibre composite thus will undergo dissolution over time naturally. In this embodiment the composite will eventually be replaced by growing bone without adverse effects. The patient will recover without an implant in the body after the bone fracture heals. 
         [0103]    Type II—Bone Cavities 
         [0104]    The treatment of large defects of trabecular bone with highly adhesive crosslinked system, mimicking extracellular matrices, and permitting osteoblast stimulation and growth and therefore bone repair. A fracture of collum is an example of Type II treatment. 
         [0105]    For this treatment, the component A and B are pre-mixed in the applicator. The premixed substance is injected into the cavity via the in-vivo applicator. 
         [0106]    In one embodiment the fibres are added with the applicator. 
         [0107]    In one embodiment the impregnated fibres are applied with a device selected from the group consisting of a surgical endoscope, an insertable catheter, and an applicator device. 
         [0108]    In a preferred embodiment, this premix will cure on demand upon injection to form the cured composition and exhibit a porous nature that is bio-resorbable. 
         [0109]    In yet another embodiment, this premix may contain bone growth stimulants such as osteoblasts, bone morphogenic proteins, growth hormones, cell attractants etc. This will encourage bone growth even before complete dissolution of the filler. 
         [0110]    In a preferred embodiment, the filled cavity will be shaped and held in place with the fibre mesh mentioned in previous embodiments, fibre. The fibre mesh will be biocompatible and resorbable. 
         [0111]    Type III—Combined Bone Cavities and Fractures 
         [0112]    The treatment of large bone defects that require both trabecular and compact bone repair. 
         [0113]    The invention is further used in various applications, not limited to bone fracture stabilization. These applications include dental fillings, maxillofacial bone fragment fixation, hip and knee replacement substitutes, small bone fracture repair, veterinary bone adhesives, post osteosarcoma repair, etc. 
         [0114]    In one embodiment the components A and B are applied with an applicator and wherein the components A and B are mixed in the applicator upon injection. 
         [0115]    In one embodiment a primer is applied before the components A and B are applied. The primer act as an adhesion-enhancing component, to increase the adhesion between the surface and the composition. Such a primer, is in one embodiment added to the bone surface followed by a mixture of component A+B, optionally reinforced with fibres. 
         [0116]    The primer is described referring to  FIG. 3A  showing an embodiment where the primer is a molecule comprising one phenolic derivative R5 and one group R6 selected from an acrylate, a methacrylate, an allyl, a vinyl, and an unsaturated cyclic ring including N-maleinimide and norbornene.  FIG. 3B  shows an embodiment where the primer is a polymer comprising at least one group R5, wherein R5 is a phenolic derivative, and at least one group R6 wherein R6 is selected from an acrylate, a methacrylate, an allyl, a vinyl, and an unsaturated cyclic ring including N-maleinimide and norbornene. 
         [0117]    In one embodiment R5 is a phenolic derivative. 
         [0118]    In one embodiment R5 is selected from p-hydroxy phenyl and 3,5-dihydroxyphenyl. 
         [0119]    In one embodiment R5 is selected from 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, and 3,4,5-trihydroxyphenyl. 
         [0120]    In one embodiment the primer is selected from aromatic and phenolic derivatives including 4-Hydroxy-3methoxybenzaldehyde, 3,4-dihydroxyphenethylamine, para ethyl phenol, para vinyl phenol, para methacrylate phenol, Bicyclo[2.2.1]hept-2-enoic acid and poly(2-hydroxy styrene), poly(3-hydroxy styrene), poly(4-hydroxy styrene), poly(2,4-dihydroxy styrene), poly(2,5-dihydroxy styrene), poly(3,4-dihydroxy styrene), poly(3,4,5-trihydroxy styrene) and poly (3,4-dihydroxyphenethyl)acrylamide. 
         [0121]    In yet one embodiment, the primer is synthesized by reacting hydrophilic linear polymers, examples include but are not limited to PVAl, PHEMA, Maleic anhydride substituted polymers with vinyl components to give vinyl substituted polymers including acrylate, methacrylat, allyl, maleinimide and norbornene functionalities. The obtained the primer based on linear polymer is defined between 1 k-100 kDa. The substitution degree is 1-99% of available functionality. Obtained linear polymers include poly (PVAl-co-Allyl)Alyllic functionalized, poly (PVAl-co-acrylate) Acrylic functionalized, poly (PVAl-co-methacrylate) Methacrylic functionalized, poly (PVAl-co-4-Maleimidobutyric) Maleimido functionalized, poly (HEMA-co-Allyl) Allyl functionalized and poly (HEMA-co-Maleinimido) Maleinimido functionalized. 
         [0122]    In another embodiment the side group R5 in  FIGS. 3A and 3B  is an aromatic phenol group. 
         [0123]    In another embodiment the side group R6 is selected from vinyl subtitutens including, acrylates, methaacrylate, allyl, vinyl and unsaturated cyclic compounds including N-substituted maleinimide and combinations thereof. 
         [0124]    In another embodiment the primer is synthesized from commercially available compounds examples include but are not limited to partly thiol or vinyl functionalized poly(para hydroxy styrene). 
         [0125]    In another embodiment the primer is a dendritic polymer structure. 
         [0126]    There is further provided an implant comprising a fibre and the composition as described above for the treatment of at least one selected from a bone fracture and a bone cavity. 
         [0127]    In the following tables there are provided further non limiting examples of compounds which can be used as component A (Table 1), component B (Table 2), and the primer (Table 3). The abbreviations in the following table are used to denote substances used according to the present invention. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                           Compontent A, Abbreviation and name of compound 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
             
               
                 SH4 Pentaerythritol tetrakis (3- mercaptopropionate) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 SH3 trimethylolpropane tris (3- mercaptopropionate) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 SHT3 tris [2- mercaptopropionyloxy) ethyl]isocyanurate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 PDMS-SH (4-6% Mercaptopropyl) methylsiloxane)- dimethylsiloxane copolymer; 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 (PDMS-SH100) poly(mercaptopropyl) methylsiloxane 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2,2′-(Ethylenedioxy) diethanethiol 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ditiotreitol 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 tetraethyleneglycol- bis (3- mercaptopropionate) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ethyleneglycol-bis (3- mercaptopropionate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dipentaerytritolhexakis (3-merkaptopropionate) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (maleic acid- functionalized with Cysteaminee, Mn: 2k- 100k, Substitution degree (0-99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0128]    Table 2 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 component B, Abbreviation and name of compound 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
             
               
                 TMPDE trimethylolpropane diallyl ether 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 1,3,5-triallyl-1,3,5- triazine- 2,4,6(1H,3H,5H)- trione 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 TMPDE-COOH trimethylolpropane diallyl ether 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 diacrylate-3 tetra(ethylene glycol) diacrylate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 diacrylate-7 poly(ethylene glycol) diacrylate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dimethacrylate-PEG 3.4 k poly(ethylene glycol) dimethacrylate Mn: 3400 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Allylfunctional polycaprolactone.  From PCL diol, triol and tetraol Mn: 1000-100000 Da 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (PVAl-co-Allyl) Alyllic functionalized poly (vinyl alcohol): Mn: 1000-500000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (PVAl-co- acrylate) Acrylic functionalized poly (vinyl alcohol): Mn: 1000-500000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (PVAl-co- methacrylate) Methacrylic functionalized poly (vinyl alcohol): Mn: 1000-500000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (PVAl-co-4- Maleimidobutyric) Maleimido functionalized poly (vinyl alcohol): Mn: 1000-500000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (HEMA-co-Allyl) Allyl functionalized poly (HEMA): Mn: 1000-100000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (HEMA-co- Maleimido) Maleimido functionalized poly (HEMA): Mn: 1000-100000 m = (0 to 99%) Substitution degree (SD) n(SD) = (1 to 100%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 tetraallyl PEO 100-1000 k poly (ethylene oxid)- Allyl Mn: 1000-10000 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Diallyl PEO 100-1000 k poly(ethylene oxide)- diallyl Mn: 500-10000 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (Maleic acid alt Methyl Vinyl Ether) functionalized with 2- allyloxyethanol Mn: 2 k-100 k, Substitution degree (0 to 99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (Maleic acid alt Methyl Vinyl Ether) functionalized with allylamine Mn: 2 k- 100 k, Substitution degree (0 to 99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0129]    Table 3 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 The primer, Abbreviation and name of compound 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
             
               
                 poly(para- hydroxy styrene) Mn: 1-50 kDa 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (Para- hydroxy styrene-co- acrylate), acrylic functional- ized poly (p- hydroxy styrene): Mn: 1-50 kDa Substitution degree (SD) = (1 to 99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (Para- hydroxy styrene-co- allyl), allyl functional- ized poly (p- hydroxy styrene): Mn: 1-50 kDa Substitution degree (SD) = (1 to 99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly (Para- hydroxy styrene-co- N- maleinmide), maleinimido functional- ized poly (p-hydroxy styrene): Mn: 1-50 kDa Substitution degree (SD) = (1 to 99%) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 poly Dopamine (poly (3,4- dihydroxy styrene)), Mn: 1-50 kDa 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dopamine 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dopamine meth- acrylamide 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Dopamine allylamide 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0130]    In one embodiment components A and B are premixed and injected/applied to the desirable designation in the body. 
         [0131]    In another embodiment components A and B are injected/applied as separate compounds and mixed at the site in the body 
         [0132]    In another embodiment an applicator is used to inject/apply components A and B. The components will then mix upon in-vivo injection and will be cured on demand at site 
         [0133]    In another embodiment, the applicator will add a primer layer, the primer, followed by the premixture of components A and B. 
         [0134]    In another embodiment, the applicator will add a primer layer, the primer, followed by the premixture of component A and B together with fibres. 
         [0135]    In another embodiment, the applicator will add fibres, separately from the other components. 
         [0136]    In one embodiment the composition comprising components A and B is additionally fixed in the bone by at least one screw. In this way there is provided a further way to fixate the composition in addition to adhesion. Optionally the composition to be fixed with screws comprises fibres. Optionally a primer is used. A skilled person realizes that also well-known alternatives to screws can be used such as but not limited to nails and plates. In one embodiment the composition is fixed in the bone by at least one selected from a screw and a plate. In one embodiment the implant further comprises at least one screw. 
         [0137]    In one embodiment the composition comprises radio-opaque components, compounds detectable in the human body by x-rays, or other components to enable detection through medical imaging devices. Examples of such detection techniques include but are not limited to X-ray, and visual light. 
         [0138]    In one embodiment the composition comprises drug molecules to further improve the healing process. 
         [0139]    There is provided a kit for the treatment of a bone fracture comprising the composition as described above, and a primer. 
         [0140]    In one embodiment said primer comprises at least one phenolic derivative and at least one another group selected from an acrylate, a methacrylate, an allyl, a vinyl, an unsaturated cyclic ring. 
         [0141]    In one embodiment the primer comprises a polymer. 
         [0142]    In one embodiment the kit further comprises at least one selected from fibres, a screw and a plate. 
         [0143]    Other features and uses of the invention and their associated advantages will be evident to a person skilled in the art upon reading the description and the examples. 
         [0144]    It is to be understood that this invention is not limited to the particular embodiments shown here. The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention since the scope of the present invention is limited only by the appended claims and equivalents thereof. 
       EXAMPLES 
       [0145]    Examples 1-7 describe synthesis methods for producing component A and B as well as the primer. 
         [0146]    Examples 8-14 describe methods for applying and curing the patch. 
         [0147]    Examples 15-16 describe cytotoxicity as well as shear strength of compositions according to the invention. 
       Example 1 
       [0148]    Synthesis of a 3 functional thiol (component A) from an allyl triazine (component B) 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Example 1 
                 Moles 
                 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Allyl 
                 1,3,5-triallyl-1,3,5- 
                 0.040117 
                 10 
               
               
                   
                 comp. 
                 triazine- 
                   
                   
               
               
                   
                   
                 2,4,6(1H,3H,5H)- 
                   
                   
               
               
                   
                   
                 trione 
                   
                   
               
               
                   
                 Thiol 
                 Thioacetic acid 
                 0.36105 
                 27.5 
               
               
                   
                 comp. 
                   
                   
                   
               
               
                   
                 Reagent 
                 AIBN 
                 0.0040117 
                 0.659 
               
               
                   
                   
               
             
          
         
       
     
         [0149]    1) The vinyl component, Thioacetic acid and AIBN was added to a round flask 
         [0150]    2) Reaction was stirred for 48 h in 60 C under Nitrogen atmosphere 
         [0151]    3) Excess of Thioacetic acid was evaporated 
         [0152]    4) Hydrolysis was conducted in 70 C in presence of THF and HCL 
         [0153]    5) Product was purified in a column using Heptane and Ethylacetate 
       Example 2 
       [0154]    Synthesis of allyl functionalized hydrophilic poly(maleic acid alt methyl vinyl ether). This reaction yields a component B. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Example 2 
                 Moles 
                 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 polymer 
                 poly(maleic anhydride 
                 0.000125 
                 2.5 
               
               
                   
                   
                 alt methyl vinyl 
                   
                   
               
               
                   
                   
                 ether), Mn = 20000 
                   
                   
               
               
                   
                 Allyl 
                 2-allyloxy ethanol 
                 0.01925 
                 1.97 
               
               
                   
                 comp. 
                   
                   
                   
               
               
                   
                 Reagent 
                 DMAP 
                 0.001925 
                 0.235 
               
               
                   
                 Solvent 
                 DMSO 
                 — 
                 30 mL 
               
               
                   
                   
               
             
          
         
       
     
         [0155]    1) The polymer and DMSO was added to a round flask and stirred until dissolved 
         [0156]    2) DMAP was dissolved in DMSO and added to the round flask 
         [0157]    3) The allyl component was diluted with DMSO and added to the round flask 
         [0158]    4) The reaction was stirred for 24 h and then quenched with water 
         [0159]    5) The product was purified with dialysis tubes (Pore size Mw=8000) in distilled water. The dialysis water was renewed three times with neutral water followed by two times with acidic water (pH 4) and three times with neutral water 
         [0160]    6) The products was then freeze-dried 
         [0161]    13C NMR characterization of the compounds reveals: 
         [0162]      FIG. 5A : 13C NMR of poly(maleic anhydride alt methyl vinyl ether) 
         [0163]      FIG. 5B : 13C NMR of allyl functionalized hydrophilic poly(maleic anhydride alt methyl vinyl ether) 
       Example 3 
       [0164]    Synthesis of a poly(para hydroxy styrene) 20% functionalized with allyl moieties. This reaction makes a compound that can be used as component B or The primer. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                 Example 3 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 polymer 
                 poly(para hydroxy 
                 0.0333 
                 4 
               
               
                   
                 styrene), Mw 
                   
                   
               
               
                   
                 approx. 5000 
                   
                   
               
               
                 Allyl 
                 4-pentenoic acid 
                 0.00666 
                 1.215 
               
               
                   
                 anhydride 
                   
                   
               
               
                 Reagent 
                 DMAP 
                 0.000666 
                 0.0815 
               
               
                 Solvent 
                 Pyridine 
                 — 
                 30 ml 
               
               
                   
               
             
          
         
       
     
         [0165]    1) The polymer was added to a round flask and dissolved in pyridine 
         [0166]    2) DMAP was added and let to dissolve 
         [0167]    3) The allyl was added slowly 
         [0168]    4) The reaction was stirred over night 
         [0169]    5) The reaction was quenched with water 
         [0170]    6) Solvents were evaporated in vacuum 
         [0171]    7) The product was dissolved in Ethanol and precipitated in cold diethyl ether 
         [0172]    8) Product was filtered and dried 
       Example 4 
       [0173]    Synthesis of a Dopamine Methacrylamide. This reaction gives compound that can be used as The primer. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Example 4 
                 Moles 
                 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Reactant 
                 Dopamine 
                 0.021 
                 4 
               
               
                   
                 1 
                   
                   
                   
               
               
                   
                 Reactant  
                 Methacrylic 
                 0.019 
                 2.92 
               
               
                   
                 2 
                 anhydride 
                   
                   
               
               
                   
                 Reagent 
                 TEA 
                 0.023 
                 2.32 
               
               
                   
                 Solvent 
                 Pyridine 
                 — 
                 30 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0174]    1) Dopamine was added to a round flask and dissolved in pyridine 
         [0175]    2) TEA was added and mixed well 
         [0176]    3) Methacrylic anhydride was added slowly under stirring 
         [0177]    4) The reaction was stirred over night 
         [0178]    5) Solvents were evaporated in vacuum 
         [0179]    6) Product was extracted and dried with Magnesium sulphate 
       Example 5 
       [0180]    Synthesis of a polyHEMA 25% functionalized with methacryates. This reaction gives a compound that can be used for component B or The primer. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Example 5 
                 Moles 
                 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Reactant 
                 polyHEMA 
                 0.0077 
                 1 
               
               
                   
                 1 
                   
                   
                   
               
               
                   
                 Reactant 
                 Methacrylic 
                 0.00192 
                 0.296 
               
               
                   
                 2 
                 anhydride 
                   
                   
               
               
                   
                 Reagent 
                 DMAP 
                 0.000196 
                 0.024 
               
               
                   
                 Solvent  
                 Pyridine 
                 — 
                 30 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0181]    1) polyHEMA was added to a round flask and dissolved in pyridine 
         [0182]    2) DMAP was added and mixed well 
         [0183]    3) Methacrylic anhydride was added slowly under stirring 
         [0184]    4) The reaction was stirred over night 
         [0185]    5) Solvents were evaporated in vacuum 
         [0186]    6) Product was precipitated in cold ether 
       Example 6 
       [0187]    Synthesis of a polycaprolactone diol functionalized with allyl moieties. This reaction makes a compound that can be used as component B. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                 Example 6 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 polymer 
                 polycaprolactone 
                 0.033 
                 100 
               
               
                   
                 diol, 3000 Da 
                   
                   
               
               
                 Allyl 
                 4-(allyloxy)-4- 
                 0.133 
                 51.5 
               
               
                   
                 oxobutanoic 
                   
                   
               
               
                   
                 anhydride 
                   
                   
               
               
                 Reagent 
                 DMAP 
                 0.00666 
                 0.815 
               
               
                 Reagent 
                 Pyridine 
                 — 
                  10 ml 
               
               
                 Solvent 
                 Dichloromethane 
                 — 
                 200 ml 
               
               
                 Solvent 
                 Methanol 
                 — 
                 41 
               
               
                   
               
             
          
         
       
     
         [0188]    1) Dissolve the polymer and DMAP in Pyridine and DCM 
         [0189]    2) The allyl was added slowly 
         [0190]    3) The reaction was stirred over night at RT 
         [0191]    4) The reaction was precipitated in methanol 
         [0192]    5) The precipitant was filtered and dried overnight under vacuum 
       Example 7 
       [0193]    Synthesis of a polycaprolactone diol functionalized with allyl moieties. This reaction makes a compound that can be used as component B. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Example 7 
                 Moles 
                 Grams 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 polymer 
                 polycaprolactone 
                 0.002 
                 100 
               
               
                   
                   
                 diol, 50000 Da 
                   
                   
               
               
                   
                 Allyl 
                 4-(allyloxy)-4- 
                 0.008 
                 3.09 
               
               
                   
                   
                 oxobutanoic 
                   
                   
               
               
                   
                   
                 anhydride 
                   
                   
               
               
                   
                 Reagent 
                 DMAP 
                 0.016 
                 1.95 
               
               
                   
                 Reagent 
                 Pyridine 
                 — 
                  10 ml 
               
               
                   
                 Solvent 
                 Dichloromethane 
                 — 
                 200 ml 
               
               
                   
                 Solvent 
                 Methanol 
                 — 
                 41 
               
               
                   
                   
               
             
          
         
       
     
         [0194]    1) Dissolve the polymer and DMAP in Pyridine and DCM 
         [0195]    2) The allyl was added slowly 
         [0196]    3) The reaction was stirred over night at RT 
         [0197]    4) The reaction was precipitated in methanol 
         [0198]    5) The precipitant was filtered and dried overnight under vacuum 
       Example 8 
       [0199]    Distribution of the cured composition, with component A and component B. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                 Example 8 
                 Structure 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tetraethylene glycol bis (3- mercaptopropionate) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B poly(Maleic anhydride-methyl vinyl ether) Substituted with 50% 2-allyloxy ethanol 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 Solvent 
                 Ethanol/water 70/30 
                   
                   
               
               
                 Initiator 
                 Camphorquinone 
               
               
                   
               
             
          
         
       
     
         [0200]    1) component B was added to an empty beaker. 
         [0201]    2) Solvent was added 
         [0202]    3) component A was added 
         [0203]    4) Initiator was added 
         [0204]    5) The components and the initiator were mixed carefully in a dark environment. 
         [0205]    6) The mixture was applied on a bone substrate 
         [0206]    7) The mixture was allowed to cure under a UV-source at 1.66 J/cm2 
         [0207]    8) The cured composition was allowed to reach ambient temperature before use. 
       Example 9 
       [0208]    Distribution of the cured composition, with component A and component B. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                 Example 9 
                   
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A poly(Maleic anhydride- methyl vinyl ether) Substituted  with 50%  Cysteamine 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B poly(Maleic anhydride- methyl vinyl ether) Substituted  with 50%  2-allyloxy ethanol 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 Solvent 
                 Ethanol/water 70/30 
                   
                   
               
               
                 Initiator 
                 Camphorquinone 
               
               
                   
               
             
          
         
       
     
         [0209]    1) component B was added to an empty beaker. 
         [0210]    2) Solvent was added 
         [0211]    3) component A was added 
         [0212]    4) Initiator was added 
         [0213]    5) The components and the initiator were mixed carefully in a dark environment. 
         [0214]    6) The mixture was applied on a bone substrate 
         [0215]    7) The mixture was allowed to cure under a UV-source at 1.66 J/cm2 
         [0216]    8) The cured composition was allowed to reach ambient temperature before use. 
       Example 10 
       [0217]    Distribution of a cured composition, with component A and component B, to bone. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                 Example 10 
                   
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tris[2- mercaptopropionyloxy)ethyl] isocyanurate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B1,3,5-triallyl- 1,3,5-triazine- 2,4,6(1H,3H,5H)-trione 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0218]    1) The vinyl component was added to an empty beaker. 
         [0219]    2) The thiol component was added to the vinyl in a dark environment. 
         [0220]    3) The components were mixed carefully in a dark environment. 
         [0221]    4) The mixture was applied on a bone substrate 
         [0222]    5) The mixture was allowed to cure under a UV-source at 1.66 J/cm2 
         [0223]    6) The formed cured composition was allowed to reach ambient temperature before use. 
         [0224]    Raman spectroscopy of the cured composition as above mentioned reveals following: 
         [0225]      FIG. 6A : component A, tris[2-mercaptopropionyloxy)ethyl]isocyanurate 
         [0226]      FIG. 6B : component B, 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione 
         [0227]      FIG. 6C : Cured composition from component A and component B 
       Example 11 
       [0228]    Distribution of a cured composition, with component A component B1 and component B2, to a substrate. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                 Example 11 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tris[2- mercaptopropionyloxy) ethyl]isocyanurate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B1 1,3,5-triallyl-1,3,5- triazine- 2,4,6(1H,3H,5H)-trione 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B2 poly(Maleic anhydride- methyl vinyl ether) Substituted with 10% 2- allyloxy ethanol 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 Initiator 
                 Camphorquinone 
               
               
                   
               
             
          
         
       
     
         [0229]    1) The vinyl component B1 was added to an empty beaker. 
         [0230]    2) The thiol component A was added to the vinyl in a dark environment. 
         [0231]    3) The hydrophilic vinyl polymer, component B2 was added. 
         [0232]    4) The components were mixed carefully in a dark environment. 
         [0233]    5) The initiator was added and mixed well. 
         [0234]    6) The mixture was applied on a bone substrate 
         [0235]    7) The mixture was allowed to cure under a UV-source at 1.66 J/cm2 
         [0236]    8) The formed cured composition was allowed to reach ambient temperature before use. 
       Example 12 
       [0237]    Distribution of a cured composition, with component A and component B, to bone. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                 Example 12 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tris[2- mercaptopropionyloxy)ethyl] isocyanurate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B tetra(ethylene glycol) diacrylate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0238]    1) The component A was added to an empty beaker. 
         [0239]    2) The component B was added to the vinyl in a dark environment. 
         [0240]    3) The components were mixed carefully in a dark environment. 
         [0241]    4) The mixture was applied on a bone substrate 
         [0242]    5) The mixture was allowed to cure under a UV-source at 1.66 J/cm2 
         [0243]    6) The formed cured composition was allowed to reach ambient temperature before use. 
       Example 13 
       [0244]    Distribution and composition of a primer, The primer, followed by a mixture of component A and component B, reinforced with the fibre. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                 Example 13 
                   
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tris[2- mercaptopropionyloxy)ethyl] isocyanurate 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B 1,3,5-triallyl-1,3,5- triazine-2,4,6(1H,3H,5H)- trione 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 The primer poly(para hydroxy styrene) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 Initiator 
                 Camphorquinone 
                   
                   
               
               
                 Solvent 
                 Ethanol/water 
                   
                   
               
               
                   
                 70/30 
               
               
                   
               
             
          
         
       
     
         [0245]    1) poly(para hydroxy styrene), The primer, was dissolved in Ethanol/water 70/30 to a concentration of 25 mg/ml 
         [0246]    2) After mixing well the thin primer layer was applied around a fracture 
         [0247]    3) the primer layer was then let to dry in approx. 1 min 
         [0248]    4) Thereafter the vinyl, component B, was added to an empty vial. 
         [0249]    5) The initiator was added to the vial in a dark environment and mixed carefully. 
         [0250]    6) The thiol, component A, was then added to the vinyl and the initiator in a dark environment and mixed carefully. 
         [0251]    7) The mixture was applied to the primer coated bone tissue as a thin layer. 
         [0252]    8) Fibre, 4 layers of a 25 g/m2 E-glass fibre veil, were then placed to on the thin mixture layer to “patch” the fracture. 
         [0253]    9) The fibre layers were then coated with a new layer of mixture to fully wet the fibres 
         [0254]    10) The composite patch was then cured under a UV-source at 1.66 J/cm2 to form a fibre reinforced cured composition. 
         [0255]    11) The patch was allowed to reach ambient temperature before use. 
       Example 14 
       [0256]    Distribution and composition of a primer, The primer, followed by a mixture of component A and component B, reinforced with the fibre. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
               
                 Example 14 
                 structure 
                 Moles 
                 Grams 
               
               
                   
               
             
             
               
                 component A tris[2- mercaptopropionyloxy)ethyl] isocyanurate  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 component B 1,3,5-triallyl-1,3,5- triazine-2,4,6(1H,3H,5H)- trione 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 the primer Dopamine Methacrylamide 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 Reagent 
                 NaOH 
                   
                   
               
               
                 Initiator 
                 Camphorquinone 
                   
                   
               
               
                 Solvent 
                 Ethanol/water 
               
               
                   
               
             
          
         
       
     
         [0257]    1) Dopamine Methacrylamide (AMD), the primer, was dissolved in Ethanol/water 50/50 to a concentration of 25 mg/ml 
         [0258]    2) After mixing well the thin primer layer was applied around a fracture 
         [0259]    3) NaOH was then added to the primer to increase pH. 
         [0260]    4) the primer layer was then let to dry in approx. 1 min 
         [0261]    5) Thereafter the vinyl, component B, was added to an empty vial. 
         [0262]    6) The initiator was added to the vial in a dark environment and mixed carefully. 
         [0263]    7) The thiol, component A, was then added to the vinyl and the initiator in a dark environment and mixed carefully. 
         [0264]    8) The mixture was applied to the primer coated bone tissue as a thin layer. 
         [0265]    9) Fibre, 4 layers of a 25 g/m2 E-glass fibre veil, were then placed to on the thin mixture layer to “patch” the fracture. 
         [0266]    10) The fibre layers were then coated with a new layer of mixture to fully wet the fibres 
         [0267]    11) The composite patch was then cured under a UV-source at 1.66 J/cm2 to form a fibre reinforced cured composition. 
         [0268]    12) The patch was allowed to reach ambient temperature before use. 
       Example 15 
       [0269]    The materials to be tested were coated on glass slides (76 mm×26 mm) and incubated with complete growth medium (CGM) for 24 h, at a concentration of 2.5 cm/ml to achieve material-CGM. MG63 osteoblast-like cells, ATCC, were cultured in Dulbecco Modified Eagle&#39;s Medium (DMEM), ATCC, containing 10% Heat inactivated Fetal Bovine Serum (FBS) and 0.5% Penicillin/Streptomycin, Sigma Aldrich, herein called as CGM. Incubation was performed at 37° C. in an atmosphere of 5% CO2 and 99% humidity. CGM renewal or cell splitting was carried out once every three days. Cells were released at confluence with trypsin/EDTA and seeded on five individual 96-well plates with approximately 20000 cells/well and 200 μl CGM in each well. Five replicates were performed for each type of material-CGM. The cells were allowed to attach for 12 h before the CGM was replaced with 200 μl of material-CGM and incubated for Oh, 12 h, 24 h, 48 h and 72 h. At each time interval each well on one plate was stained with 0.5 mg/ml MTT and incubated for another 3 h. After incubation the supernatant was replaced with 200 μl of DMSO and the coloured solution in the wells was transferred to a new plate where absorbance was measured at 570 nm in an ELISA plate reader. No toxicity could be seen for any of the tested adhesives or primers.  FIG. 7  shows a comparison between [1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione(allyl-triazine)+tris[2-mercaptopropionyloxy)ethyl]isocyanurate (thiol-triazine)], denoted as TT and the commercially available Histoacryl. It is visible that TT is more biocompatible than Histoacryl. 
       Example 16 
       [0270]    Bovine femur bones were obtained from an abattoir and split into rectangular blocks with dimensions of approximately 10×5×50 mm. Each block was then wet sanded with grain size 80 sandpaper until a smooth and even surface was achieved. A generic fracture was created by sawing each rod into two halves. The bone surface of the two halves were then prepared with a thin layer of primer and a thereafter a layer of adhesive at an approximately 8×8 mm square adjacent to the fracture. The primer-adhesive layer was then cured by exposure to UV-irradiation at a total dose of 1.66 J/cm 2 , divided by 4 passes under a Fusion Corporation instrument with a Hg-lamp prior to the application of the fibre reinforced adhesive patch (FRAP). The FRAP bond was performed with an initial layer of adhesive followed by 6 lamina of fibres and a final top coat of adhesive. The patch was then further cured. After bonding the bone specimen were submerged in saline for 24 h to mimic in vivo conditions. All mechanical tests were performed in an Instron 5568 with a 30 kN load cell and with a cross head speed of 5 mm/min. The tensile tests were performed by inserting two parallel metal pins through the distal ends of the specimen with wire connection to the load cell. All specimens were tested until either cohesive or adhesive failure was observed. Depending on the failure mode, either cohesive failure area or patch/bone adherent area was measured and maximum tensile strength or maximum shear strength was calculated. Testing the FRAP made from E-glass fibre reinforced [1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (allyl-triazine)+tris[2-mercaptopropionyloxy)ethyl]isocyanurate(thiol-triazine)] revealed a maximum patch strength above 85MPa and a maximum shear strength when used together with a PHS primer of 3.42 MPa, compared as “TT” to the commercially available butyl-cyanoacrylate “Histoacryl” and an Industrial Epoxy in  FIG. 8 .