Adhesive composition

Abstract

The present disclosure relates to an adhesive composition comprising a source of metal ions, polycaprolactone, and a cellulose compound, and to a method for repairing bone or tooth material using the adhesive composition.

Description

[0001] ADHESIVE COMPOSITION

[0002] CROSS REFERENCE TO RELATED APPLICATION

[0003] The present application claims the priority of United Kingdom Patent Application No.

[0004] 2416796.7, filed on 14 November 2024, the entirety of which is herein incorporated by reference.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to an adhesive composition, more particularly, to an adhesive composition which can be used for repairing damaged bone or tooth material, and to a method for using said adhesive composition.

[0007] BACKGROUND

[0008] Bone is one of the most delicate tissues in the human body supporting the skeleton and acting as a reservoir for progenitor cells and important minerals and ions for the function of vital organs.

[0009] In the acute setting of traumatic bone injuries, bone loss, and fragility fractures in the elderly, the two major post fixation complications that continue to dominate the work of clinicians are bone infection and non-union. The incidence of fracture non-union ranges between 5 and 10% whereas a 2-5% of infection has been cited after closed fractures, but this increases to 18% after open injuries (exposure of bone to the environment)

[0010] For non-unions that require bone debridement leading to bone loss and for bone defect treatment a two-stage treatment modality has been popularised known as the 'Masquelet technique'. (Chloros GD, Kanakaris NK, Harwood PJ, Giannoudis PV. Induced membrane technique for acute bone loss and nonunion management of the tibia. OTA Int. 2022 Apr 18;5(2 Suppl):el70. doi: 10.1097 / 019.0000000000000170.) The Masquelet technique is a known treatment for critical bone defects and comprises a two-step procedure. In the first step after debridement, a bone cement spacer, which is typically manufactured from polymethylmethacrylate (PMMA), is introduced into the bone defect followed by the reconstruction of the soft tissue. In the second step, performed after six to eight weeks, the spacer is removed and the defect is filled with bone graft. However, in order to mould the PMMA spacer to the defect, the spacer during thermosetting reaction may heat up to a temperature of about 65 °C. This is higher than the critical temperature of 54 °C at which temperature-induced cellular necrosis occurs. More importantly, the PMMA as a spacer does not promote bone formation, nor even neo osteogenesis, which is why it is removed after the termination of first stage surgery. The PMMA spacer, however, induces periosteum membrane formation which is triggered via foreign body reaction when PMMA spacer is placed after washing and clearing infection during wound cleaning. The periosteum membrane is a regenerative membrane, carrier of progenitor stem cells for bone and blood vessel formation. This membrane is protected after first stage when the PMMA spacer is removed. In the 2ndstage of Masquelet technique, the autologous bone tissue is harvested from the patient's donor site (e.g. iliac crest) and it is mixed with bone morphogenic protein (BMP-2) and platelet rich plasma (PRP) or bone marrow aspirate (BMA) extracted from patient. Both the PRP and BMA are an endogenous source of stem cells for stimulating osteoinduction, osteoconduction leading to ossification. In the Masquelet technique, besides the autologous tissue harvesting and placing it in the mixed form with PRP or BMA / BMP-2, which is encapsulated within the periosteum membrane, the biomechanical stabilisation of the fracture is critical. By using plates and intramedullary nails, the fracture site misalignment can be minimized so that when the fracture site heals via ossification, there is no risk of biomechanical torsional force which may cause discomfort and potentially become the cause of joint failure.

[0011] In dental implantology and regenerative dentistry, peri-implantitis is a significant clinical problem. This results from infections associated with bacterial colonisation around implants and scaffolds. Epidemiological data suggest that between 12% and 43% of dental implants will at some point develop symptoms of peri-implantitis, while in orthopaedics, 2-5% of all implant-related procedures will be complicated by bacterial infections but after open bone injuries infection can rise as high as 40%. Although, so far, the use of antibiotics is common practice for preventing or treating these conditions, the potential risk of antibiotic resistance is a concern, and the effectiveness of their long-term use is disputable. To meet this critical clinical need and overcome the implications of the current treatment strategies, there is increased interest in developing novel biomaterials with both antimicrobial properties and the potential to trigger bone regeneration.

[0012] Adhesive compositions can be used to bond or fix broken or injured bone and tooth material. Currently, medical adhesives are used to improve wound healing and implant anchorage in hard tissues such as bone and tooth. Standard medical adhesives include fibrin glue, polymethyl methacrylate (PMMA), cyanoacrylates, glass ionomer cement (GIC), polyurethanes and biomimetic adhesives. Polymethyl methacrylate (PMMA) is a biomaterial which is stable in wet environments and can allow antibiotics to be loaded into the cement, thus reducing the probability of bacterial infection or contamination. However, the setting procedure is an exothermic reaction commonly causing tissue necrosis due to the temperature rise. Moreover, it does not have the capacity to resorb and for bone reconstruction / regeneration procedures it will have to be removed (requiring a second surgical procedure) and replaced with a bone graft.

[0013] Cyanoacrylates, on the other hand, do not set via an exothermic process and express good micro-tensile bond strength. However, the strength of cyanoacrylates in wet environments is poor and they can cause inflammation and partial graft incorporation. For this reason, regulatory approval for cyanoacrylates is restricted to non-invasive and topical wound closure, such as for skin adhesives.

[0014] Glass ionomer cements (GIC) are mainly used in dentistry. Their setting process is not exothermic and they are effective in dry environments. However, aluminium-based GICs can cause neurotoxicity, and zinc-based GICs demonstrate low osteoblast metabolic activity and cell death. Polyurethanes are used as injectable and expandable bone cements. The degradation products of polyurethanes are non-cytotoxic. However, the osteoconductive productivity of this type of bone adhesive is relatively poor. Biomimetic adhesives such as fibrin glues and mussel adhesive proteins can have good biocompatibility and biodegradability but lack mechanical strength and have poor adhesion to bone.

[0015] A commercially available bone adhesive composition known as OsStic® comprises calcium and the non-essential amino acid phosphoserine. However, the composition has a setting time of approximately 24 hours which is undesirably long. This long setting time can have an impact on the degree of adhesion and stability achieved on the applied bone during surgery and after surgery affecting patient mobilisation and outcomes.

[0016] There is, therefore, need for an adhesive composition which addresses the above-mentioned problems, at least to some extent.

[0017] SUMMARY OF THE INVENTION

[0018] In accordance with a first aspect of this invention, there is provided an adhesive composition comprising a source of metal ions, polycaprolactone (PCL), and a cellulose compound.

[0019] The adhesive composition is able to at least partially melt when heated. The combination of PCL and the cellulose compound surprisingly forms a eutectic composition having an overall lower melting point than the melting points of the cellulose compound and PCL. This melting point reduction consequently lowers the temperature at which the composition must be heated in order to melt and subsequently set. Similarly, the heat released from the molten composition during cooling is lower than compositions which contain PCL or cellulose compound, but not both. When the composition is used to repair damaged bone or tooth material, the lower temperature advantageously minimises the risk of damaging tissue surrounding the site of repair.

[0020] The metal ions may be releasable from the composition to produce an anti -infective (antibacterial) effect in use. The composition provides a strong adhesive which attaches to bone or tooth material, and which can be used as a bone / tooth substitute. The composition may be particularly useful as a bone substitute because it promotes osteogenesis.

[0021] The composition may be adapted to at least partially melt when subjected to laser irradiation. Melting assists in intimately mixing the components of the composition so that they form a uniform mixture or solution. The molten composition may be caused or allowed to solidify to form a bone-like substance or tooth-like substance, as the case may be. The use of laser irradiation to melt the composition is superior to radiative or conductive heating methods (such as using a soldering iron or heating element) which emit heat over a broad area and thereby risk damaging tissue surrounding the site of repair. In contrast, the laser may be focused on a relatively small area to provide accurate heating with minimal damage to the surrounding tissue. The laser irradiation may heat the composition to a sufficient temperature to evaporate solvent from the composition.

[0022] The source of metal ions may comprise a source of iron ions and a source of cerium ions.

[0023] The source of iron ions may be present in an amount of from about 0.1% w / w to about 10% w / w based on the total weight of the composition.

[0024] The source of cerium ions may comprise a mixture of CeC and CezC . The source of cerium ions may be present in an amount of from about 0.1% w / w to about 10% w / w, or from about 0.1 wt% to about 5 wt%, based on the total weight of the composition.

[0025] The composition may further comprise a source of copper ions. The copper ions may be released from the composition under physiological conditions and may advantageously provide an anti-infective action on the area surrounding the composition in use. The source of copper ions may be present in the composition in an amount of from 0.1 wt% to 10 wt%, based on the total weight of the composition. Optionally, the copper ion may be Cu2+.

[0026] The source of metal ions may comprise a combination of metal ions which react in a redox reaction, such as Ce4+and Ce3+in combination with Fe3+and Fe2+, or Ce4+and Ce3+in combination with Fe2+and Fe3+, or Ce4+and Ce3+in combination with Cu2+and Cu1+. The redox reactions between different combinations of ions are regulated by different pH levels. The pH-regulated redox reaction control is important in infection abatement during bone healing. Ce4+and Ce3+ions are particularly beneficial in reducing oxidative stress and cell induced peroxidase reaction caused by bacterial infection.

[0027] The adhesive composition may further comprise a source of Ch ions. The Ch ions may be present in an amount of from 0.01wt% to 2.0wt% based on the total weight of the composition. The Cl- ions may be present as counter ions to the metal ions. For example, the source of Ch ions may be CuCl2. The Cl- ions may contribute to the adhesive composition's biocidal activity.

[0028] The polycaprolactone (PCL) may be present in an amount of from 0.1 wt% to 90 wt% based on the total weight of the composition.

[0029] The cellulose compound may be present in the composition in an amount of from 0.1 wt% to 90 wt% based on the total weight of the composition.

[0030] The cellulose compound may be alkyl cellulose, such as methyl cellulose or ethyl cellulose.

[0031] The composition may further comprise a scaffold selected from graphene, chitosan, or a combination thereof.

[0032] The graphene may be present in an amount of from 0.01% to 5% w / w, preferably from 0.5 to 1.0 wt% based on the total weight of the composition. The chitosan may be present in an amount of from 0.1 to 20 wt%, such as 1 to 10 wt%. The composition may further comprise calcium phosphate as a mineral constituent. The calcium phosphate may be present in an amount of from 1 to 50 wt% based on the total weight of the composition.

[0033] In accordance with a second aspect of this invention, there is provided a composition as described above for use in bone or tooth repair. The advantages associated with the first aspect apply equally to the second aspect.

[0034] The use may comprise contacting bone or tooth to be repaired with the composition, heating the composition by laser irradiation to at least partially melt the composition, and causing or allowing the composition to set.

[0035] The composition may be allowed to set by permitting solvent in the composition to passively evaporate from the composition. Alternatively, the composition may be caused to set by heating the composition to a sufficient temperature to evaporate solvent from the composition. The solvents may be selected from acetone, ethyl alcohol, and propyl alcohol. When mixed with chitosan, the solvent may produce water which may be removed by evaporation.

[0036] In accordance with a third aspect of this invention, there is provided a method for repairing bone or tooth material, the method comprising:

[0037] contacting the bone or tooth material with the adhesive composition as described above;

[0038] heating the adhesive composition to at least partially melt the composition; and - causing or allowing the composition to set.

[0039] The advantages associated with the first and second aspects apply equally to the third aspect.

[0040] The heating may comprise heating by laser irradiation. The laser irradiation may be continuous wave or pulsed wave irradiation.

[0041] The laser may comprise infrared radiation having a wavelength of from 700 nm to 11000 nm, 700 nm to 4000 nm, or 700 nm to 2100 nm. The laser irradiation may be in the near IR to mid-IR range which may be absorbed by the adhesive composition to initiate laser-induced fusion of the components.

[0042] Unless otherwise stated, each of the integers described may be used in combination with any other integer as would be understood by the person skilled in the art. Further, although all aspects of the invention preferably "comprise" the features described in relation to that aspect, it is specifically envisaged that they may "consist" or "consist essentially" of those features outlined in the claims. In addition, all terms, unless specifically defined herein, are intended to be given their commonly understood meaning in the art. As used herein and in the accompanying claims, unless the context requires otherwise, "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0043] The term "consist(s) / (ing) essentially of", with respect to the components of a composition or mixture, means the composition or mixture contains the indicated components and may contain minor additional components in an amount less than 1 wt% based on the total weight of the composition or mixture, and provided that the additional components do not substantially alter the reactivity of the composition or mixture.

[0044] The term "cellulose compound" refers to substituted or unsubstituted cellulose. Cellulose is a polysaccharide compound with the formula (C6HioOs)n comprising a linear chain of several hundred to many thousands of 0(l->4) linked D-glucose units. Each cellulose monomer in the polysaccharide chain contains three unsubstituted hydroxyl (-OH) groups.

[0045] The term "substituted cellulose" refers to cellulose which has been substituted with one or more functional group(s), typically at one or more of the -OH groups. Substituted cellulose compounds include alkyl cellulose (e.g. methyl cellulose and ethyl cellulose) and acetyl cellulose. In a preferred embodiment, the substituted cellulose is ethyl cellulose.

[0046] Throughout the present description, the term "physically mixed" refers to components of a composition which have been physically mixed together in the absence of a solvent, and the term "chemically mixed" refers to components which have been mixed together in the presence of a solvent that was subsequently removed so as to order to obtain a greater degree of mixing between the components of the composition. An example of chemical mixing is the Sol-Gel method described below. The terms "physical mixture" and "chemical mixture" refer to compositions made by these methods.

[0047] Further, in the discussion of the invention, unless stated to the contrary, the disclosure of alternative values for the upper or lower limit of the permitted range of a parameter, is to be construed as an implied statement that each intermediate value of said parameter, lying between the smaller and greater of the alternatives, is itself also disclosed as a possible value for the parameter.

[0048] In addition, unless otherwise stated, all numerical values appearing in this application are to be understood as being modified by the term "about". As used herein, the term "about" means that the stated value can vary by ± 10%. For example, about 90 wt% means 90±9 wt%, and about 0.1 wt% means 0.1±0.01 wt%. When used with reference to a range, the term "about" applies to all values in the range.

[0049] The present invention will be better understood in light of the following examples and the accompanying figures, which are given in an illustrative manner only and should not be interpreted in a restrictive manner.

[0050] BRIEF DESCRIPTION OF THE FIGURES

[0051] In the accompanying Figures:

[0052] Figure 1 shows the antibacterial properties of samples comprising scaffolds of chitosan containing 10, 20, and 30 (wt)% cerium oxide (denoted as 10- CeO2, 20-CeO2, and 30-CeO2, respectively) and 30 (wt)% Fe-DCPD. Antibacterial properties were tested against (a) Gram-positive (S. aureus and S. epidermidis} and (b) Gram-negative (5. coli and P. aeruginosa} bacteria. Bacteria were grown in BHI broth for 24 h and tested using a manual colony counting method. Data are presented as the mean ± standard error of the mean (n=3 in each group); * p < 0.05, ** p < 0.01 and **** p < 0.0001.

[0053] Figure 2 shows the antibacterial properties of l(wt)% copper (II) chloride freeze- dried chitosan scaffolds. Antibacterial properties were tested against (a) Gram-positive (S. aureus and S. epidermidis and (b) Gram-negative (5. coli and P. aeruginosa} bacteria. Bacteria were grown in BHI broth for 24 h and tested using a manual colony counting method. Data are presented as the mean ± standard error of the mean (n=3 in each group); * p < 0.05, ** p < 0.01 and **** p < 0.0001.

[0054] Figure 3 shows the antibacterial properties of l(wt)% copper (II) chloride and 10(wt)% cerium oxide freeze-dried chitosan scaffolds. Antibacterial properties were tested against (a) Gram-positive (S. aureus and S. epidermidis} and (b) Gram-negative (5. coli and P. aeruginosa}. Bacteria were grown in BHI broth for 24 h and tested using a manual colony counting method. Data are presented as the mean ± standard error of the mean (n=3 in each group); * p < 0.05, ** p < 0.01 and **** p < 0.0001. Figure 4 shows the lowering of the melting points of a binary physical mixture of 62.5 wt.% PCL - 37.5 wt.% ethyl cellulose with respect to pure samples of PCL and ethyl cellulose.

[0055] Figure 5 shows a comparison of the melting temperature and energy stored in the physically mixed and chemically mixed ternary mixtures of ethyl cellulose, PCL and metal ion-containing mineral. The proportion of components in both mixtures was: 50wt% PCL, 30wt% ethyl cellulose and 20 wt% mineral. Laser power used was 3W for 60 seconds.

[0056] Figure 6 shows a comparison of melting behaviour of a binary mixture of PCL with metal ion-containing mineral for both physically mixed and chemically mixed compositions.

[0057] Figure 7 shows a comparison of melting behaviour of a binary mixture of ethyl cellulose with metal ion-containing mineral for both physically mixed and chemically mixed compositions.

[0058] Figure 8 shows a comparison of melting behaviour of two binary mixtures against a ternary mixture according to the present invention, all of which have been prepared by physical mixing.

[0059] Figure 9 shows a comparison of melting behaviour of two binary mixtures against a ternary mixture according to the present invention, all of which have been prepared by chemical mixing.

[0060] Figure 10 shows the thermal behaviour of three physically mixed compositions, two binaries (80wt% PCL+20wt% Mineral and 80 wt%Ethyl cellulose+20wt% Mineral), and a ternary (50wt% PCL, 30 wt% Ethyl Cellulose, and 20wt% mineral). The mixtures were heated with a 3W 980 nm fibre optic laser for longer than 60 seconds to identify that after prolonged melting of 200 seconds, the temperature of the adhesive mixture tends to saturate.

[0061] Figure 11 shows Alexa Fluor and DAPI images for the time points of 1, 7 and 14 days of i) first row: binary chemical mixture of 50 wt.% PCL - 50 wt.% (hydroxyapatite 10 wt.% iron-doped), ii) second row: binary chemical mixture of 50 wt.% ethyl cellulose - 50 wt.% (hydroxyapatite 10 wt.% iron- doped), and iii) third row: ternary chemical mixture of 50 wt.% PCL - 30 wt.% ethyl cellulose - 20 wt.% (hydroxyapatite iron-doped).

[0062] Figure 12 illustrates the tensile strength of different adhesive compositions.

[0063] "Adhesive" refers to a ternary composition according to the present invention which comprises a metal ion-containing mineral, polycaprolactone and ethyl cellulose.

[0064] DETAILED DESCRIPTION

[0065] The present invention relates to an adhesive composition that can be used for repairing or replacing damaged bone or tooth material. The adhesive composition comprises a source of metal ions, polycaprolactone (PCL), and a cellulose compound. The adhesive composition can also be used as an adhesive for securing implant materials to the bone or tooth material, or for attaching fractured bone or tooth fragments together. In addition, the composition may be used as a prosthesis to replace missing or damaged bone or tooth material. The adhesive composition has a rapid setting time which provides an advantage over known adhesive compositions which take longer to set. The adhesive composition may be considered to be a biomorphic composition, in which the composition is mouldable into a shape resembling a biological feature, such as bone or tooth material.

[0066] The source of metal ions can be any metal compound that can release metal ions, such as metal salts, oxides, hydroxides, or phosphates, under physiological conditions. The metal ions can be selected from the group consisting of cerium, iron, silver, copper, zinc, magnesium, calcium, cobalt, nickel, titanium, and zirconium. Preferably, the metal is selected from the group consisting of iron, cerium, copper, and calcium ions. The metal ions provide anti-infective, antimicrobial and osteogenic effects to the adhesive composition.

[0067] A source of cerium ions may be present in an amount of from 0.1 to 5 wt% based on the total weight of the dry composition. The source of cerium ions may be selected from cerium oxide, cerium nitrate, and combinations thereof.

[0068] A source of iron ions may be present in an amount of from 0.1 to 10 wt% based on the total weight of the dry composition. The source of iron ions may be selected from iron (II) oxide, iron (III) oxide, FeCIz, iron doped minerals [for example, iron doped hydroxyapatite (Caio(P04)e(OH)2), iron doped fluorapatite (Cas(PO4)3F), iron doped brushite (CaHPO4.2H2O), iron doped p-pyrophosphate, iron doped monetite (CaHPC ), iron doped tricalcium phosphate (Ca3(PO4)2)], and combinations thereof. In the iron doped minerals, the ratio of Ca:(PO4)3'=l: 1 to 4:1. The iron-doped mineral may be co-doped with Mg2+or Sr2+. In some preferred embodiments, the source of iron ions may be iron doped brushite (CaHPO4.2H2O).

[0069] The source of metal ions may comprise a source of cerium ions and a source of iron ions. The cerium ions and iron ions may undergo a redox reaction. For example, Ce4+may oxidise Fe2+to Fe3+and be reduced to Ce3+in the process. The Fe3+may be released from the composition under physiological conditions to provide an anti-infective action by increasing oxygen carriers in blood vessels in the area surrounding the composition in use. Cerium (III) is poorly soluble under physiological conditions and may therefore be slowly released from the composition over time to provide a long-term anti -infective action on the area surrounding the composition in use. In the presence of reactive oxygen species (ROS), the Ce3+may oxidise to Ce4+and neutralise the ROS.

[0070] A source of copper ions may be present in an amount of from 0.1 to 10 wt%, 0.1 to 5 wt%, 0.1 to 2 wt%, 0.5 to 1.5 wt%, or a range constituted by any two of the aforementioned time values, based on the total weight of the composition. The source of copper ions may be selected from copper chloride, copper nitrate, and combinations thereof.

[0071] The metal ions may be incorporated in a calcium phosphate mineral matrix. The calcium phosphate mineral matrix may comprise from about 1 wt% to about 60 wt% of the adhesive composition, with the balance being made up of the cellulose compound and PCL. The ratio of PCL:cellulose compound may vary from 0.1 wt% to 99.9 wt%, from 5 wt% to 95 wt%, from 10 wt% to 90 wt%, from 20 wt% to 80 wt%, from 30 wt% to 70 wt%, from 40 wt% to 60 wt%, or about 50 wt%. Preferably, the ratio of PCL:cellulose compound is from 40 wt% to 60 wt%.

[0072] The polycaprolactone is a biodegradable polymer that can act as a binder and a filler for the adhesive composition. The polycaprolactone can have a molecular weight ranging from 500 to 80,000 g / mol.

[0073] The cellulose compound can enhance the mechanical strength and biocompatibility of the adhesive composition and can be present in the form of unsubstituted or substituted cellulose. The substituted cellulose may comprise alkylated cellulose (such as methyl and / or ethyl cellulose). The cellulose may preferably be ethyl cellulose. The cellulose can be derived from various sources, such as wood, cotton, hemp, or algae. The cellulose compound can have a degree of polymerization ranging from 100 to 10,000 glucose units.

[0074] When combined, the PCL and cellulose compound can form a eutectic composition having a lower melting point than the melting point of either the cellulose compound, which may be in the range of 175-250 °C, or PCL, which is in the range of 57-70 °C. For example, a comparison of the thermal data of Figures 4-10 shows that the melting point range of PCL on its own is about 40-66 °C with an enthalpy of 128J / g (as shown in Figure 5), whereas the melting point range of PCL in the binary mixture with ethyl cellulose is from 36-72 °C with an enthalpy of 55.9 J / g (as shown in Figure 5). The wider melting range of the ternary composition of metal ions + PCL + ethyl cellulose shows seven times less energy stored (see enthalpy values) than in PCL, ethyl cellulose, or a binary mixture of PCL + ethyl cellulose. This indicates that the mixture holds less heat energy which allows it to cool faster. Furthermore, by retaining less heat, when the mixture cools it releases less heat to the surrounding tissue. A low magnitude of enthalpy is advantageous because it reduces the risk of damaging tissue at the site of repair by excessive heating.

[0075] The composition may further comprise chitosan. Chitosan may provide an antimicrobial effect and enhance the binding properties of the composition. The chitosan may also enhance mixing of the components together. The viscosity of the chitosan may be modified by combining it with ethanol. The quantity of chitosan present may be selected to achieve a desired rheology and viscosity of the composition. For example, the composition may comprise from 1 wt% to 20 wt%, from 2 wt% to 10 wt%, or about 5 wt% chitosan. Above this percentage, the bone repair may be compromised by a lack of adhesion process leading to weak bond formation.

[0076] The composition may further comprise graphene. The graphene may assist in dissipating heat, particularly during laser irradiation. The graphene may be present in an amount of from 0.1 to 10 wt%. For example, the graphene may be present in an amount of from 0.1 to 5 wt%, 0.5 to 5 wt%, 0.5 to 2 wt%, about 1 wt%, or a range constituted by any two of the aforementioned values, based on the total weight of the composition.

[0077] The mass ratio of the inorganic components (comprising the metal ion sources and their optional calcium phosphate matrix and graphene) to the organic / macromolecular components (comprising optional chitosan, PCL and cellulose compound) may be from 1 : 1 to 1:8, 1:2 to 1:6, 1:3 to 1:5, or about 1:4. The adhesive composition can be prepared by mixing the source of metal ions, polycaprolactone, and cellulose compound in a solvent, such as water, ethanol, or acetone. The solvent can be evaporated to form a paste. Evaporation may be carried out by passive evaporation or by heating the composition, for example, with a laser. The adhesive composition can be applied to a bone or tooth surface by any suitable method, such as by using a syringe, spatula, or surgical instrument. Advantageously, the adhesive composition sets and hardens within a short period of time. For example, the setting time may range from 10 seconds to 1 hour, from 10 seconds to 30 minutes, from 10 seconds to 15 minutes, from 10 seconds to 5 minutes, from 10 seconds to 1 minute, from 30 seconds to 1 hour, from 30 seconds to 30 minutes, from 30 seconds to 15 minutes, from 30 seconds to 5 minutes, from 30 seconds to 1 minute, or in a range constituted by any two of the aforementioned time values. The short setting time permits the composition to be used in bulk quantities for repairing large bone or tooth defects.

[0078] The adhesive composition can be heated by laser (pulsed or a constant wave [CW] source) irradiation to set or harden the composition. The laser may be any suitable laser. The laser may be a semiconductor laser (such as a diode laser), a CO2 laser, or a solid-state laser (such as a neodymium doped laser, including yttrium orthovanadate (Nd:YVO4), yttrium lithium fluoride (Nd:YLF) and yttrium aluminium garnet (Nd:YAG) lasers). In some preferred embodiments, the laser may be a continuous wave diode (CWD) laser which may offer the simultaneous advantages of compact size, tuneability, constant output laser energy over time, and high-power emissions at a relatively low cost. The CWD laser may produce radiation in the IR nanometer range. The laser generates sufficient heat to evaporate solvent from the composition and melt the solid components, at least partially. The ternary formulation comprising the metal ions, PCL and cellulose compound begins melting during laser heating. The temperature rises and then cools rapidly. The laser irradiation can increase the speed at which the composition sets or hardens. The laser can also sterilize the adhesive composition and the surrounding tissue by killing microorganisms which may be present. The laser can be produced by a handheld device, such as a pen, wand, or needle, that can deliver the laser beam to the desired location for the required period of time.

[0079] The adhesive composition can be used as a dental implant. The composition can be formulated into a paste and moulded into a desired shape and size that matches a defect or gap in tooth material, and heated by laser irradiation to form a solid prosthesis that can restore the function and appearance of the tooth. The adhesive composition can also be used as an adhesive for attaching implant materials, such as metal, ceramic, or composite braces, crowns, bridges, fillings, veneers, and other materials used in dental repair, to the tooth surface. The adhesive composition can form a strong bond with the implant material and the tooth material. The adhesive composition can also be used for repairing fractured or decayed tooth fragments by applying the adhesive composition to the fracture site or cavity and allowing or causing the composition to set. The adhesive composition can fill the defect, join the tooth fragments together, and prevent further infection through the release of metal ions over time.

[0080] The adhesive composition can also be used as an orthopaedic implant. The composition can be formulated into a paste and moulded into a desired shape to fit a defect or gap in bone material. The adhesive composition can then be heated by laser irradiation to form a solid prosthesis that can restore the function and appearance of the bone. The adhesive composition can also be used as an adhesive for attaching bone fixation and repair devices, such as metallic plates, nails, etc. to the bone surface.

[0081] The adhesive composition can be applied in multiple layers with different layers having different rheological properties and / or compositions. For example, ions of different metals, sizes and charges can be included in the different layers. Release of the metal ions can be controlled through the creation of a gradient of layer thickness and by the positioning / selection of the metal ions. Additive manufacturing approaches may be used to create the layered adhesive composition.

[0082] The invention will now be described in further detail with reference to the following nonlimiting examples.

[0083] EXAMPLES

[0084] Chitosan Solution

[0085] An amount of 3 (wt)% chitosan (molecular weight (Mw)) of 3100 to 3750 kDa and degree of deacetylation (DD) > 75%) was prepared in a 2(v / v)% acetic acid solution. The solution was stirred with a magnetic stirrer for 24 h. After the stipulated time, the beaker was covered with aluminium foil and left undisturbed overnight to allow air bubbles to rise to the solution surface. The chitosan solution was stored at 4 °C and was utilised to fabricate a synthetic cancellous bone scaffold.

[0086] Iron-Dooed Brushite (Fe-DCPD)

[0087] A 0.1 M aqueous solution (200 mL) of Ca(NO3)2-4H2O (Fisher Chemicals, CAS: 13477-34-4) was heated to 37 °C and designated as solution A. A 0.1M solution (200 mL) of (NH4)3PO4 (Acros Organics, CAS: 7783-28-0) was mixed with 10(mol)% iron nitrate powder (Fe(NO3)3-9H2O) (VWR Chemicals, CAS:7782-61-8) and added dropwise to solution A while continuously stirring at 37°C for 2 h. The mixture was left to settle for 1 h, allowing the precipitation of the Fe-DCPD (CaHPO4-2H2O). The precipitated crystals were then collected on filter paper (Whatman grade 44 with 3 pm pores), washed multiple times with distilled water, and dried for 24 h at 80 °C.

[0088] Cerium Oxide Nanoparticles (CeC )

[0089] The nanoparticles were synthesised using a hydroxide-mediated method, employing cerium nitrate hexahydrate (Ce(NO3)3-6H2O, Sigma-Aldrich, CAS: 10294-41-4) as a precursor. In brief, 10.85 g of Ce(NO3)3-6H2O(S) was dissolved in 250 mL of distilled water and stirred continuously for 20 min, yielding a 0.1 M solution (A). Next, 0.3M sodium hydroxide (NaOH, Sigma-Aldrich, CAS: 1310-73-2) solution was added dropwise to the solution (A) at 50°C under continuous magnetic mixing to facilitate the hydrolysis of cerium oxide nanoparticles. The solution was covered with aluminium foil and maintained at 50 °C under constant stirring for 24 h. The nanoparticles were filtered and washed five times with distilled water and ethanol. The recovered nanoparticles were frozen at -80 °C for 24 h and then subjected to freeze-drying at -100 °C and a pressure of 43 mTorr for 24 h.

[0090] Synthetic Cancellous Bone Scaffold

[0091] The cancellous region of the synthetic bone scaffolds was created by mixing chitosan (CH) with 30 (wt)% iron-doped dicalcium phosphate dihydrate minerals (Fe-DCPD) and varying quantities of cerium oxide nanoparticles (CeC ) (10, 20 and 20 (wt)%). The scaffolds were produced using a 10 mL suspension batch and stirred for 2 h on a hot plate to achieve a uniform mixture. The mixed suspensions were injected into well plates (24-well) and subsequently frozen at -80 °C for 24 h, then placed in a freeze-drier operating at 43 mTorr at -100 °C for 24 h.

[0092] Table 1. Freeze-dried chitosan scaffolds, including their mineral ratio formulations

[0093]

[0094] Antibacterial Test

[0095] All freeze-dried scaffold types were examined against Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The bacterial inhibition was investigated after 24 h to determine the antibacterial effect of cerium oxide nanoparticles. Chitosan is known to exhibit antibacterial properties; therefore, an un-doped freeze-dried chitosan scaffold was used as a control to compare against scaffolds containing varying concentrations of CeO2nanoparticles. CB denotes the control bacterial growth experiment without adding the samples. The bacterial reduction results of the freeze-dried scaffolds against the Grampositive and Gram-negative bacteria are illustrated in Table 2.

[0096] Table 2. Antibacterial results of Gram-positive and Gram-negative bacteria against varying cerium oxide doped scaffold concentrations.

[0097]

[0098] Double-Layered Scaffolds Containing Copper (II) Chloride and Cerium Oxide Nanoparticles The overall aim of this study was to optimise the amount of the copper (II) chloride based on the cytotoxicity and investigate the effect of cerium oxide and copper chloride doped Fe-DCPD mineral incorporation into a porous chitosan scaffold on the micro architectural and mechanical properties, antibacterial activity, and the ability of the scaffolds to support cell proliferation.

[0099] Copper (II) Chloride-Chitosan Scaffolds

[0100] The scaffolds (Table 3) were prepared by adding 30(wt)% iron-doped dicalcium phosphate dihydrate minerals and l(wt)% copper (II) chloride (CuCI2) to 10 mL suspension of chitosan solution (prepared as described above) and stirred for 2 h on a hot plate to achieve a uniform mixture. The mixed suspensions were injected into well plates (24-well) and subsequently frozen at -80 °C for 24 h, then placed in a freeze-drier operating at 43 mTorr at -100 °C for 24 h.

[0101] Table 3. Freeze-dried chitosan scaffold embedded with iron-doped brushite and copper(II) chloride

[0102]

[0103] Antibacterial Testing

[0104] The antibacterial properties of the fabricated l(wt)% CuCl2 / Fe-DCPD scaffold against Gram-positive (S. aureus and S. epidermidis) and Gram-negative (E. coli and P. aeruginosa) bacteria are presented in Figure 2. The bacteria growth in the synthesised scaffold with l(wt)% concentration of CuCl2 was analysed after 24 h to determine the antibacterial properties of CuCl2. CB represents the control bacterial growth with an optical density (OD) of 0.15 ABS as a reference for bacterial growth without the addition of the scaffolds. The results in Figure 2 indicate that the synthesised l-CuCl2 scaffold reduced the bacterial growth of both bacteria types (Gram-positive and Gram-negative). The percentage reductions are shown in Table 4.

[0105] Table 4. Bacterial growth reduction results for freeze-dried chitosan scaffolds containing l(wt)% copper (II) chloride.

[0106]

[0107] Antibacterial Testing of Copper (II) Chloride and Cerium Oxide Nanoparticles Scaffolds The antibacterial effectiveness of adding 10(wt)% CeC nanoparticles in the l-CuCl2 scaffold (referred to below and in Figure 3 as CeO2-CuCl2) results are presented in Figure 3 and Table 5. It has been shown that fabricating freeze-dried scaffold by adding CeCh nanoparticles in the l-CuCl2 sample increases the antibacterial effectiveness. The antibacterial percentages of the CeO2-CuCl2 against the Gram-positive (S. aureus and S. epidermidis) and Gram-negative (5. coli and P. aeruginosa) are displayed in Table 5. The addition of CeC with the l-CuCl2 scaffold decreased the number of bacteria colonies. Hence the fabricated CeO2-CuCl2 scaffold presented excellent antibacterial properties compared to other fabricated scaffolds (CH, 10-CeO2, 20-CeO2, 30-CeO2, and I-CUCI2).

[0108] Table 5. Bacterial growth reduction results for freeze-dried chitosan scaffolds containing l(wt)% copper (II) chloride and 10(wt)% cerium oxide nanoparticles

[0109]

[0110] Methods for forming adhesive composition: Sol-Gel method

[0111] Method 1: Step-1: 500 ml of acetone was taken in a litre capacity beaker and it was heated slowly (l-2°C / minute) on a hot plate equipped with a magnetic stirrer until the temperature reached to 50-55°C. The isothermal temperature range 50-55°C was maintained for dissolving and mixing polycaprolactone and ethyl cellulose. The isothermal temperature around 50-55°C increases the solubility of both the PCL and ethyl cellulose. Increasing the temperature beyond this range enhances the loss of acetone and reduces the solubility of both the PCL and ethyl cellulose. The isothermal temperature was maintained while mixing 3g of PCL and 2g of ethyl cellulose, which took approximately 20 minutes to dissolve while the mixture was stirred continuously. Note that for increasing the dissolved weight proportion of PCL and / or ethyl cellulose in acetone, for example to a larger mass, it is also necessary to proportionately increase the volume of acetone by maintaining the dissolution temperature of 50-55°C. For molecular-scale mixing of calcium phosphate or fluorapatite mineral into the heated acetone solution containing 3g of PCL and 2g of ethyl cellulose, the mineral phase synthesis must be carried out in parallel while the acetone / PCL / ethyl cellulose solution remains maintained in the 50-55°C temperature range.

[0112] Step-2: In a separate beaker, 4.44g of calcium nitrate (0.1M) was dissolved in 200mL of de-ionized water. Note that for making ion-doped calcium phosphate (for example Ce4+'3+or Fe3+'2+, Cu2+'1+, Sr2+, Mg2+ions), it is necessary to incorporate the bio-functional ions in the required weight / mass or volume proportion (needed for a range biomorphic adhesive, depending on clinical indications) while preparing the calcium nitrate (0.1M solution). The pH was maintained between 8 and 9. It is important that the calcium nitrate solution with the required dopants is also maintained at isothermal temperature range 50-55°C, before being added slowly (drop-by-drop) into the PCL / ethyl cellulose mixture, while stirring constantly. The drop-by-drop mixing was achieved by using a graduated burette. After combining the solutions, the mixture was constantly stirred while maintaining the temperature at 50-55°C.

[0113] Step-3: In a third beaker 2.92g of ammonium phosphate was dissolved in 200mL of distilled water (0.1M) which was also heated to 50-55°C (Ammonium fluoride added to this solution if needed). This solution is also heated to approximately 50-55°C and then added to the PCL, ethyl cellulose, and acetone mixture dropwise using a burette while constant stirring the mixture is maintained. pH was maintained between 8 and 9 for promoting formation of apatite phase.

[0114] Step-4: During mixing of solutions in Steps 1-3, a gel mixture forms which is viscous like a paste was covered and left stirring for Ih and then left to stand unstirred for Ih, before being filtered and frozen at -80°C for 24h after which it was then freeze dried for 48h at -90°C.

[0115] Method-2: minimizing the volume of the acetone / water prior to freeze drying

[0116] Method-2 is identical to Method 1 in terms of following the steps 1 to 3 and selecting the mass proportions of ethyl cellulose, PCL, calcium nitrate, ammonium phosphate and ammonium fluoride. The isothermal temperature range 50-55°C and pH between 8 and 9 were maintained. The dopant ions were incorporated as required for clinical applications (bone or dental), as explained in Method-1. The weight proportion of ammonium fluoride is less than 2wt% in apatite / hydroxyapatite minerals used for bone related applications. For dental applications, the fluoride content was higher than 2wt% for achieving acid resistance and bacterial resistance on enamel surface and in implants.

[0117] As explained in Method 1, depending on the weight proportions of PCL and ethyl cellulose, the acetone volume may be adjusted. For example, in Method 2, 5g of PCL and 2g ethyl cellulose were dissolved in 500ml of hot acetone maintained in 50-55°C range instead of 3g of PCL and 2g ethyl cellulose as described in Method 1.

[0118] For hydroxyapatite synthesis, the mixture of ammonium phosphate and calcium nitrate (0.1M each) at pH (8-9) was mixed drop-by-drop into the PCL / ethyl cellulose / acetone solution while stirring continuously for an hour while suspension was stirred. The suspension was stirred for an hour and then left to stand for another hour, which allowed the mineral dispersed with PCL / ethyl cellulose to settle at the bottom of the beaker. After this point, 75% of the volume of supernatant liquid above the precipitated mineral / ethyl cellulose / PCL slurry was removed carefully using a pipette without disturbing the settled precipitate. This method of extraction proved necessary for producing the molecular-scale mixed slurry in finer form than that observed in Method 1. Larger volume of solution left in Method 1 took longer time to remove acetone during freeze drying which then made it difficult to make dry molecular-scale mixed mineral, PCL, and ethyl cellulose. After extraction of the supernatant, the remaining volume of slurry was around 150ml which was frozen at -80°C for 24h and then freeze-dried at -90°C for 48h.

[0119] Thermal Analysis

[0120] Since the adhesive composition comprises a mixture of inorganic (e.g. iron oxide doped calcium phosphate, graphene, oxides of cerium, copper ions in oxide form etc.) and organic / macromolecular (e.g. chitosan, PCL, EC) phases, which can be mixed together to form a photo-active or photo-absorptive adhesive composite, the heat accumulation and dissipation rates during laser heating can be tailored by controlling the ratio of organic (especially PCL, EC) to inorganic constituents, respectively. The rapid dissipation of heat in laser heating is particularly beneficial as the process allows much controlled thermal management than that in a resistive heating process in which the contribution of radiative heat transfer is negligible. For preventing heat accumulation and reducing the risks of collateral tissue damage, the adhesive composition can be treated with either continuous wave (CW) or pulsed laser irradiation operating in the photo-absorptive wavelength of the composition. In the present examples, 800-1050 nm pulsed and CW lasers were used. The localisation of energy derived from laser irradiation is much more efficient than conductive and convective heating methods. Localisation of heating and cooling confines the energy reservoir for adhesive bonding. The mixture of minerals (containing metal ions) with PCL and EC provides a much lower energy reservoir than the composition without the minerals. Minerals in the composition help with heat dissipation. Furthermore, the mineral phase is needed for promoting osteogenesis by maintaining an antimicrobial environment.

[0121] Experimental Set-Up:

[0122] 1. Nine adhesive compositions, as shown in Table 6 below, were prepared.

[0123] 2. The samples were heated using a CW 980 nm diode laser at 3W with a fibre optic fibre delivery cable and the temperature monitored.

[0124] 3. A distance between the sample and the diode laser fibre optic end was set at 10cm.

[0125] The beam diameter at the focal point was 6.6 mm.

[0126] 4. The temperature of the sample was recorded using a thermal camera and a thermocouple (K-type). The data was processed using PicoLog (Thermocouple) and ThermoB (Thermal Camera).

[0127] 5. The thermocouple was buried under lOOmg of powdered sample before the laser was switched on.

[0128] 6. During heating, the power setting was set in such a way that the samples did not reach above 200°C to prevent oxidation of ethyl cellulose and polymer.

[0129] 7. The laser was switched off and the samples allowed to cool under ambient conditions.

[0130] 3W of laser power was applied to each sample for 60 seconds after which the laser was switched off to allow cooling under ambient conditions. The experimental data is shown in Figures 4-10.

[0131] As shown in Figure 4, the ethyl cellulose sample had the slowest cooling rate. The stored thermal energy (enthalpy) in PCL, ethyl cellulose, and the binary mixture, determined from the area under the cooling curves, was 2125J, 2603J and 1470J, respectively. As shown in Figure 5, the energy stored in the physically mixed ternary sample was 1811 J and the energy stored in the chemically mixed ternary sample was 1633J. As shown in Figure 6, the energy stored in the physically mixed binary sample of PCL-mineral was 2499J and the energy stored in the chemically mixed binary sample of PCL-mineral was 2086J. As shown in Figure 7, the energy stored in the physically mixed binary sample of ethyl cellulose- mineral was 2578J and the energy stored in the chemically mixed binary sample of ethyl cellulose-mineral was 2160J.

[0132] In Figures 8 and 9, the melting characteristics for binary and ternary compositions were compared for physically mixed and chemically mixed compositions. In Figure 8, the thermal behaviour of three physically mixed compositions, two binaries (80wt% PCL+20wt% Mineral and 80wt% Ethyl cellulose+20wt% Mineral) and a ternary (50wt% PCL, 30 wt% Ethyl Cellulose, and 20wt% mineral) are shown. These can be compared with the data in Figure 9, which shows the corresponding compositions which were prepared by chemical mixing rather than physical mixing. The mass of materials tested was 0.25g mixed 1 ml of acetone.

[0133] In Figure 10, binary and ternary mixtures were heated with a 3W 980 nm fibre optic laser for longer than 60 seconds to identify that after prolonged melting of 200 seconds, the temperature of the adhesive mixture saturates.

[0134] Table 6: Sample adhesive compositions and their thermal characteristics based on Figures 4-10

[0135]

[0136] 1 PCL 59 2125 0.733 2 Ethyl Cellulose 55 2603 0.25 3 37.5wt% Ethyl Cellulose - 62.5wt% PCL 45 1470 0.685 4 Physically mixed binary: 63 2499 0.72

[0137] 80wt% PCL - 20 wt% Minerals

[0138] 5 Physically mixed binary: 50 2086 1.16

[0139] 80wt% Ethyl Cellulose - 20 wt% Minerals

[0140] 6 Chemically mixed binary: 52 2578 0.25

[0141] 80wt%PCL-20 wt% Minerals

[0142] 7 Chemically mixed binary: 48 2160 0.28

[0143] 80 wt% Ethyl Cellulose -20% Minerals

[0144] 8 Physically mixed ternary: 43 1811 0.21 50 wt%PCL-30wt% Ethyl Cellulose - 20wt%

[0145] Minerals

[0146] 9 Chemically mixed ternary: 39 1633 0.27

[0147] 50wt% PCL-30wt% Ethyl Cellulose -20 wt%

[0148] Minerals

[0149] The data in Table 6 and Figures 4-10 show that the ternary composition comprising PCL, ethyl cellulose and a mineral (i.e. a source of metal ions) consistently has a lower maximum temperature when exposed to laser radiation than a binary composition containing any two components of the ternary composition, regardless of whether the composition is prepared by physical mixing or chemical mixing using a solvent. Furthermore, the ternary mixture also has a lower total energy, regardless of method of formation, indicating that it releases less energy to surrounding tissue when used in a bone or tooth adhesive application.

[0150] Biological evaluation

[0151] The proliferation of G292 osteoblast cells on three compositions was visualised using Alexa Fluor dye and DAPI (4',6-diamidino-2-phenylindole) in fluorescence microscopy studies. The samples that were tested were: i) a chemical binary mixture of 50 wt.% PCL - 50 wt.% (hydroxyapatite 10 wt.% iron-doped); ii) a chemical binary mixture of 50 wt.% ethyl cellulose - 50 wt.% (hydroxyapatite 10 wt.% iron-doped), and iii) a chemical ternary mixture of 50 wt.% PCL - 30 wt.% ethyl cellulose - 20 wt.% (hydroxyapatite iron-doped). The analysis was performed at three time points: Day 1, Day 7, and Day 14, and the results, as shown in Figure 11, demonstrate progressive cell proliferation across all samples over time. This confirmed that the adhesive composition according to the present invention promotes osteogenesis and is therefore suitable for use in bone repair.

[0152] Tensile Strength

[0153] The tensile strengths of different adhesive compositions attached to cortical bone were determined. The compositions were (i) a ternary adhesive composition according to the present invention, (ii) a binary composition of PCL and mineral, and (iii) a binary composition of ethyl cellulose and mineral. The compositions were cured using laser irradiation and tested using a universal tensile tester which measured force (kN) versus displacement (mm). The results are illustrated in Figure 12 and show that the ternary adhesive composition according to the present invention provided the highest tensile strength of 76 ± 8 MPa at a maximum force of 0.28 kN, which is comparable to cortical bone itself which has a tensile strength of 112.5 MPa.

[0154] References (each of which is incorporated herein by reference) Mohamed, A., et al., Thermal properties of PCL / gluten bioblends characterized by TGA, DSC, SEM, and infrared-PAS. 2008. 110(5): p. 3256-3266.

[0155] Mahnaj, T., et al., Characterization of ethyl cellulose polymer. 2013. 18(5): p. 982-989.

[0156] Trivedi, M.K., et al., Characterization of physicochemical and thermal properties of biofield treated ethyl cellulose and methyl cellulose. 2015. 3(6): p. 83-91.

[0157] Davidovich-Pinhas, M., S. Barbut, and A .C. Marangoni, Physical structure and thermal behavior of ethylcellulose. 2014. 21: p. 3243-3255.

Claims

CLAIMS1. An adhesive composition comprising a source of metal ions, polycaprolactone, and a cellulose compound.

2. The composition according to claim 1, wherein the composition is adapted to at least partially melt when subjected to laser irradiation.

3. The composition according to claim 1 or 2, wherein the source of metal ions comprises a source of iron ions and a source of cerium ions.

4. The composition according to claim 3, wherein the source of iron ions is selected from the group consisting of iron doped hydroxyapatite (Caio(P04)e(OH)2), iron doped fluorapatite (Cas PC jsF), iron doped brushite (CaHPO4.2H2O), iron doped p- pyrophosphate, iron doped monetite (CaHPC ) and iron doped tricalcium phosphate (Ca3(PO4)2).

5. The composition according to claim 3 or 4, wherein the source of iron ions is present in an amount of from about 1% w / w to about 30% w / w based on the total weight of the composition.

6. The composition according to claim 3, wherein the source of cerium ions comprises CeCh.

7. The composition according to claim 3, wherein the source of cerium ions is present in an amount of from about 1% w / w to about 30% w / w based on the total weight of the composition.

8. The composition according to any preceding claim, further comprising a source of copper ions.

9. The composition according to claim 8, wherein the source of copper ions is present in the composition in an amount of from 0.1 wt% to 5 wt% based on the total weight of the composition, optionally wherein the copper ion is Cu2+.

10. The composition according to any preceding claim, wherein the polycaprolactone is present in an amount of from 0.1 wt% to 90 wt% based on the total weight of the composition.

11. The composition according to any preceding claim, wherein the cellulose compound is present in the composition in an amount of from 0.1 wt% to 90 wt% based on the total weight of the composition.

12. The composition according to any preceding claim, wherein the cellulose compound is alkyl cellulose, optionally methyl cellulose or ethyl cellulose.

13. The composition according to any preceding claim, further comprising graphene and / or chitosan.

14. The composition according to claim 13, wherein the graphene and / or chitosan is present in an amount of from 0.01% to 5% w / w based on the total weight of the composition.

15. The composition according to any preceding claim, wherein the metal ions are releasable from the composition in use to produce an anti -infective effect.

16. A composition according to any preceding claim for use in bone or tooth repair.

17. The composition for use according to claim 16, wherein the use comprises contacting bone or tooth to be repaired with the composition, heating the composition by laser irradiation to at least partially melt the composition, and causing or allowing the composition to set.

18. A method for repairing bone or tooth material, the method comprising:contacting the bone or tooth material with the adhesive composition according to any one of claims 1 to 15;heating the adhesive composition by laser irradiation to at least partially melt the composition; and- causing or allowing the composition to set.

19. The method according to claim 18 wherein the laser irradiation is continuous wave or pulsed wave irradiation.

20. The method according to claim 18 or 19 wherein the laser comprises infrared radiation having a wavelength of from 700 nm to 11000 nm, such as 700 nm to 4000 nm.

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