Background: Compared to metallic hardware, an effective bone adhesive can revolutionize the treatment of clinically challenging situations such as comminuted, articular and pediatric fractures. The present study aims at developing such a bio-inspired bone adhesive, based upon a modified mineral-organic adhesive with tetracalcium phosphate (TTCP) and phosphoserine (OPS) by incorporating nanoparticles of polydopamine (nPDA). Methods: The optimal formulation was screened using in vitro instrumental traction tests. Adhesion to bone, cohesion, setting time, and biomineralization of the optimized adhesive was then assessed with ex vivo instrumental and manual tests, compression tests, setting time measurement and simulated body fluid assay. Cytotoxicity was assessed by extraction test (ISO 10993-5). A new in vivo model was developed: the rat fibula was glued to the ipsilateral tibia, simulating the clinical scenario of autograft fixation under low mechanical load. Analysis was performed clinically, radiologically with micro-computed tomography and histologically (without decalcification). Results: The optimal formulation was found as 50%molTTCP/50%molOPS-2%wtnPDA with a liquid-to-powder ratio of 0.21 mL/g. This adhesive has a substantially stronger adhesive strength (1.0–1.6 MPa) to bovine cortical bone (after a 24-hour soak in a physiological saline) than the adhesive without nPDA (0.5–0.6 MPa), and is more quickly induced and has more abundant surface mineralization when immersed in simulated body fluid. Moreover, non-cytotoxicity of this adhesive was confirmed in vitro. In vivo, the TTCP/OPS-nPDA adhesive (n=7) was shown to be effective in stabilizing the graft without displacement (clinical success rate of 86% and 71% respectively at 5 and 12 weeks) compared to a sham control (0%). Significant coverage of newly formed bone was particularly observed on the surface of the adhesive, thanks to the osteoinductive property of nPDA. Conclusions: To conclude, the TTCP/OPS-nPDA adhesive fulfilled many clinical requirements for the bone fixation, and potentially could be functionalized via nPDA to offer more biological activities, e.g. anti-infection after antibiotics loading. Trial Registration: Not applicable

In the past decade, the adhesive properties of catechol derivatives have inspired researchers for the design of various macromolecular architectures featuring fascinating properties and finding applications in energy storage, coatings, adhesives and biomaterials. In this work, the complexation of catechol end-functionalized polymers prepared by RAFT polymerization was investigated in aqueous media with the electron-deficient tetracationic cyclophane cyclobis(paraquat-p-phenylene) (CBPQT 4+ ) by using UV-Vis and 1 H NMR experiments. The formation of pseudorotaxanes between the catechol end-functionalized polymers and the CBPQT 4+ ,4Cl À leads to the formation of colored guest-specific complexes displaying tunable complexation properties. In particular, we demonstrated that the thermo-responsiveness i.e. the lower critical solution temperature (LCST) of the catechol end-functionalized poly(NIPAM) could be used as a simple and convenient tool to disrupt the complexation with CBPQT 4+ ; 4Cl À resulting in the disappearance of the characteristic color of the Catechol/BB complex while releasing the cyclophane in the aqueous solution. Furthermore, these supramolecular host/guest assemblies could be disrupted, on demand, by the addition of a competitive Naphthalene derivative leading to the appearance of the characteristic purple color of Naphthalene/CBPQT 4+ complexes. These results pave the way for the design of a new generation of stimuli responsive materials with control properties.catechol end-functionalized polymers, CBPQT 4+ , host-guest complexation, thermoresponsive polymers | INTRODUCTIONNature is a fascinating source of inspiration for stimulating research in materials science. Indeed, recent progress in the adhesion mechanism of marine mussels 1 has led to the emergence of a new generation of materials mimicking the properties of these natural systems and finding various applications in coatings, 2 adhesives 3 and biomaterials. 4 In

Compared to metallic hardware, an effective bone adhesive can revolutionize the treatment of clinically challenging situations such as comminuted, articular, and pediatric fractures. The present study aims to develop such a bio-inspired bone adhesive, based upon a modified mineral-organic adhesive with tetracalcium phosphate (TTCP) and phosphoserine (OPS) by incorporating nanoparticles of polydopamine (nPDA). The optimal formulation, which was screened using in vitro instrumental tensile adhesion tests, was found to be 50%molTTCP/50%molOPS-2%wtnPDA with a liquid-to-powder ratio of 0.21 mL/g. This adhesive has a substantially stronger adhesive strength (1.0–1.6 MPa) to bovine cortical bone than the adhesive without nPDA (0.5–0.6 MPa). To simulate a clinical scenario of autograft fixation under low mechanical load, we presented the first in vivo model: a rat fibula glued to the tibia, on which the TTCP/OPS-nPDA adhesive (n = 7) was shown to be effective in stabilizing the graft without displacement (a clinical success rate of 86% and 71% at 5 and 12 weeks, respectively) compared to a sham control (0%). Significant coverage of newly formed bone was particularly observed on the surface of the adhesive, thanks to the osteoinductive property of nPDA. To conclude, the TTCP/OPS-nPDA adhesive fulfilled many clinical requirements for the bone fixation, and potentially could be functionalized via nPDA to offer more biological activities, e.g., anti-infection after antibiotic loading.