| The therapy of large bone defects induced by bone tumor resection,congenital diseases,traumatic injury,or infection remains an enormous challenge in clinical practice.Although bone tissue possesses a natural self-healing ability,the defects are difficult to recover unaidedly within a short time,especially for those exceeding the critical size threshold.Traditional bone cement scaffold is one of the most widely used injectable biological scaffolds in clinical treatment,such as poly(methylmethacrylate)(PMMA)cement and bioactive calcium phosphate cement(CPC),which can provide sufficient mechanical support for the damaged site and induce the formation of bonelike apatite layers,thus facilitating the bone regeneration process.Nevertheless,those bone cement scaffolds lack interconnected pore structure and are plagued by uncontrollable and limited biodegradability,leading to poor osteoconductivity and bone repair efficiency.Hence,fast-setting cement systems(Calcium/Magnesium Phosphate Cement,CMPC)with higher early strength and an increased degradation rate have captured increasing attention.However,the clinical use of CMPC presents some problems due to the exothermic process of its fast acid-base reaction,which must be strictly controlled to avoid tissue necrosis.Hydrogel scaffolds have shown great promise for bone tissue regeneration as their hydrophilic networks possess hierarchical architectures with large porosity for metabolites and nutrients,they can also absorb a large amount of water to create an appropriate microenvironment for cell migration and osteogenic differentiation.However,the weak mechanical properties and interfacial reactions between the organic polymer network and the host bone may result in the dislocation of the implants,severely diminishing the healing efficiency.Moreover,multiple triggering factors including external heating,UV-irradiation,and electricity inducement have to be applied to facilitate the gelation process,which has further complicated the hydrogel preparation and clinical application.Inspired by the hydration process of traditional CMPC particles,we have designed and developed an injectable and robust hydrogel nanocomposite with in-situ generation capability and excellent cell attachment performance for bone repair based on the combination of CMPC particles and hydrogel networks.Firstly,we designed the materials and structure of the composite hydrogel:the calcium/magnesium ions released from the dissolution of CMPC particles could ionically crosslink-arginine-glycine-aspartic acid(RGD)-grafted oxidized sodium alginate(OSA)to form the first hydrogel network within seconds,therefore avoiding the injected hydrogel precursor from leaking out of the target site under the flow of body fluid.The formation of a second poly(acrylamide)(PAM)hydrogel network is a free-radical polymerization process that could be accelerated by absorbing the heat released from the hydration reaction of the CMPC particles.Then,the gelation time and heat release could be regulated by adjusting the composition and incorporation dosage of CMPC particles to better meet the stringent requirements for in-situ bone regeneration.Subsequently,the mineral composition and microstructure of the composite hydrogel were investigated by X-ray diffraction and scanning electron microscope,and the results indicated that this hydrogel system could be reinforced by the hydration products of CMPC by forming a rigid skeleton,leading to enhanced toughness.The compressive strength could be improved from less than 0.1 MPa to around 6.2 MPa.Those nanoparticulate fillers are also exploited to increase the interface roughness due to the formation of a gel/bone hybrid layer at the interface for the improvement of osteoblast adhesion.Furthermore,hydration products of CMPC particles can continuously release calcium and magnesium ions,which can make up for the poor osteoinductivity of the pure hydrogel system.Furthermore,a series of cell experiments and animal experiments have demonstrated its excellent biocompatibility and the capacity of promoting cell differentiation thereby promoting the osteogenesis process.After figuring out the relationship between materials and structure of the composite hydrogel,we further demonstrated its excellent biocompatibility and also observed the morphology of cells cultured on the hydrogel.By monitoring the alkaline phosphatase expression,the m RNA,and protein expression of some genes essential for new bone formation,we verified its superb ability to facilitate the osteogenic differentiation of L929,MC3T3-E1,and h BMSCs.In the end,the relatively high-volume fraction of new bone tissues demonstrated the ability of this composite hydrogel to accelerate bone formation in vivo.Furthermore,the new bone tissues are distributed at the defects more evenly.Generally speaking,this novel hybrid hydrogel has the characteristics of simple preparation procedures,controllable solidification time and temperature rise,well-interconnected pore structure,excellent biocompatibility,and biodegradability,which is convenient and suitable for clinical application.The innovative synergistic mechanism between inorganic particles and organic hydrogels also provides a new idea for the material and structural design of bone repair scaffolds. |
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