Immobilized thrombin on X-ray radiopaque polyvinyl alcohol/chitosan embolic microspheres for precise localization and topical blood coagulation

Trans-catheter arterial embolization(TAE)plays an important role in treating various diseases.The available embolic agents lack X-ray visibility and do not prevent the reflux phenomenon,thus hindering their application for TAE therapy.Herein,we aim to develop a multifunctional embolic agent that combines the X-ray radiopacity with local procoagulant activity.The barium sulfate nanoparticles(BaSO4 NPs)were synthesized and loaded into the polyvinyl alcohol/chitosan(PVA/CS)to prepare the radiopaque BaSO4/PVA/CS microspheres(MS).Thereafter,thrombin was immobilized onto the BaSO4/PVA/CS MS to obtain the thrombin@BaSO4/PVA/CS MS.The prepared BaSO4/PVA/CS MS were highly spherical with diameters ranging from 100 to 300μm.In vitro CT imaging showed increased X-ray visibility of BaSO4/PVA/CS MS with the increased content of BaSO4 NPs in the PVA/CS MS.The biocompatibility assessments demonstrated that the MS were non-cytotoxic and possessed permissible hemolysis rate.The biofunctionalized thrombin@BaSO4/PVA/CS MS showed improved hemostatic capacity and facilitated hemostasis in vitro.Additionally,in vivo study performed on a rabbit ear embolization model confirmed the excellent X-ray radiopaque stability of the BaSO4/PVA/CS MS.Moreover,both the BaSO4/PVA/CS and thrombin@BaSO4/PVA/CS MS achieved superior embolization effects with progressive ischemic necrosis on the ear tissue and induced prominent ultrastructural changes in the endothelial cells.The findings of this study suggest that the developed MS could act as a radiopaque and hemostatic embolic agent to improve the embolization efficiency.

Improved osteointegration and angiogenesis of strontium-incorporated 3D-printed tantalum scaffold via bioinspired polydopamine coating

Tantalum(Ta)is used in orthopedic implants because it has excellent biocompatibility.However,high elastic modulus,bio-inertness,and unsatisfactory osteointegration limits its wider use in clinical applications.Herein,a 3 D porous Ta scaffold with low elastic modulus was fabricated using selective laser melting(SLM).Strontium(Sr)was incorporated on the surface of the scaffold with the aid of polydopamine(PDA)to further improve its osteointegration ability.The prepared scaffolds exhibited a stable Sr ion release in 14 d.Rat bone marrow stem cells(BMSCs)showed improved early adhesion and spreading after Sr was incorporated on the porous Ta surface.The osteogenic behavior,including extracellular matrix mineralization(ECM),alkaline phosphatase activity(ALP),and expression of bone-related RNA,were all enhanced.Furthermore,the Sr-incorporated porous Ta scaffolds exhibited better angiogenic behavior,such as promoting migration,tube formation,and angiogenesis-related RNA expression abilities of human vascular endothelial cells(HUVECs).Additionally,histological images(H&E,Masson and CD31 immunofluorescent staining)suggested that Sr-incorporated porous Ta scaffolds displayed enhanced osteointegration and angiogenesis after implantation in rat femur for 12 weeks.These findings prove that the PDA-based Sr-incorporated porous Ta scaffolds show promising use in orthopedic implants.

Biomimetic Ti-6Al-4V alloy/gelatin methacrylate hybrid scaffold with enhanced osteogenic and angiogenic capabilities for large bone defect restoration

Titanium-based scaffolds are widely used implant materials for bone defect treatment.However,the unmatched biomechanics and poor bioactivities of conventional titanium-based implants usually lead to insufficient bone integration.To tackle these challenges,it is critical to develop novel titanium-based scaffolds that meet the bioadaptive requirements for load-bearing critical bone defects.Herein,inspired by the microstructure and mechanical properties of natural bone tissue,we developed a Ti-6Al-4V alloy(TC4)/gelatin methacrylate(GelMA)hybrid scaffold with dual bionic features(GMPT)for bone defect repair.GMPT is composed of a hard 3D-printed porous TC4 metal scaffold(PT)backbone,which mimics the microstructure and mechanical properties of natural cancellous bone,and a soft GelMA hydrogel matrix infiltrated into the pores of PT that mimics the microenvironment of the extracellular matrix.Ascribed to the unique dual bionic design,the resultant GMPT demonstrates better osteogenic and angiogenic capabilities than PT,as confirmed by the in vitro and rabbit radius bone defect experimental results.Moreover,controlling the concentration of GelMA(10%)in GMPT can further improve the osteogenesis and angiogenesis of GMPT.The fundamental mechanisms were revealed by RNA-Seq analysis,which showed that the concentration of GelMA significantly influenced the expression of osteogenesis-and angiogenesis-related genes via the Pi3K/Akt/mTOR pathway.The results of this work indicate that our dual bionic implant design represents a promising strategy for the restoration of large bone defects.

A pH-response chemotherapy synergistic photothermal therapy for tumor suppression and bone regeneration by mussel-inspired Mg implant

Primary malignant bone tumors can be life-threatening.Surgical resection of tumor plus chemotherapy is the standard clinical treatment.However,postoperative recovery is hindered due to tumor recurrence caused by residual tumor cells and bone defect caused by resection of tumor tissue.Herein,a multifunctional mussel-inspired film was fabricated on Mg alloy,that is,an inner hydrothermal-treated layer,a middle layer of polydopamine,and an outer layer of doxorubicin.The modified Mg alloy showed excellent photothermal effect and thermal/pH-controlled release of doxorubicin.The synergistic effect of chemotherapy and photothermal therapy enabled the modified Mg alloy to kill bone tumor in vitro and inhibit tumor growth in nude mice.Moreover,because of the controlled release of Mg ions and biocompatibility of polydopamine,the modified Mg alloy supported extracellular matrix mineralization,alkaline phosphatase activity,and bone-related gene expression in C3H10T1/2.Bone implantation model in rats verified that the modified Mg showed excellent osteointegration.These findings prove that the use of mussel-inspired multifunction film on Mg alloy offers a promising strategy for the therapy of primary malignant bone tumor.