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Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer-mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA-based MB products, facilitating the potential translation of next-generation PBCA MB., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The regeneration of bone defects that exceed 2 cm is a challenge for the human body, necessitating interventional therapies. Demineralized bone matrices (DBM) derived from biological tissues have been employed for bone regeneration and possess notable osteoinductive and osteoconductive characteristics. Nevertheless, their efficiency in regenerating critically sized injuries is limited, and therefore additional signaling cues are required. Thanks to the piezoelectric properties of the bone, external physical stimulation is shown to accelerate tissue healing. We have implanted human DBM in critically sized cranial bone defects in rat animal models and exposed them to an external magnetic field (1 T) to enhance endogenous bone formation. Our in vitro experiments showed the superior cytocompatibility of DBM compared to cell culture plates. Furthermore, alkaline phosphatase activity after 14 days and Alizarin red staining at 28 days demonstrated differentiation of rat bone marrow mesenchymal stem cells into bone lineage on DBM. Computer tomography images together with histological analyses showed that implanting DBM in the injured rats significantly enhanced bone regeneration. Notably, combining DBM transplantation with a 2 h daily exposure to a 1 T magnetic field for 2 weeks (day 7 to 21 post-surgery) significantly improved bone regeneration compared to DBM transplantation alone. This research indicates that utilizing external magnetic stimulation significantly enhances the potential of bone allografts to regenerate critically sized bone defects.

Photoacoustic (PA) imaging is an emerging diagnostic technology that combines the penetration depth of ultrasound (US) imaging and the contrast resolution of optical imaging. Although PA imaging can visualize several endogenous chromophores to obtain clinically-relevant information, multiple applications require the administration of external contrast agents. Metal phthalocyanines have strong PA properties and chemical stability, but their extreme hydrophobicity requires their encapsulation in delivery systems for biomedical applications. Hence, we developed hybrid US/PA contrast agents by encapsulating metal phthalocyanines in poly(butyl cyanoacrylate) microbubbles (PBCA MB), which display acoustic response and ability to efficiently load hydrophobic drugs. Six different metal chromophores were loaded in PBCA MB, showing greater encapsulation efficiency with higher chromophore hydrophobicity. Notably, while the US response of the MB was unaffected by the loading of the chromophores, the PA characteristics varied greatly. Among the different formulations, MB loaded with zinc and cobalt naphthalocyanines showed the strongest PA contrast, as a result of high encapsulation efficiencies and tunable optical properties. The strong US and PA contrast signals of the formulations were preserved in biological environment, as demonstrated by in vitro imaging in serum and whole blood, and ex vivo imaging in deceased mice. Taken together, these findings highlight the advantages of combining highly hydrophobic PA contrast agents and polymeric MB for the development of contrast agents for hybrid US/PA imaging, where different types of information (structural, functional, or potentially molecular) can be acquired by combining both imaging modalities.

Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer-based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US-mediated blood-brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface-modified with BBB-specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod-shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti-TfR-MB bind more efficiently to BBB endothelium than spherical anti-TfR-MB, both in vitro and in vivo. BBB-associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB-targeted MB. These findings exemplify the potential of antibody-modified nonspherical MB for targeted and triggered drug delivery to the brain., (© 2023 Wiley-VCH GmbH.)

Ultrasound (US) is routinely used for diagnostic imaging and increasingly employed for therapeutic applications. Materials that act as cavitation nuclei can improve the resolution of US imaging, and facilitate therapeutic US procedures by promoting local drug delivery or allowing temporary biological barrier opening at moderate acoustic powers. Polymeric materials offer a high degree of control over physicochemical features concerning responsiveness to US, e.g. via tuning chain composition, length and rigidity. This level of control cannot be achieved by materials made of lipids or proteins. In this perspective, we present key engineered polymeric materials that respond to US, including microbubbles, gas-stabilizing nanocups, microcapsules and gas-releasing nanoparticles, and discuss their formulation aspects as well as their principles of US responsiveness. Focusing on microbubbles as the most common US-responsive polymeric materials, we further evaluate the available chemical toolbox to engineer polymer shell properties and enhance their performance in US imaging and US-mediated drug delivery. Additionally, we summarize emerging applications of polymeric microbubbles in molecular imaging, sonopermeation, and gas and drug delivery, based on refinement of MB shell properties. Altogether, this manuscript provides new perspectives on US-responsive polymeric designs, envisaging their current and future applications in US imaging and therapy., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

While bone regenerates itself after an injury, a critical bone defect requires external interventions. Engineering approaches to restore bone provide a temporary scaffold to support the damage and provide beneficial biological cues for bone repair. Biomimetically generated scaffolds replicate the naturally occurring phenomena in bone regeneration. In this study, a gelatin-calcium phosphate nanocomposite was synthesized by an efficient and cost-effective double-diffusion biomimetic approach. Calcium and phosphate ions are impregnated in the gelatin, mimicking the natural bone mineralization process. Glutaraldehyde from 0.5 to 2 w/v% was used for gelatin cross-linking and mechanical properties of the scaffold, and its biological support for rat bone marrow mesenchymal stromal cells was analyzed. Analysis of scanning electron microscopy images of the nanocomposite scaffolds and Fourier transform infrared (FTIR) and X-ray diffraction (XRD) characterizations of these scaffolds confirmed precipitation of calcium phosphates in the gelatin. Moreover, lysozyme degradation assay showed that scaffold degradation reversely correlates with the concentration of the cross-linking agent. Increased glutaraldehyde concentrations enhanced the mechanical properties of the scaffolds, bringing them closer to those of cancellous bone. Rat bone marrow mesenchymal stromal cells maintained their viability on these scaffolds compared to standard cell culture plates. In addition, these cells showed differentiation into bone lineage as evaluated from alkaline phosphatase activity up to 21 days and Alizarin red staining of the cells over 28 days. Eventually, scaffolds were implanted in a cranial defect in a rat animal model with a 5 mm diameter. Bone regeneration was studied over 90 days. Analysis of histological sections of the injury and computer tomography images revealed that nanocomposite scaffolds cross-linked with 1% w/v glutaraldehyde provide the maximum bone regeneration after 90 days. Collectively, our data show that nanocomposite scaffolds developed here provide effective regeneration for extensive bone defects in vivo .

In this work, neat and supported H 6 P 2 W 18 O 62 into nanocage of β-zeolite were synthesized. However, H 6 P 2 W 18 O 62 into nanocage of β-zeolite was synthesized via template synthesis method. In addition, TiO 2 was supported on H 6 P 2 W 18 O 62 /β zeolite by impregnation method. The obtained materials were characterized by XRD, FT-IR, UV-Vis, FESEM and EDS techniques. Also, W and Ti contents of the catalyst were determined by ICP and EDS technique. The results reveal that the photocatalyst performance depends on catalyst loading, pH effect, and methyl orange concentration. Photocatalytic degradation of methyl orange follows a pseudo-first order kinetic. The chemical oxygen demand (COD) experimental proved mineralization of methyl orange. Another reason for degradation and mineralization of methyl orange is the absence of hydrazine at the end of reaction which is one of the photodecolorization products. The plausible mechanism for photodegradation of MO was proposed., (© 2018 The American Society of Photobiology.)

In this work, graphene oxide (GO) reinforcement was used to improve the strength and fracture toughness of the calcium phosphate (CaP) coating applied on the anodized titanium using pulse electrodeposition. Based on the results, the CaP coating consisted of mixed phases of octa-calcium phosphate (OCP), dicalcium phosphate dehydrate (DCPD) and hydroxyapatite (HAp); however, compositing of this coating with GO caused deposition of the pure HAp phase. Moreover, the nanohardness and Young's modulus of the CaP-GO coating increased over 52% and 41%, respectively, as compared to those measured for the GO-free coating. An improvement of about 16% in the adhesion strength of the CaP coating composited with GO to the anodized titanium was also arisen from improving integrity, crystallinity and decreasing the Young's modulus mismatch of this coating with titanium substrate. Finally, uniformity in the microstructure and more biostability of the CaP-GO coating led to its better protection against the corrosion of anodized titanium., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this study, the ultrasound-assisted pulse electrodeposition was introduced to fabricate the graphene oxide (GO)-hydroxyapatite (HA) coating on TiO 2 nanotubes. The results of the X-ray diffraction (XRD), Fourier Transform Infrared spectroscope (FTIR), Transmission Electron Microscope (TEM) and micro-Raman spectroscopy showed the successful synthesis of GO. The Scanning Electron Microscope (SEM) images revealed that in the presence of ultrasonic waves and GO sheets a more compact HA-based coating with refined microstructure could be formed on the pretreated titanium. The results of micro-Raman analysis confirmed the successful incorporation of the reinforcement filler of GO into the coating electrodeposited by the ultrasound-assisted method. The FTIR analysis showed that the GO-HA coating was consisted predominantly of the B-type carbonated HA (CHA) phase. The pretreatment of the substrate and incorporation of the GO sheets into the HA coating had a significant effect on improving the bonding strength at the coating-substrate interface. Moreover, the results of the fibroblast cell culture and 3‑(4,5‑dimethylthiazolyl‑2)‑2, 5‑diphenyltetrazolium bromide (MTT) assay after 2 days demonstrated a higher percentage of cell activity for the GO-HA coated sample. Finally, the 7-day exposure to simulated body fluid (SBF) showed a faster rate of apatite precipitation on the GO-HA coating, as compared to the HA coating and pretreated titanium., (Copyright © 2018 Elsevier B.V. All rights reserved.)