Microfluidic-prepared, monodisperse, X-ray-visible, embolic microspheres for non-oncological embolization applications.
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ABSTRACT:
SUBMITTER: Beh CW
PROVIDER: S-EPMC7531348 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Catheter embolization is a minimally invasive technique that relies on embolic agents and is now widely used to treat various high-prevalence medical diseases. Embolic agents usually need to be combined with exogenous contrasts to visualize the embolotherapy process. However, the exogenous contrasts are quite simply washed away by blood flow, making it impossible to monitor the embolized location. To solve this problem, a series of sodium hyaluronate (SH) loaded with bismuth sulfide (Bi2S3) nanorods (NRs) microspheres (Bi2S3@SH) were prepared in this study by using 1,4-butaneglycol diglycidyl ether (BDDE) as a crosslinker through single-step microfluidics. Bi2S3@SH-1 microspheres showed the best performance among other prepared microspheres. The fabricated microspheres had uniform size and good dispersibility. Furthermore, the introduction of Bi2S3 NRs synthesized by a hydrothermal method as Computed Tomography (CT) contrast agents improved the mechanical properties of Bi2S3@SH-1 microspheres and endowed the microspheres with excellent X-ray impermeability. The blood compatibility and cytotoxicity test showed that the Bi2S3@SH-1 microspheres had good biocompatibility. In particular, the in vitro simulated embolization experiment results indicate that the Bi2S3@SH-1 microspheres had excellent embolization effect, especially for the small-sized blood vessels of 500-300 and 300 μm. The results showed the prepared Bi2S3@SH-1 microspheres have good biocompatibility and mechanical properties, as well as certain X-ray visibility and excellent embolization effects. We believe that the design and combination of this material has good guiding significance in the field of embolotherapy.
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Project description:The synthesis of organic-inorganic hybrid particles with highly controlled particle sizes in the micrometer range is a major challenge in many areas of research. Conventional methods are limited for nanometer-scale fabrication because of the difficulty in controlling the size. In this study, we present a microfluidic method for the preparation of organic-inorganic hybrid microparticles with poly (1,10-decanediol dimethacrylate-co-trimethoxysillyl propyl methacrylate) (P (DDMA-co-TPM)) as the core and silica nanoparticles as the shell. In this approach, the droplet-based microfluidic method combined with in situ photopolymerization produces highly monodisperse organic microparticles of P (DDMA-co-TPM) in a simple manner, and the silica nanoparticles gradually grow on the surface of the microparticles prepared via hydrolysis and condensation of tetraethoxysilane (TEOS) in a basic ammonium hydroxide medium without additional surface treatment. This approach leads to a reduction in the number of processes and allows drastically improved size uniformity compared to conventional methods. The morphology, composition, and structure of the hybrid microparticles are analyzed by SEM, TEM, FT-IR, EDS, and XPS, respectively. The results indicate the inorganic shell of the hybrid particles consists of SiO2 nanoparticles of approximately 60 nm. Finally, we experimentally describe the formation mechanism of a silica-coating layer on the organic surface of polymeric core particles.
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Project description:Degradable embolic agents that provide transient arterial occlusion during embolization procedures have been of interest for many years. Ideally, embolic agents are visible with standard imaging modalities and offer on-demand degradability, permitting physicians to achieve desired arterial occlusion tailored to patient and procedure indication. Subsequent arterial recanalization potentially enhances the overall safety and efficacy of embolization procedures. Here, we report on-demand degradable and MRI-visible microspheres for embolotherapy. Embolic microspheres composed of calcium alginate and USPIO nanoclusters were synthesized with an air spray atomization and coagulation reservoir equipped with a vacuum suction. An optimized distance between spray nozzle and reservoir allowed uniform size and narrow size distribution of microspheres. The fabricated alginate embolic microspheres crosslinked with Ca2+ demonstrated highly responsive on-demand degradation properties in vitro and in vivo. Finally, the feasibility of using the microspheres for clinical embolization and recanalization procedures was evaluated with interventional radiologists in rabbits. Digital subtraction angiography (DSA) guided embolization of hepatic arteries with these embolic microspheres was successfully performed and the occlusion of artery was confirmed with DSA images and contrast enhanced MRI. T2 MRI visibility of the microspheres allowed to monitor the distribution of intra-arterial (IA) infused embolic microspheres. Subsequent on-demand image-guided recanalization procedures were also successfully performed with rapid degradation of microspheres upon intra-arterial infusion of an ion chelating agent. These instant degradable embolic microspheres will permit effective on-demand embolization/recanalization procedures offering great promise to overcome limitations of currently available permanent and biodegradable embolic agents.
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Project description:Monodisperse polyvinyl alcohol (PVA) microspheres have been widely used for targeted drug delivery, embolization, and templates. However, the fast and facile fabrication of PVA microspheres with uniform size and internal structure and good sphericity remains a challenge. In this study, the PVA microspheres with uniformity in the size, shape, and internal structure were rapidly fabricated, using single-emulsion droplet templates by an on-chip approach. First, we designed a polydimethylsiloxane (PDMS) microfluidic chip integrated with three functional units, used for the droplet generation, mixing of reagents, and pre-curing of PVA microspheres, respectively. Then, we precisely controlled the generation of PVA aqueous droplets, mixing of reagents, and the gelation rate for the production of high-quality microspheres by adjusting the pH value, flow rate, and the channel structure. The prepared PVA microspheres are characterized with good sphericity, uniform internal structure, and narrow size distribution. The microspheres have good adsorption capacity and recyclability for small-molecule drugs, as demonstrated by the adsorption and desorption of methylene blue (MB). The adsorption behavior is well described by the pseudo-second-order model, and intraparticle diffusion is as fast as the external film diffusion.
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Project description:We report a facile and robust microfluidic method to fabricate polymeric core-shell microspheres as delivery vehicles for biomedical applications. The characteristics of core-shell microspheres can be precisely and easily tuned by manipulating the microfluidic double emulsion templates. The addition of a shell can significantly improve the versatility as well as functionality of these microspheres as delivery vehicles. We demonstrate that the nature of the shell material plays an important role in the properties of the core-shell delivery vehicles. The release kinetics is significantly influenced by the material of the shell and other characteristics such as the thickness. For example, by adding a poly(lactic-co-glycolic acid) (PLGA) shell to an alginate core, the encapsulation efficiency is enhanced and undesired leakage of hydrophilic actives is prevented. By contrast, adding an alginate shell to PLGA core can lead to a reduction of the initial release rate, thus extending the release period of hydrophobic actives. Microfluidic fabrication enables the generation of precisely controlled core-shell microspheres with a narrow size distribution, which enables the investigation of the relationship between the release kinetics of these microspheres and their characteristics. The approach of using core-shell particles as delivery vehicles creates new opportunities to customize the release kinetics of active ingredients.
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Project description: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 300 μm. 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.
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Project description:PurposeTransarterial chemoembolization is accepted therapy for hepatocellular carcinoma (HCC). No randomized trial has demonstrated superiority of chemoembolization compared with embolization, and the role of chemotherapy remains unclear. This randomized trial compares the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres.Materials and methodsAt a single tertiary referral center, patients with HCC were randomly assigned to embolization with microspheres alone (Bead Block [BB]) or loaded with doxorubicin 150 mg (LC Bead [LCB]). Random assignment was stratified by number of embolizations to complete treatment, and assignments were generated by permuted blocks in the institutional database. The primary end point was response according to RECIST 1.0 (Response Evaluation Criteria in Solid Tumors) using multiphase computed tomography 2 to 3 weeks post-treatment and then at quarterly intervals, with the reviewer blinded to treatment allocation. Secondary objectives included safety and tolerability, time to progression, progression-free survival, and overall survival. This trial is currently closed to accrual.ResultsBetween December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, -0.1%; 95% CI, -9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively.ConclusionThere was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.
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Project description:Biodegradable polymer double-wall microspheres (DWMS) are promising vehicles for macromolecular therapeutics such as proteins and peptides. Using precision particle fabrication (PPF) technology, uniform DWMS with outer diameter approximately 55 ?m were fabricated comprising poly(lactide-co-glycolide) cores encapsulating bovine serum albumin (BSA) and approximately 10 ?m thick, drug-free, poly(lactic acid) (PLA) shells of varying PLA molecular weight. Also, monolithic single-wall microspheres (SWMS) were fabricated to mimic the BSA-loaded core. The use of relatively fast-extracting ethyl acetate and slowly extracting dichloromethane as shell- and core-phase solvents, respectively, was found to produce DWMS with well-defined core-shell structure, high BSA encapsulation efficiency, and the desired localization of protein in the particle core. Initial protein distribution, particle erosion, and in vitro protein release from DWMS and SWMS were examined. The presence of a BSA-free shell in DWMS decreased the protein release rate and extended the duration of release from approximately 50 days to 70-80 days, demonstrating the capacity of such DWMS to provide enhanced control of protein delivery rates.
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