| Interventional therapy has been developed as one of the most widely used treatments for diseases in parallel with medical treatment and surgical operation treatment. It has many advantages, such as small wound, facility, safety, effectivity and fewer complications. Therefore, it has been widely used in the treatment of cancer and arteriovenous malformation and so on. However, present interventional embolic microspheres are non-uniform and lack of inherent visibility under an accurate radiographical or magnetic resonant(MR) instrument. The former affects the effect of the embolization and the later restricts the postoperative evaluation due to the shortness of non-invasive tracking and mapping the fate of embolic agents. In this paper, two kinds of inherent visible calcium alginate microspheres with uniform shape and size were prepared controllably for interventional embolotherapy based on a microfluidic technique. The main contents and results are as follows:1. Monodispersed spherical calcium alginate(denoted as Ca-ALG) microspheres with uniform and controllable size was prepared by using microfluidics technique. Herein, an aqueous solution of sodium alginate(denoted as Na-ALG) was used as a dispersed phase, and the liquid paraffin containing CaCl2 nanoparticles formed in situ was used as a continuous phase and the CaCl2 nanoparticles was the pre-crosslinker of Na-ALG droplets produced in the microchannel. The size of CaCl2 nanoparticles was characterized by dynamic light scattering method. The morphology of Ca-ALG gel microspheres was observed by using an optical microscope and scanning electron microscope(SEM). In addition, the flowing and packing state of spherical and nonspherical microspheres in microcatheter was observed under an optical microscope. The results show that the pre-crosslinked Na-ALG droplets have great rigidity and can resist the deformation caused by gravity and interfacial tension during entering the collection solution. And the spherical morphology of Ca-ALG microspheres are not affected by the preparation conditions including microfluidic devices, flow rates, droplets' size and collection height. In addition, the size of the spherical Ca-ALG microspheres can be well controlled from 40 to 700 ?m in diameter by changing the dimension of the microchannels and the flow rate ratios of the dispersed phase and continuous phase. Compare to nonspherical microspheres, spherical Ca-ALG microspheres is easy to push and pack closely and orderly in the microcatheter, which meets the requirement of the interventional embolotherapy.2. Inherent radiopaque embolic materials, alginate microspheres loaded with in situ synthesized BaSO4(denoted as BaSO4/Ba-ALG microspheres) was prepared in one step based on the flow-focusing microfluidic devices combining with external ionic crosslinking method. Herein, sodium alginate aqueous solution containing Na2SO4 was used as the dispersed phase and BaCl2 aqueous solution was used as a collection solution. The morphology of the prepared BaSO4/Ba-ALG microspheres was studied by an optical microscope and SEM, and their visibilities under X-ray in vitro and in vivo were investigated on a digital subtraction angiography(DSA) and computed tomography(CT) instrument used in clinic. The results show the prepared microspheres are uniform and have excellent visibility under X-ray. In addition, the embolic efficacy is similar to that of commercial Ca-ALG embolic agent assessed by histopathological analysis.3. Magnetic Ca-ALG microspheres was prepared via T-junction microfluidic device.The concentration of Fe3O4 in the prepared microspheres was varied to get the clear nuclear magnetic resonance imaging(MRI).The prepared microspheres was characterized in morphology, structure, magnetic properties and thermal stability using various methods. 5- Fluorouracil(5-FU) and Doxorubicin hydrochloride(DOX?HCl) were choosed as model drugs and the release kinetics of the drug-loaded magnetic Ca-ALG microspheres were investigated in vitro. These results show that the prepared magnetic microspheres possess superparamagnetism with uniform shape and size, and the suitable content of Fe3O4 in microspheres is 0.6 mg/mL for MRI. In addition, the microspheres have a sustainable drug release profile in vitro. Especially, the magnetic Ca-ALG microspheres loaded with two kinds of drugs have more obvious sustainable release. Therefore, the magnetic microspheres are multi-functional combined with MR-visibility, embolization and chemotherapy.In a word, kinds of functional calcium alginate microspheres with uniform and controllable size were prepared based on a microfluidic technique. These microspheres have the advantages of fluent moving, ordered packing in a microcatheter and direct real-time investigation on the position of the microspheres in vivo as used as embolic microspheres. Furthermore, the drug-loaded microspheres have the profile of sustainable release. |
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