WO2023278159A1 - Appareils et procédés de production de microsphères emboliques - Google Patents

Appareils et procédés de production de microsphères emboliques Download PDF

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Publication number
WO2023278159A1
WO2023278159A1 PCT/US2022/033671 US2022033671W WO2023278159A1 WO 2023278159 A1 WO2023278159 A1 WO 2023278159A1 US 2022033671 W US2022033671 W US 2022033671W WO 2023278159 A1 WO2023278159 A1 WO 2023278159A1
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WIPO (PCT)
Prior art keywords
droplets
monomer solution
microspheres
mma monomer
size distribution
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PCT/US2022/033671
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English (en)
Inventor
Weiling YU
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Varian Medical Systems, Inc.
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Publication of WO2023278159A1 publication Critical patent/WO2023278159A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the disclosure relates to apparatuses and methods for the production of embolic microspheres. More specifically, the disclosure relates to apparatuses and methods for the production of embolic microspheres having a narrow size distribution.
  • embolization involves the introduction of particles into the circulation to occlude blood vessels, for example, so as to either arrest or prevent hemorrhaging or to cut off blood flow to a structure or organ as a means to restrict necessary oxygen and nutrients to the targeted tissue. Permanent or temporary occlusion of blood vessels is desirable for managing various diseases and conditions.
  • Embolic particles are then deposited through the catheter. Embolic particles have been used, for example, in bland transarterial embolization (TAE) and transarterial chemoembolization (TACE).
  • TACE transarterial embolization
  • TACE transarterial chemoembolization
  • the embolic particles are chosen, for example, based on the size of the vessel to be occluded, the desired duration of occlusion, and/or the type of disease or condition to be treated, among others factors. Other characteristics are important when choosing an embolic particle such as the material of the particle, coatings of the particle, chemicals that may be delivered or released by the particle and other characteristics.
  • embolic particles have a spherical shape and are commonly termed microspheres due to their small size.
  • Embolic microspheres in some examples, can have sizes ranging from 20 microns to 1500 microns. Other sizes may also be used well.
  • Current apparatuses and methods of producing embolic microspheres can be costly and inefficient for various reasons. There exists a need, therefore, for improved apparatuses and methods of producing embolic microspheres that produce the microspheres in the desired size at reduced cost and increased efficiency.
  • the methods and apparatuses described herein are directed to embodiments and examples that can be used to produce embolic microspheres having dimensional characteristics and/or sizes in a narrow distribution.
  • the methods and apparatuses described herein have improved performance over existing processes. The improved performance can result in reduced cost due to the elimination of processing steps and/or equipment used in existing apparatuses and methods.
  • the methods and apparatuses of the present disclosure can reduce costs and increase efficiency by reducing the amount of waste because there are reduced amounts of embolic microspheres that do not meet the desired dimensional characteristics.
  • the methods and apparatuses of the present disclosure can also reduce the costs to produce embolic microspheres and improve the through-put of manufacturing processes.
  • the present invention provides apparatus for producing embolic microspheres, as defined in claim 1.
  • a method of producing embolic microspheres may include combining input materials to produce a methyl methacrylate (MMA) monomer solution and forming droplets from the MMA monomer solution wherein the droplets have a predetermined size distribution.
  • the method may also include depositing the droplets into a polyvinyl alcohol (PVA) solution to form polymethyl methacrylate (PMMA) microspheres.
  • PVA polyvinyl alcohol
  • the predetermined size distribution of the droplets can have a narrow size distribution in which at least 95% of the droplets have a size within a range of ⁇ 15pm.
  • the step of forming droplets from the MMA monomer solution may include a high-volume microfluidic process in which the MMA monomer solution is passed through a plurality of microchannels.
  • the step of forming droplets from the MMA monomer solution may include a precision particle fabrication process in which the MMA monomer solution is passed through a nozzle vibrated at a predetermined frequency and amplitude.
  • the step of forming droplets from the MMA monomer solution may include a membrane droplet formation process in which the MMA monomer solution is passed through a membrane having a predetermined porosity.
  • the step of forming droplets from the MMA monomer solution may include a microfluidic process in which the MMA monomer solution is passed through a nozzle having a predetermined opening and length.
  • FIG. 1 is process flow diagram illustrating an example existing process of producing embolic microspheres that includes a stir process to create droplets.
  • FIG. 2 is a process flow diagram illustrating an example process of producing embolic microspheres in accordance with the present disclosure that includes an alternate droplet formation process to create particles.
  • FIG. 3 is an example apparatus that can be used in an alternate droplet formation process in accordance with the present disclosure.
  • FIG. 4 is another example apparatus that can be used in an alternate droplet formation process in accordance with the present disclosure.
  • FIG. 5 is flow chart illustrating an example method of producing embolic microspheres in accordance with the present disclosure.
  • Couple should be broadly understood to refer to connecting devices or components together either mechanically, electrically, wired, wirelessly, or otherwise, such that the connection allows the pertinent devices or components to operate ( e.g ., communicate) with each other as intended by virtue of that relationship.
  • the recited range may be construed as including situations whereby any of 1, 2, 3, 4, or 5 are negatively excluded; thus, a recitation of “1 to 5” may be construed as “1 and 3-5, but not 2”, or simply “wherein 2 is not included.” It is intended that any component, element, attribute, or step that is positively recited herein may be explicitly excluded in the claims, whether such components, elements, attributes, or steps are listed as alternatives or whether they are recited in isolation.
  • the methods and apparatuses of the present disclosure are directed to methods and apparatuses to produce embolic microspheres with a narrow size distribution.
  • the methods and apparatuses of the present disclosure are improvements over existing methods and apparatuses because existing apparatuses and methods can be inefficient and costly.
  • many existing production methods for embolic microspheres include a separating step in which the microspheres are passed through a sieve or other separator.
  • the sieve can separate microspheres that do not meet a desired dimensional characteristic from microspheres that meet the desired dimensional characteristic.
  • the microspheres can be separated by a desired diameter, for example.
  • the step of separating the microspheres based on a dimensional characteristic can be very labor-intensive and have a low throughput. In some instances, the separating process yields only 10% to 20% of the total quantity of microspheres originally produced.
  • the methods and apparatuses of the present disclosure can allow the producer to eliminate the separating step since the microspheres that are produced have a narrow size distribution in which most, if not all, the microspheres meet the desired dimensional characteristics. The time and resources spent to separate acceptable microspheres from unacceptable microspheres can be reduced and/or minimized. In some embodiments, the methods and apparatuses of the present disclosure can improve the yield of acceptable microspheres 5 to 12 times over that of existing processes.
  • the microspheres of the present disclosure may be used to treat various diseases and conditions in a variety of subjects.
  • Subjects include vertebrate subjects, particularly humans and various warm-blooded animals, including pets and livestock.
  • the term treatment refers to the prevention of a disease or condition, the reduction or elimination of symptoms associated with a disease or condition, or the substantial or complete elimination of a disease or condition.
  • Preferred treatments include embolization treatments.
  • microspheres when used that have wide ranges of dimensional characteristics, the treatment efficacy and the consistency of treatment can be reduced.
  • the microspheres of the present disclosure can have a narrow range of dimensional characteristics that can result in improvements in treatment efficacy and in treatment consistency.
  • microsphere While the term microsphere is used in the present disclosure, the methods and apparatuses described herein may be used to produce embolic particles that do not have a spherical shape or have shapes and/or dimensions that may vary from a sphere.
  • the microspheres of the present disclosure can have various sizes that may be desired for a particular procedure or treatment.
  • the microspheres of the present disclosure can have a diameter in the range of about 5 pm to about 1500 pm.
  • the microspheres can have a diameter of about 40 pm to about 1300 pm.
  • the microspheres can have a particular nominal size and can have a particular tolerance.
  • a microsphere used for a particular application or treatment can have a nominal diameter size of about 40 pm and a tolerance of ⁇ 10 pm.
  • the microsphere can have a nominal diameter size of about 1300 pm and a tolerance of ⁇ 10 pm.
  • the microspheres can have other nominal ranges and other tolerances in the ranges described above.
  • the microspheres of the present disclosure may vary significantly in size, with typical diameters ranging, for example, from 25 pm or less to 5000 pm or more, for example, ranging from 25 pm to 50 pm to 75 pm to 100 pm to 150 pm to 250 pm to 500 pm to 750 pm to 1000 pm to 1500 pm to 2000 pm to 2500 pm to 5000 pm (i.e., including all ranges spanning any two of the preceding values). Where collections of microspheres are measured, at least 95 vol % of the population in the collection may fall within these ranges.
  • microspheres can be evaluated as a collection of microspheres, for example.
  • a traditional normal distribution can be used to characterize the collection of microspheres and determine the acceptability of the microspheres.
  • the microspheres can be described using numerical specifications such as a median nominal size with an upper limit and a lower limit and range width. The microspheres in such an example can then be accepted if a predetermined percentage of the microspheres in the collection meet the median and range characteristics.
  • the acceptability of a distribution of microspheres can be determined using one of the specifications for a particular ID of microspheres listed below.
  • the injectable particles and portions thereof in accordance with the present disclosure may be formed using a variety of inorganic materials (e.g., glasses, ceramics, metals, etc.), organic materials (e.g., non-polymeric organic compounds, polymers, monomers, etc.), as well as combinations of inorganic and organic materials.
  • the microspheres can be made from a methyl methacrylate (MMA) monomer solution.
  • MMA methyl methacrylate
  • PMMA polymethyl methacrylate
  • This step can form the bead of the microsphere from raw solid and liquid chemicals.
  • the input materials that can be used during such polymerization step in the formation of the microspheres can include phosphate buffer saline solution, polyvinyl alcohol solution, lauroyl peroxide, methyl methacrylate, triethylene glycol dimethacrylate, and n-dodecyl mercaptan.
  • MMA monomer droplets can be formed into the PMMA microspheres by depositing the MMA monomer droplets into a polyvinyl alcohol (PVA) solution in which the chemical reaction can take place.
  • PVA polyvinyl alcohol
  • a process 100 illustrates an example method of producing embolic microspheres using existing processes.
  • a MMA monomer solution 102 can be deposited into a PVA solution 104.
  • the MMA monomer solution 102 can undergo a stirring process 106 to cause the MMA monomer solution 102 to separate into droplets.
  • the stirring process 106 can be performed in a suitable receptacle using an impeller.
  • the impeller can agitate the monomer solution 102 to cause droplets of the monomer solution 102 to form.
  • the size of the droplets that ultimately form the microspheres can be changed by varying the shear forces that are imposed on the MMA solution by the impeller.
  • the shear forces can be varied, for example, by changing the speed of the impeller and/or the geometry of the stir blade of the impeller.
  • the MMA droplets in the PVA solution 108 can undergo a stirring and heating process 110 during which time the MMA monomer droplets form into polymer particles via chemical reaction and agitation.
  • the stirring and heating process 110 can provide agitation to the MMA monomer droplets and PVA suspension so that the MMA monomer droplets remain separated and coalescence effects are minimized.
  • the MMA monomer droplets form into solid PMMA microspheres 112.
  • the size of the droplets that are formed using the stirring process 106 cause significant size variations between the droplets to occur.
  • the size variation is significant because the resulting solid PMMA microspheres 112 also have significant size variations among the population.
  • the collection of microspheres 112 undergoes a sieving process 114.
  • a sieve is used that has openings of a predetermined size to separate acceptable size microspheres from unacceptable size microspheres.
  • the sieving process 114 can include multiple sieving steps and is often performed manually by an operator such that the process is labor-intensive and costly.
  • the variation among the population of microspheres is so significant that about 80% to about 90% of the microspheres are found to be of an unacceptable size and are discarded. As such, the process 100 can often result in a yield of about 10% to about 20%.
  • the microspheres can undergo hydrolysis 116.
  • the methods and apparatuses of the present disclosure can be used to improve on the process 100.
  • the methods and apparatuses of the present disclosure eliminate or minimize the amount of sieving or other separation that needs to be performed after the formation of the solid PMMA microspheres.
  • the elimination of minimization of the sieving process 114 can reduce the cost to produce embolic microspheres by eliminating or minimizing this process which is often very labor intensive.
  • the yield of the microsphere production processes of the present disclosure can improve throughput and yield by about 5 to about 12 times over that of existing processes such as process 100 described above.
  • the process 100 was used to produce embolic microspheres and the method resulted in a yield of about 300 grams of dried embolic microspheres.
  • the methods of the present disclosure yielded about 3.5 kilograms of dried embolic microspheres translating into about a 11.7 times increase in yield.
  • an example process 200 of producing embolic microspheres is shown. As can be seen many of the individual steps or processes are similar to the process 100 previously described. As shown, the MMA monomer solution 202 can be produced from input materials as previously described. In the process 200, however, the MMA droplets are formed using an alternate droplet formation process 206. Various alternate droplet formation processes 206 are contemplated in the present disclosure as will be further described below. The alternate droplet formation processes 206 can form droplets having a much narrower size distribution. In this manner, the resulting solid PMMA microspheres 212 that are formed after the droplets are deposited in the PVA solution 204 and are stirred and heated at process 210 also have a small or narrow size distribution. [0038] As discussed above, the size distribution of the PMMA microspheres can result in a significant increase in the yield when the process 200 is used. In addition, the sieving step 114 of process 100 is eliminated from the process 200.
  • alternate droplet formation processes 206 can be used in the process 200.
  • the alternate droplet formation process 206 can be a high-volume microfluidic process.
  • the alternate droplet formation process 206 can be a precision particle fabrication process.
  • the alternate droplet formation process 206 can be a membrane droplet formation process.
  • the alternate droplet formation process 206 can be a microfluidic process.
  • the alternate droplet formation process 206 is a high-volume microfluidic process.
  • the high-volume microfluidic process can use one or more dispensers that can separate the MMA monomer solution into droplets of a predetermined size.
  • the dispensers can include a plurality of micro-channels.
  • the MMA monomer solution can flow through the dispenser. Surface tension can cause the MMA monomer solution to separate into droplets.
  • the high-volume micro-fluidic process can be controlled so that the resulting population of droplets has a narrow size distribution. In one example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 17 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 15 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 17 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 15 pm.
  • the high-volume micro-fluidic apparatus 300 can include a dispenser 302.
  • the dispenser 302 can be coupled to a source of MMA monomer solution and can be conveyed to the dispenser using a suitable conduit and a suitable pump (not shown).
  • the MMA monomer solution can be conveyed through the dispenser 302 that includes a plurality of microchannels 304.
  • the MMA monomer solution can be dispensed from the dispenser 302 in the form of droplets 308 having the narrow size distribution.
  • the droplets 308 can be dispensed into a suitable collector 306, such as a reactor holding the PVA solution previously discussed.
  • the properties and characteristics of the dispenser 302 and the microchannels 304 as well as the flow rate of the MMA monomer solution and the pressure at which the MMA monomer solution is conveyed through the dispenser 302 can be modified and changed to change the size of the droplets 308 and to vary the dimensional characteristics of the droplets 308 in the population of droplets.
  • the alternate droplet formation process 206 is a precision particle fabrication process.
  • the MMA monomer solution can be dispensed from one or more nozzles.
  • the nozzle or nozzles can be vibrated at a predetermined frequency and amplitude to cause the MMA monomer solution to be dispensed as droplets having a desired size and size distribution.
  • the droplets that are formed using the precision particle fabrication process can be tightly controlled to produce droplets having a narrow size distribution.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 17 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 15 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 17 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 15 pm.
  • the precision particle fabrication apparatus 400 includes a receptacle 402, a nozzle 404, a vibration generator 406 and a collector 410.
  • the receptacle 402 can be a suitable container that can hold the MMA monomer solution.
  • the MMA monomer solution can be dispensed from the nozzle 404.
  • the nozzle 404 can be vibrated by the vibration generator 406 to that the MMA monomer solution is dispensed from the nozzle 404 in the form of droplets 408.
  • the droplets 408 can have dimensional characteristics as desired that can have the narrow size distribution.
  • the frequency and amplitude at which the nozzle 404 is vibrated by the vibration generator 406 can be varied to obtain droplets 408 having the size and size distribution that is required.
  • the droplets 408 can be dispensed into the collector 410, such as a reactor holding the PVA solution previously discussed.
  • the alternate droplet formation process 206 is a membrane droplet formation process.
  • the MMA monomer solution can be can be passed through a membrane having a predetermined porosity to form droplets.
  • the size of the droplets can be changed by varying the properties (e.g., the porosity) of the membrane.
  • the droplets that are formed using the membrane droplet formation process can be tightly controlled to produce droplets having a narrow size distribution.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 17 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 15 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 17 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 15 pm.
  • the alternate droplet formation process 206 is a microfluidic process.
  • the MMA monomer solution can be can be passed through a nozzle or channel.
  • the size of the droplets can be changed by varying the properties (e.g., size and shape) of the nozzle or channel.
  • the microfluidic process is similar to the high-volume microfluidic process previously described.
  • the microfluidic process may include a single nozzle or a single channel.
  • the droplets that are formed using the microfluidic process can be tightly controlled to produce droplets having a narrow size distribution.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 17 pm.
  • the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by about ⁇ 15 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 17 pm. In still another example, the narrow size distribution is characterized in that 95% of the population of droplets has a size (or diameter) that varies by less than or equal to about ⁇ 15 pm.
  • a method 500 of producing embolic microspheres having a narrow size distribution is shown.
  • the microspheres produced using the method 500 can have the narrow size distributions described above.
  • the method 500 starts with step 502.
  • input materials can be combined to produce a MMA monomer solution.
  • the input materials can include the input materials described above, such as phosphate buffer saline solution, polyvinyl alcohol solution, lauroyl peroxide, methyl methacrylate, triethylene glycol dimethacrylate, and n-dodecyl mercaptan.
  • an alternate droplet formation process can be used to form droplets of the MMA monomer solution.
  • the alternate droplet formation process can include any suitable process that can form the droplets in a desired size and in the narrow size distribution previously described.
  • the alternate droplet formation process is a process other than a stirring process that is used in existing processes.
  • the alternate droplet formation process can include a high-volume microfluidic process, a precision particle fabrication process, a membrane droplet formation process or a microfluidic process. Any one of theses processes as previously described can be used at step 504.
  • the apparatus 300 or the apparatus 400 can be used at step 504.
  • the MMA monomer droplets and PVA solution can be stirred and heated to allow the polymerization chemical reaction to occur.
  • PMMA microspheres having the size and narrow size distribution are formed.
  • the microspheres can undergo hydrolysis.
  • the method 500 is an improvement over existing processes.
  • the method 500 can eliminate or minimize the amount of sieving or other separation that needs to be performed after the formation of the solid PMMA microspheres.
  • the elimination of minimization of the sieving process 114 (FIG. 1) can reduce the cost to produce embolic microspheres by eliminating or minimizing this process which is often very labor intensive.
  • the yield of the microsphere production method 500 can improve throughput and yield by about 5 to about 12 times over that of existing processes such as process 100 described above. These improvements can reduce costs, increase throughput and improve the consistency of treatments that use the microspheres produced using method 500.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polymerisation Methods In General (AREA)

Abstract

L'invention concerne un procédé de production de microsphères emboliques comprenant la combinaison (502) de matériaux d'entrée pour produire une solution de monomères de méthacrylate de méthyle (MMA) et la formation (504) de gouttelettes à partir de la solution de monomères de MMA, les gouttelettes présentant une distribution prédéterminée des grosseurs. Le procédé comprend également le dépôt (506) des gouttelettes dans une solution de poly(alcool vinylique) (PVA) pour former des microsphères de poly(méthacrylate de méthyle) (PMMA). La distribution prédéterminée des grosseurs des gouttelettes est une distribution étroite des grosseurs, dans laquelle au moins 95 % des gouttelettes présentent une grosseur dans une plage de ± 15 µm.
PCT/US2022/033671 2021-06-30 2022-06-15 Appareils et procédés de production de microsphères emboliques WO2023278159A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7838035B2 (en) * 2006-04-11 2010-11-23 E. I. Du Pont De Nemours And Company Microsphere powder of high density, swellable, deformable, durable occlusion-forming microspheres
CN102898579B (zh) * 2012-10-23 2015-04-22 中国科学技术大学 粒径可控的单分散聚丙烯酰胺凝胶微球及其制备方法和所用装置
WO2019222700A1 (fr) * 2018-05-18 2019-11-21 Bard Peripheral Vascular, Inc. Microsphères contenant des isotopes radioactifs et d'autres marqueurs, et procédés associés
CN108890937B (zh) * 2018-06-29 2020-07-07 山东省科学院能源研究所 一种树枝状通道结构的水凝胶芯片的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7838035B2 (en) * 2006-04-11 2010-11-23 E. I. Du Pont De Nemours And Company Microsphere powder of high density, swellable, deformable, durable occlusion-forming microspheres
CN102898579B (zh) * 2012-10-23 2015-04-22 中国科学技术大学 粒径可控的单分散聚丙烯酰胺凝胶微球及其制备方法和所用装置
WO2019222700A1 (fr) * 2018-05-18 2019-11-21 Bard Peripheral Vascular, Inc. Microsphères contenant des isotopes radioactifs et d'autres marqueurs, et procédés associés
CN108890937B (zh) * 2018-06-29 2020-07-07 山东省科学院能源研究所 一种树枝状通道结构的水凝胶芯片的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SARALIDZE ET AL: "New acrylic microspheres for arterial embolization: Combining radiopacity for precise localization with immobilized thrombin to trigger local blood coagulation", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 15, 13 March 2007 (2007-03-13), pages 2457 - 2464, XP005919506, ISSN: 0142-9612, DOI: 10.1016/J.BIOMATERIALS.2006.12.031 *

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