Microrobotic platform for intravascular embolism

Abstract

Materials, methods, and systems are provided that are particularly useful for embolizing, for example, a target vascular sac using microgels applied with a microrobot. The microrobot comprises a microgel based on a self-healing material for on-demand controllable aggregation, magnetic agents, such as magnetite nanoparticles, encapsulated in microgels for driving and aggregating microrobots at targeted intravascular locations under physiological blood flow and imaging agents, such as tantalum microparticles, for accurately tracking microrobots in living organisms through clinical medical devices. Related systems and methods are disclosed for delivering and guiding microrobots to accumulate and gather at targeted locations to provide on-demand and reliable embolization therapy under real-time monitoring.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 461,179, filed April 21, 2023, and U.S. Provisional Application No. 63 / 533,103, filed August 16, 2023, the entire disclosure of which is incorporated herein by reference for all purposes. Background Technology

[0003] Embolization is an emerging minimally invasive endovascular procedure involving the occlusion of blood vessels as a treatment for various conditions, such as tumors, fistulas, and arteriovenous malformations. By deploying embolic devices (e.g., metal coils) with the aid of interventional catheter techniques, a vascular balloon can be occupied and blood flow into the artery can be blocked from circulation, preventing the aneurysm from continuing to expand to its rupture point or thus cutting off the nutrient supply to the tumor. However, applying embolic coils to targets that include large vascular spaces (e.g., the space between giant aneurysms and those in the pseudo-lumen of an open aorta) can be impractical, as the procedure would involve numerous coils and prolonged operation time, potentially resulting in incomplete embolization performance. Other embolic materials have also been developed, including protein sponges, hydrogel microspheres, and liquid agents. However, with these alternatives, practical performance and long-term outcomes remain unsatisfactory due to the occurrence of uneven filling effects, and more seriously, accidental distal arterial occlusion caused by leakage and breakage of the embolic material. Therefore, there is an urgent need for new embolization strategies with better filling controllability, intravascular biocompatibility, and clinical performance.

[0004] The emerging field of microrobots offers a revolutionary opportunity for embolization therapy. Microrobots, which convert energy from their environment into mechanical motion, are capable of skillfully and accurately accessing hard-to-reach lesions within the body due to their small size, active mobility, and remote controllability, promising significant benefits across various biomedical fields. Therefore, employing active microrobots as embolic agents presents an encouraging embolization strategy to achieve complete filling of the targeted vascular sac while avoiding unintentional blockage of off-target vessels.

[0005] However, existing microrobot technologies cannot yet achieve this goal, and several issues must be carefully considered beforehand. For example, effective and precise navigation of microrobots in complex and dynamic intravascular environments places critical demands on microrobot control and imaging methods, especially in the branches of the aorta, where physiological blood flow velocities can reach 10-20 cm / s. Furthermore, crucial for the clinical feasibility of embolization therapy is the ability, after a large number of microrobots reach the target aneurysm, to be non-invasively triggered to completely occlude the sac without postoperative leakage and fragmentation. Additionally, the stability and compatibility of the embolization microrobots with the surrounding biological environment should be carefully evaluated to ensure their safety of use and the long-term therapeutic effects they provide. This disclosure addresses these and other issues by providing compositions and methods related to pH-responsive and magnetically guided microrobots, which offer several beneficial advantages for embolization therapy.

[0006] Brief Overview

[0007] The following overview provides a high-level summary of various aspects of the invention and introduces some concepts described and illustrated in this application and the accompanying drawings. This overview is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used alone to determine the scope of the claimed subject matter. The embodiments covered by this disclosure are not limited by this overview. The subject matter should be understood by referring to appropriate portions of the specification throughout, any or all of the accompanying drawings, and each claim. Some exemplary embodiments of this disclosure are discussed below.

[0008] This disclosure generally relates to a cluster of microrobot platforms integrated with interventional catheters. This platform is particularly useful for real-time medical imaging-guided embolization of aneurysms and blood vessels. Each component of the microrobot cluster acting as an embolic agent is a micro-sized sphere composed of a pH-responsive self-healing hydrogel matrix, magnetic nanoparticles, and imaging dopants. The disclosed microrobot embolization strategy can be initiated via catheter-assisted delivery and deployment of the cluster's microgels to, for example, intravascular sites, providing a high-speed channel across biological barriers and protecting the microrobots from the in vivo immune system. Subsequently, a programmable or otherwise controllable external magnetic field can be applied to navigate the cluster of microrobots and concentrate them into, for example, a targeting capsule. The application of the magnetic field can be assisted by real-time guidance via ultrasound and fluoroscopic imaging. An acidic buffer solution can be injected via catheter to activate the self-healing behavior of the microgels, followed by catheter removal, which triggers the formation of intermolecular / intramolecular hydrogen bonds in the hydrogel matrix, thereby causing the microrobots to spontaneously adhere to each other.

[0009] In one aspect, this disclosure relates to pH-responsive self-healing microgels. The microgels comprise polymer products of two or more polymer precursors and crosslinking agents. The microgels also comprise magnetic agents and developers.

[0010] On the other hand, this disclosure relates to a group of pH-responsive self-healing microgels. This group includes pH-responsive self-healing microgels as described herein.

[0011] On the other hand, this disclosure relates to a system for treating subjects requiring embolization at a targeted intravascular location. The system comprises a population of pH-responsive self-healing microgels as described herein. The system also includes a magnetron sputtering module and an imaging module.

[0012] On the other hand, this disclosure relates to a method for treating a subject requiring embolization at a targeted intravascular location. The method includes applying a population of pH-responsive self-healing microgels as described herein to the subject. The method further includes applying a magnetic field to at least a portion of the subject. The method further includes using the magnetic field to guide the population of pH-responsive self-healing microgels to the targeted intravascular location. The method further includes introducing a certain amount of acidic solution into the targeted intravascular location. This amount effectively induces the formation of hydrogen bonds between pH-responsive self-healing microgels within the population of pH-responsive self-healing microgels. Brief description of the attached diagram

[0014] The illustrative aspects of this disclosure are described in detail below with reference to the accompanying drawings. The embodiments and drawings disclosed herein are intended to be illustrative rather than restrictive. The same reference numerals and names denote the same elements in the various drawings.

[0015] Figure 1 A schematic diagram of a catheter-assisted microrobot platform for on-demand embolization of aneurysms and arteries, based on the provided implementation scheme, is shown.

[0016] Figure 2 An exemplary setup of a microrobot platform for on-demand embolization of aneurysms and arteries, according to the provided implementation, is shown.

[0017] Figure 3 The workflow for preparing an embolization microrobot according to the provided implementation is shown.

[0018] Figure 4 A pH-responsive self-adhesion mechanism of an embolization microrobot according to the provided embodiment is illustrated.

[0019] Figure 5 Images demonstrating the self-healing process of the provided hydrogel under biological conditions are shown.

[0020] Figure 6 The results of mechanical tensile tests are presented to evaluate the healing strength of hydrogels under different conditions and the effect of healing time on the fracture stress of the healed hydrogels.

[0021] Figure 7 The diagram shows the FTIR-ATR and Raman spectra of the hydrogel provided during the healing process, where the highlighted areas indicate the formation of two types of hydrogen bonds: the interleaved interaction between carboxyl and amide groups and the face-on interaction between opposing carboxyl groups.

[0022] Figure 8 Optical images of microgels prepared according to the provided embodiment are shown, as well as a graph depicting the size distribution of the prepared microgels.

[0023] Figure 9 The diagram shows the spontaneous adhesion between the microgels provided in saline and blood when acidic buffer solution (pH: 4.5–5) is added.

[0024] Figure 10 Images and graphs show the temporal shape changes of the provided disc-shaped embolic material in anticoagulated pig blood, the effect of blood incubation time on the area and compressive modulus of the disc-shaped embolic material, and hemolysis analysis of erythrocytes after incubation with different concentrations of the provided microgel for 24 h.

[0025] Figure 11 Images showing the coagulation behavior of blood incubated with the provided disc-shaped embolic material are displayed.

[0026] Figure 12 The figure shows the effect of microgel concentration on the viability of stem cells, 3T3 cells, and HUVECs after 48 h of co-culture.

[0027] Figure 13 Images of a clinical catheter for deploying microgels, according to the provided implementation scheme, are shown.

[0028] Figure 14 Images showing the effect of Ta concentration on the imaging contrast of the provided microgel under fluoroscopy are presented.

[0029] Figure 15A schematic diagram of an aneurysm embolization procedure in dynamic fluid according to the provided embodiment is shown, including targeted catheter insertion (I), deployment and active accumulation of clustered microgels into the aneurysm sac under the actuation of a robotic magnet (II), on-demand embolization via mild acid stimulation (III), and removal of the catheter and robotic magnet (IV). Images showing experimental results using the provided procedure are also presented. Additional images show the morphology of the welded microgels after incubation at 37°C for 6 months.

[0030] Figure 16 Real-time ultrasound imaging of the aneurysm embolization process is presented in a dynamic blood environment with an inlet mean velocity of 20 cm / s. Two imaging planes (I and II) are used to reflect the embolization status in the horizontal and vertical cross-sections of the aneurysm sac, respectively. The area enclosed by dashed lines in the images indicates targeted aggregation of microgels. The disappearance of the ultrasound Doppler signal within the aneurysm sac indicates that the blood flow entering the aneurysm is excluded from circulation.

[0031] Figure 17 Images are shown of an experimental apparatus for embolizing a saccular aneurysm replica in the bloodstream under real-time guidance of C-arm fluoroscopy. The apparatus includes a saccular aneurysm replica, a robotic magnet for magnetic cluster control, a peristaltic pump for blood flow control, a catheter controller for microrobot deployment, and a C-arm fluoroscopic system.

[0032] Figure 18 Real-time fluoroscopic imaging of the aneurysm embolization process according to the provided implementation is shown.

[0033] Figure 19 Images showing the filling rate of aneurysm replicas under different magnetic field parameters and flow conditions are presented. Inset images illustrate specific embolization performance in different regions. The rotation frequency of the magnetic field is fixed at 2 Hz.

[0034] Figure 20 A schematic diagram and images of an experimental apparatus for arterial embolization in an isolated human placenta are shown.

[0035] Figure 21 Real-time ultrasound images of the vascular embolization process in the human placenta according to the provided implementation scheme are shown.

[0036] Figure 22 Images used to evaluate arterial embolism performance via ultrasound Doppler signals are shown.

[0037] Figure 23 Real-time fluoroscopic images of the vascular embolization process according to the provided implementation scheme are shown.

[0038] Figure 24Images are shown illustrating the occlusion welded by self-adhesive microgel after on-demand arterial embolization, according to the provided implementation scheme. Detailed Implementation

[0039] I. General Information

[0040] This disclosure will be more readily understood by referring to the following detailed description and examples. This disclosure is not limited to the specific materials, apparatuses, methods, or systems described and / or illustrated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although similar or equivalent materials, apparatuses, methods, and systems to those described herein may be used in the practice or testing of this invention, suitable methods and materials are described below.

[0041] This disclosure provides a multifunctional microgel as a microrobot, and the resulting embolization system based on catheters and clinical imaging devices. The specific composition of the provided hydrogel matrix for the microrobot is carefully designed to advantageously meet the requirements of on-demand embolization. For example, polymer precursors and crosslinking agents are specifically selected to obtain the provided functional hydrogel material exhibiting several beneficial properties. It is also advantageous that the synthesis of the provided embolization microrobot can be achieved via a simple emulsion method. Typically, a self-healing hydrogel precursor containing a thermal initiator is first mixed with appropriate amounts of a magnetic agent and a developer to obtain a homogeneous aqueous phase, which is then emulsified via liquid paraffin (oil phase). Subsequently, the mixture is heated to initiate a polymerization reaction of the hydrogel precursor, thereby solidifying the microemulsion into a multifunctional embolization microrobot.

[0042] The disclosed materials and methods have demonstrated efficient and selective accumulation of microgels in aneurysm models, achieving a fill rate greater than 95%, even under dynamic blood flow conditions with average velocities, such as up to 20 cm / s. Effective embolization and hemostasis according to the provided embodiments have been validated by Doppler ultrasound and X-ray imaging. By carefully tuning the polymer chains of the hydrogel, the welding of the microrobots exhibits excellent self-adhesive and physical stability, as well as satisfactory biocompatibility and blood compatibility, in physiological environments for at least six months. Furthermore, the provided embodiments have been used to occlude blood vessels in ex vivo human placenta, validating the applicability of the disclosed embolization strategy to real vascular systems. Therefore, this disclosure presents an integrated microrobot platform with efficient targeting and on-demand embolization capabilities, representing a substantial leap forward in the field of minimally invasive embolization therapy.

[0043] II. Definition

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0045] As used herein, the terms “fill ratio” and “filling ratio” refer to the percentage of the volume of intravascular site occupied by the aggregation of the microgels disclosed herein.

[0046] As used herein, the term "heteroalkyl" itself, or as part of another substituent, refers to an alkyl group of any suitable length having one to three heteroatoms, such as N, O, and S. Additional heteroatoms can also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, for example, but not limited to -S(O)- and -S(O)2-. For example, heteroalkyl groups can include ethers, thioethers, and alkylamines. The heteroatom moiety of a heteroalkyl group can replace the hydrogen atom of the alkyl group to form a hydroxyl, thio, or amino group. Alternatively, the heteroatom moiety can be a linking atom or inserted between two carbon atoms. The heteroalkyl group can be substituted or unsubstituted.

[0047] As used herein, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched saturated aliphatic group having an indication of the number of carbon atoms. A branched alkyl group may include one or more branches having a geminal, ortho, and / or isolated configuration. For example, an alkyl group may include a gemdimethyl group. An alkyl group may include any number of carbons, such as C10, C20, C30, C40, C50, C60, C7 ... 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 For example, C 1-6Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, and decyl. Alkyl groups can be substituted or unsubstituted. Unless otherwise stated, a "substituted alkyl" group can be substituted by one or more groups selected from the following: halogen, hydroxyl, amino, alkylamino, amide, acyl, nitro, cyano, and alkoxy.

[0048] As used herein, the term "hydrogel" refers to a highly interdependent biphasic matrix comprising a solid component (typically a polymer, and more typically a highly cross-linked polymer) with both hydrophilic and hydrophobic properties, and a liquid dispersion medium (e.g., water) retained within the matrix by intermolecular forces. The hydrophobic properties provide a degree of water insolubility in the matrix, while the hydrophilic properties provide water permeability. Those skilled in the art will understand that several different types of polymers can be combined to form hydrogels usable in the methods of the present invention. As a polymer network with high water absorption capacity, hydrogels typically closely mimic the natural extracellular matrix. Due to their relatively high water content, hydrogels also tend to exhibit a degree of flexibility very similar to natural tissues. In some cases, hydrogels can contain more than 90% water.

[0049] As used herein, the term "polymer" refers to an organic substance composed of multiple repeating structural units (monomer units) covalently linked to each other.

[0050] As used herein, the term “microgel” refers to a hydrogel structure with an equivalent sphere diameter of 10 nm to 1 mm (i.e., in the nanometer and micrometer range).

[0051] As used herein, the term "equivalent sphere diameter" refers to a property of a three-dimensional object that indicates the maximum diameter of any cross-section of the object, including its geometric center. The "maximum diameter" of a two-dimensional graphic (e.g., a cross-section of a three-dimensional object) is the longest distance between any two points on the boundary of the graphic. The "geometric center" of a three-dimensional object is the arithmetic mean of all points on the object's surface.

[0052] As used herein, the term "substantially spherical" refers to a representation of an object for which any cross-section of the object, including its geometric center, has a maximum diameter within 50% of the equivalent sphere diameter. A substantially spherical object may also include an object for which any difference between such maximum diameter and the equivalent sphere diameter is less than 35% of the equivalent sphere diameter, for example, less than 25%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2% of the equivalent sphere diameter, or less than 1% of the equivalent sphere diameter.

[0053] Hydrogels, microgels, or polymers are "pH-responsive" if the chemical structure of the gel or polymer changes in response to changes in the pH of the gel environment. A pH-responsive gel or polymer can be one in which chemical bonds (e.g., dynamic bonds) form or break in response to changes in the pH of the environment.

[0054] Hydrogels, microgels, or polymers are "self-healing" or "self-adhesive" if dynamic bonds are formed at the interface of a gel or polymer, causing the gel or polymer portions on opposite sides of the interface to adhere to each other, resulting in interfacial welding of two or more surfaces. Therefore, self-healing gels or polymers can fully or partially recover their structure and properties after being damaged, thus fully or partially restoring their physical integrity. Self-healing gels or polymers can also be used to combine two or more previously separate structures of a gel or polymer to form larger composite structures. This self-healing occurs due to the presence of dynamic bonds that can spontaneously recover after breakage.

[0055] As used herein, the term "developer" refers to a reagent containing detectable material that can be used to generate an image of a target volume, and in particular, an image that can include more visual information than would be present in the absence of a developer. A developer can be, for example, a material incorporated into, combined with, or otherwise accumulated within the volume to be imaged.

[0056] A developing agent, acting as a "contrast agent," is a material that significantly attenuates incident radiation (e.g., X-ray radiation), resulting in a reduction in the amount of radiation transmitted through the target volume. After image reconstruction and typical post-processing, this increased attenuation (e.g., X-ray attenuation) is interpreted as an increase in the density of the target volume, which produces a contrast enhancement relative to the background (e.g., background tissue) in the image within the volume containing the contrast agent.

[0057] As used herein, the term "magnetic agent" refers to a reagent containing magnetic materials (e.g., ferromagnetic, ferrimagnetic, or superparamagnetic materials). These materials are highly sensitive to magnetization. When a magnetic field is applied to a material, it can become magnetized, and the strength of the magnetization can depend on the strength of the magnetic field. In some such materials, magnetization can persist for a period of time after the magnetic field is removed. Magnetic materials do not have to be permanent magnets, but can include materials like iron, which can be magnetized by a magnetic field from a permanent magnet or electromagnet. Magnetic materials can be attracted to permanent magnets, but may not exert any magnetic attraction on their own.

[0058] As used herein, the term "object" refers to a vertebrate, and preferably a mammal. Suitable mammalian objects for the provided compositions include, but are not limited to, mice, rats, apes, humans, farm animals, sporting animals, and pets. In some embodiments, the object is a human. In some embodiments, the object is a male. In some embodiments, the object is a female. In some embodiments, the object is an adult. In some embodiments, the object is a teenager. In some embodiments, the object is a child. In some embodiments, the object is 10 years of age or older, for example, 20 years of age or older, 30 years of age or older, 40 years of age or older, 50 years of age or older, 60 years of age or older, 70 years of age or older, or 80 years of age or older. In some embodiments, the object is less than 80 years of age, for example, less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age.

[0059] As used herein, the term "treatment" refers to a method of obtaining a beneficial or desired outcome, including but not limited to therapeutic and / or preventative benefits. A therapeutic benefit is any associated improvement or effect on one or more diseases, conditions, or symptoms during treatment. For preventative benefits, the composition may be applied to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more physiological symptoms of a disease, even if the disease, condition, or symptom may not yet have manifested. Treatment may include any of the following: improving one or more symptoms of a disease (e.g., cancer), preventing the manifestation of such symptoms before they appear; slowing or completely preventing the progression of the disease (which can be manifested by longer intervals between relapses, slowing or preventing the worsening of symptoms, etc.), promoting the onset of remission, slowing irreversible damage caused in the progressive-chronic phases of the disease (in the primary and secondary phases), delaying the onset of said progressive phase, or any combination thereof.

[0060] As used herein, the terms “comprising,” “including,” “having,” “containing,” and variations thereof are inclusive and open-ended, and do not exclude additional unstated elements or method steps beyond those expressly described. As used herein, the phrase “consisting of” is closed and excludes any element, step, or ingredient not expressly specified. As used herein, the phrase “substantially constitutes” limits the scope of the described feature to the specified materials or steps and those materials or steps that do not substantially affect the basic and novel features of the disclosed feature.

[0061] As used herein, the singular forms “a,” “an,” and “the” include plural indicators unless the content clearly specifies otherwise. Thus, for example, reference to “a polymer” optionally includes combinations of two or more polymers, etc.

[0062] As used herein, the term “about” indicates a range of values ​​within + / - 10% of a specified value. For example, “about 10” indicates a range of values ​​from 9 to 11 (10 + / - 1).

[0063] III. Microgels

[0064] On the one hand, this disclosure provides various pH-responsive self-healing microgels, which typically comprise the polymerization product of two or more polymer precursors and crosslinking agents. The microgels also typically contain one or more magnetic agents and one or more imaging agents. In some embodiments, the microgel consists of the polymerization product, one or more magnetic agents, and one or more imaging agents. In some embodiments, the microgel consists essentially of the polymerization product, one or more magnetic agents, and one or more imaging agents. The specific combinations and relative amounts of these components provide the microgels with several surprising improvements in a variety of important properties. These improved properties are particularly advantageous when the provided groups of pH-responsive self-healing microgels are used in medical applications, and especially when used for embolization therapy as, for example, a swarm of remotely controlled and detectable microrobots.

[0065] The provided pH-responsive self-healing microgel's polymerization product is a product of two or more polymer precursors and crosslinking agents. The number of different types of polymer precursors used to form the polymerization product can be, for example, three, four, five, six, seven, eight, nine, ten, or more than ten. The number of different types of crosslinking agents used to form the polymerization product can also be, for example, three, four, five, six, seven, eight, nine, ten, or more than ten. In some embodiments, the microgel contains only one polymerization product. In some embodiments, the microgel contains two or more different types of polymerization products, for example, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more different types of polymerization products. The composition and relative amounts of one or more polymerization products of the microgel can be selected or configured to provide the microgel with its beneficial properties, including its pH responsiveness and self-healing properties.

[0066] In some embodiments, at least one of two or more polymer precursors of the polymerization product comprises one or both of an acryloyl group and an acrylamide group. Using polymer precursors having acryloyl and / or acrylamide groups can provide the polymerization product with desired properties, including, for example, high water solubility and good biocompatibility. In some embodiments, each of the two or more polymer precursors comprises one or both of an acryloyl group and an acrylamide group. In some embodiments, at least one of the two or more polymer precursors of the polymerization product comprises an acryloyl group. In some embodiments, each of the two or more polymer precursors of the polymerization product comprises an acryloyl group. In some embodiments, each of the two or more polymer precursors of the polymerization product comprises an acrylamide group. In some embodiments, at least one of the two or more polymer precursors of the polymerization product comprises both an acryloyl group and an acrylamide group. In some embodiments, each of the two or more polymer precursors comprises both an acryloyl group and an acrylamide group.

[0067] The acryloyl group of the polymer precursor of the polymerization product may include, for example, N-acryloyl-2-glycine, substituted N-acryloyl-2-glycine, N-acryloyl-4-aminobutyric acid, substituted N-acryloyl-4-aminobutyric acid, N-acryloyl-6-aminohexanoic acid, substituted N-acryloyl-6-aminohexanoic acid, N-acryloyl-8-aminooctanoic acid, substituted N-acryloyl-8-aminooctanoic acid, N-acryloyl-11-aminoundecanoic acid, substituted N-acryloyl-11-aminoundecanoic acid, or any combination thereof. The acrylamide group of the polymer precursor of the polymerization product may include, for example, N-isopropylacrylamide, substituted N-isopropylacrylamide, acrylamide, substituted acrylamide, acrylic acid, substituted acrylic acid, or any combination thereof.

[0068] In some embodiments, the provided microgel polymerization product comprises multiple pendant side chains. In some embodiments, each pendant side chain of at least a portion of the pendant side chains independently comprises an amide group. In some embodiments, each pendant side chain of the polymerization product independently comprises an amide group. In some embodiments, each pendant side chain of at least a portion of the pendant side chains independently comprises a carboxyl group. In some embodiments, each pendant side chain of the polymerization product independently comprises a carboxyl group. In some embodiments, each pendant side chain of at least a portion of the pendant side chains independently comprises both an amide group and a carboxyl group. In some embodiments, each pendant side chain of the polymerization product independently comprises both an amide group and a carboxyl group. The use of polymerization products having amide and / or carboxyl groups in the pendant side chains can provide polymerization products with desired properties, including, for example, enhanced water solubility and the ability to form hydrogen bonds, such as hydrogen bonds that provide the microgel with its pH responsiveness and self-healing properties. The polymerization product may contain only one type of dangling side chain, or it may contain two or more different types of dangling side chains, such as three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more different types of dangling side chains.

[0069] In some embodiments, each of at least a portion of the suspended side chains independently comprises, or is composed of, an optionally oxy-substituted 3- to 12-membered heteroalkyl group. In some embodiments, each of the suspended side chains of the polymerization product independently comprises, or is composed of, an optionally oxy-substituted 3- to 12-membered heteroalkyl group. In some embodiments, each of at least a portion of the suspended side chains has the following structure: .

[0070] In some implementations, each dangling side chain of the polymerization product has the structure described above.

[0071] In some embodiments, multiple dangling side chains of the polymerization product can form hydrogen bonds with each other. Hydrogen bonds can include, for example, hydrogen bonds between a carboxyl group of one dangling side chain and carboxyl groups of different dangling side chains (e.g., dangling side chains across the microgel interface and / or dangling side chains of different microgels). Hydrogen bonds can additionally or optionally include hydrogen bonds between a carboxyl group of one dangling side chain and amide groups of different dangling side chains (e.g., dangling side chains across the microgel interface, dangling side chains of different microgels). Hydrogen bonds can include hydrogen bonds between terminal functional groups (e.g., terminal carboxyl groups) of different dangling side chains, or a combination thereof. Such hydrogen bonds are referred to herein as “face-on” hydrogen bonds. Hydrogen bonds can optionally or additionally include hydrogen bonds between terminal functional groups and medium-chain functional groups of different dangling side chains, or a combination thereof. Such hydrogen bonds are referred to herein as “interleaved” hydrogen bonds. The ability of the polymerization product to form a combination of face-on and interleaved hydrogen bonds can advantageously provide the microgel with its self-healing properties.

[0072] In some embodiments, when the microgel is exposed to an acidic environment with a pH below a certain threshold, the polymerization products of the provided microgel form hydrogen bonds. This property of the polymerization products can provide the microgel with its advantageous pH-responsive properties. When the microgel is exposed to a pH of, for example, less than about 6, such as less than about 5.75, less than about 5.5, less than about 5.25, less than about 5, less than about 4.75, less than about 4.5, less than about 4.25, less than about 4, or less than about 3.75, the polymerization products can be selectively or configured to form hydrogen bonds. The threshold pH that triggers the formation of hydrogen bonds in the dangling side chains of the polymerization products can be, for example, from about 3.5 to about 6, such as from about 3.5 to about 5, from about 3.75 to about 5.25, from about 4 to about 5.5, from about 4.25 to about 5.75, or from about 4.5 to about 6. Advantageously, once hydrogen bonds are formed, they can be stable under typical physiological conditions. For example, the hydrogen bonds formed by the polymerization product can be maintained at 37°C in 0.9 wt% brine for at least about 8 hours, for example, at least about 10 hours, at least about 12 hours, at least about 15 hours, at least about 19 hours, at least about 24 hours, at least about 30 hours, at least about 37 hours, at least about 46 hours, at least about 58 hours, or at least about 72 hours.

[0073] The crosslinking agent used to form the polymer reaction product of the provided microgel can be selected to provide a microgel with desired beneficial mechanical strength. In some embodiments, at least one crosslinking agent in the polymer reaction product comprises an acrylamide group. In some embodiments, each crosslinking agent in the polymer reaction product independently comprises an acrylamide group. In some embodiments, at least one crosslinking agent in the polymer reaction product comprises an acrylate group. In some embodiments, each crosslinking agent in the polymer reaction product independently comprises an acrylate group. In some embodiments, at least one crosslinking agent in the polymer reaction product comprises a methacrylate group. In some embodiments, each crosslinking agent in the polymer reaction product independently comprises a methacrylate group. In some embodiments, at least one crosslinking agent in the polymer reaction product comprises a vinyl ether group. In some embodiments, each crosslinking agent in the polymer reaction product independently comprises a vinyl ether group. Crosslinking agents suitable for forming polymerization products include, for example, N,N'-methylenebisacrylamide, substituted N,N'-methylenebisacrylamide, poly(ethylene glycol) diacrylate, substituted poly(ethylene glycol) diacrylate, 1,4-cyclohexanediethanol diethylene ether, substituted 1,4-cyclohexanediethanol diethylene ether, trimethylolpropane triacrylate, substituted trimethylolpropane triacrylate, methacrylamide gelatin, substituted methacrylamide gelatin, and any combination thereof.

[0074] The amount of polymerization product components within the provided microgel can be selected to impart beneficial pH responsiveness and self-healing properties to the microgel, and to enhance other desired properties of the microgel, including, for example, water solubility, biocompatibility, and mechanical strength. The combined concentration of two or more polymer precursors in the microgel (i.e., the concentration of polymer precursors present in the microgel as components of the polymerization product) can be, for example, from about 10 wt% to about 30 wt%, for example, from about 10 wt% to about 22 wt%, from about 12 wt% to about 24 wt%, from about 14 wt% to about 26 wt%, from about 16 wt% to about 28 wt%, or from about 18 wt% to about 30 wt%. At an upper limit, the combined concentration of polymer precursors in the microgel can be, for example, less than about 30 wt%, for example, less than about 28 wt%, less than about 26 wt%, less than about 24 wt%, less than about 22 wt%, less than about 20 wt%, less than about 18 wt%, less than about 16 wt%, less than about 14 wt%, or less than about 12 wt%. With regard to the lower limit, the combined concentration of polymer precursors in the microgel can be, for example, greater than about 10 wt%, such as greater than about 12 wt%, greater than about 14 wt%, greater than about 16 wt%, greater than about 18 wt%, greater than about 20 wt%, greater than about 22 wt%, greater than about 24 wt%, greater than about 26 wt%, or greater than about 28 wt%. Higher polymer precursor concentrations (e.g., greater than about 30 wt%) and lower polymer precursor concentrations (e.g., less than about 10 wt%) have also been considered.

[0075] The concentration of the crosslinking agent in the provided pH-responsive self-healing microgel (i.e., the concentration of the crosslinking agent present in the microgel as a component of the polymerization product) can be, for example, from about 0.1 wt% to about 1 wt%, for example, from about 0.1 wt% to about 0.64 wt%, from about 0.19 wt% to about 0.73 wt%, from about 0.28 wt% to about 0.82 wt%, from about 0.37 wt% to about 0.91 wt%, or from about 0.46 wt% to about 1 wt%. At the upper limit, the concentration of the crosslinking agent in the microgel can be, for example, less than about 1 wt%, for example, less than about 0.91 wt%, less than about 0.82 wt%, less than about 0.73 wt%, less than about 0.64 wt%, less than about 0.55 wt%, less than about 0.46 wt%, less than about 0.37 wt%, less than about 0.28 wt%, or less than about 0.19 wt%. With regard to the lower limit, the concentration of crosslinking agent in the microgel can be, for example, greater than about 0.1 wt%, such as greater than about 0.19 wt%, greater than about 0.28 wt%, greater than about 0.37 wt%, greater than about 0.46 wt%, greater than about 0.55 wt%, greater than about 0.64 wt%, greater than about 0.73 wt%, greater than about 0.82 wt%, or greater than about 0.91 wt%. Higher crosslinking agent concentrations (e.g., greater than about 1 wt%) and lower crosslinking agent concentrations (e.g., less than about 0.1 wt%) have also been considered.

[0076] In some embodiments, the magnetic agent of the provided pH-responsive self-healing gel comprises one or more transition metals, such as two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more transition metals. Suitable transition metals to be included in the magnetic agent of the microgel include, for example, iron, nickel, cobalt, scandium, titanium, vanadium, chromium, manganese, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, gold, cadmium, lanthanum, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, silver, actinium, and any combination thereof. In some embodiments, the magnetic agent comprises iron, nickel, cobalt, or combinations thereof. In some embodiments, the magnetic agent comprises nickel microparticles, or is composed of the above. In some embodiments, the magnetic agent comprises iron microparticles, or is composed of the above. In some embodiments, the magnetic agent comprises iron nanoparticles, or is composed of the above. In some embodiments, the magnetic agent comprises iron oxide nanoparticles, or is composed of the above. In some embodiments, the magnetic agent comprises cobalt oxide nanoparticles, or is composed of the above. In some embodiments, the magnetic agent comprises iron-platinum nanoparticles, or is composed of the above. The magnetic agent may, for example, comprise one or more magnetite nanoparticles, or be composed of the above.

[0077] The amount of magnetic agent within the provided pH-responsive self-healing microgel can be selected to be sufficiently high to advantageously allow the microgel to be effectively and efficiently guided remotely (e.g., by an applied magnetic field), while also being sufficiently low to not interfere with other beneficial microgel properties, such as biocompatibility and mechanical properties. The concentration of the magnetic agent in the microgel can be, for example, from about 10 wt% to about 30 wt%, e.g., from about 10 wt% to about 22 wt%, from about 12 wt% to about 24 wt%, from about 14 wt% to about 26 wt%, from about 16 wt% to about 28 wt%, or from about 18 wt% to about 30 wt%. At the upper limit, the concentration of the magnetic agent in the microgel can be, for example, less than about 30 wt%, e.g., less than about 28 wt%, less than about 26 wt%, less than about 24 wt%, less than about 22 wt%, less than about 20 wt%, less than about 18 wt%, less than about 16 wt%, less than about 14 wt%, or less than about 12 wt%. With regard to the lower limit, the concentration of the magnetic agent in the microgel can be, for example, greater than about 10 wt%, such as greater than about 12 wt%, greater than about 14 wt%, greater than about 16 wt%, greater than about 18 wt%, greater than about 20 wt%, greater than about 22 wt%, greater than about 24 wt%, greater than about 26 wt%, or greater than about 28 wt%. Higher magnetic agent concentrations (e.g., greater than about 30 wt%) and lower magnetic agent concentrations (e.g., less than about 10 wt%) have also been considered.

[0078] In some embodiments, the imaging agent of the provided pH-responsive self-healing microgel comprises one or more contrast agents, or is composed of the above. Suitable contrast agents for use with the microgel include, for example, barium sulfate microparticles, tantalum microparticles, iodipin, and any combination thereof. In some embodiments, the imaging agent of the microgel comprises one or more tantalum microparticles, or is composed of the above.

[0079] The amount of imaging agent within the provided pH-responsive self-healing microgel can be selected to be sufficiently high to advantageously allow the microgel to be imaged effectively and efficiently (e.g., inside the body of a subject), while also being sufficiently low to not interfere with other beneficial microgel properties, such as biocompatibility and mechanical properties. The concentration of the imaging agent in the microgel can be, for example, from about 5 wt% to about 15 wt%, e.g., from about 5 wt% to about 11 wt%, from about 6 wt% to about 12 wt%, from about 7 wt% to about 13 wt%, from about 8 wt% to about 14 wt%, or from about 9 wt% to about 15 wt%. At the upper limit, the concentration of the imaging agent in the microgel can be, for example, less than about 15 wt%, e.g., less than about 14 wt%, less than about 13 wt%, less than about 12 wt%, less than about 11 wt%, less than about 10 wt%, less than about 9 wt%, less than about 8 wt%, less than about 7 wt%, or less than about 6 wt%. With regard to the lower limit, the concentration of the developer in the microgel can be, for example, greater than about 5 wt%, such as greater than about 6 wt%, greater than about 7 wt%, greater than about 8 wt%, greater than about 9 wt%, greater than about 10 wt%, greater than about 11 wt%, greater than about 12 wt%, greater than about 13 wt%, or greater than about 14 wt%. Higher developer concentrations (e.g., greater than about 15 wt%) and lower developer concentrations (e.g., less than about 5 wt%) have also been considered.

[0080] It has been demonstrated that the particularly useful properties of the provided microgels are not only a result of the individual concentrations of the various components within the microgel, but also of the amounts of the components relative to each other. It is noteworthy that the importance of component ratios in simultaneously achieving different advantageous properties has not been previously recognized. For example, certain relative amounts of polymer precursors to crosslinking agents provide the microgels with their advantageous characteristics. The mass ratio of polymer precursors to crosslinking agents in the microgel can be, for example, from about 10:1 to about 300:1, such as about 10:1 to about 77:1, about 14:1 to about 110:1, about 20:1 to about 150:1, about 28:1 to about 210:1, or about 39:1 to about 300:1. Regarding the upper limit, the mass ratio of polymer precursor to crosslinking agent in the microgel can be, for example, less than about 300:1, such as less than about 210:1, less than about 150:1, less than about 110:1, less than about 77:1, less than about 55:1, less than about 39:1, less than about 28:1, less than about 19:1, or less than about 14:1. Regarding the lower limit, the mass ratio of polymer precursor to crosslinking agent in the microgel can be, for example, greater than about 10:1, such as greater than about 14:1, greater than about 20:1, greater than about 28:1, greater than about 39:1, greater than about 55:1, greater than about 77:1, greater than about 110:1, greater than about 150:1, or greater than about 210:1. Higher mass ratios (e.g., greater than about 300:1) and lower mass ratios (e.g., less than about 10:1) are also considered.

[0081] Certain relative amounts of polymer precursors and magnetic agents in pH-responsive self-healing microgels have also been shown to provide the microgels disclosed herein with their surprisingly useful properties. The mass ratio of polymer precursors to magnetic agents in the microgel can be, for example, from about 0.3:1 to about 3.3:1, e.g., from about 0.3:1 to about 2.1:1, from about 0.6:1 to about 2.4:1, from about 0.9:1 to about 2.7:1, from about 1.2:1 to about 3:1, or from about 1.5:1 to about 3.3:1. At the upper limit, the mass ratio of polymer precursors to magnetic agents in the microgel can be, for example, less than about 3.3:1, e.g., less than about 3:1, less than about 2.7:1, less than about 2.4:1, less than about 2.1:1, less than about 1.8:1, less than about 1.5:1, less than about 1.2:1, less than about 0.9:1, or less than about 0.6:1. With regard to the lower limit, the mass ratio of the polymer precursor to the magnetic agent in the microgel can be, for example, greater than about 0.3:1, such as greater than about 0.6:1, greater than about 0.9:1, greater than about 1.2:1, greater than about 1.5:1, greater than about 1.8:1, greater than about 2.1:1, greater than about 2.4:1, greater than about 2.7:1, or greater than about 3:1. Higher mass ratios (e.g., greater than about 3.3:1) and lower mass ratios (e.g., less than about 0.3:1) are also considered.

[0082] Certain relative amounts of polymer precursors and developers in pH-responsive self-healing microgels have also been shown to provide the microgels disclosed herein with their surprisingly useful properties. The mass ratio of polymer precursors to developers in the microgel can be, for example, from about 0.6:1 to about 6.1:1, e.g., from about 0.6:1 to about 3.9:1, from about 1.15:1 to about 4.45:1, from about 1.7:1 to about 5:1, from about 2.25:1 to about 5.55:1, or from about 2.8:1 to about 6.1:1. At the upper limit, the mass ratio of polymer precursors to developers in the microgel can be, for example, less than about 6.1:1, e.g., less than about 5.55:1, less than about 5:1, less than about 4.45:1, less than about 3.9:1, less than about 3.35:1, less than about 2.8:1, less than about 2.25:1, less than about 1.7:1, or less than about 1.15:1. With regard to the lower limit, the mass ratio of polymer precursor to developer in the microgel can be, for example, greater than about 0.6:1, such as greater than about 1.15:1, greater than about 1.7:1, greater than about 2.25:1, greater than about 2.8:1, greater than about 3.35:1, greater than about 3.9:1, greater than about 4.45:1, greater than about 5:1, or greater than about 5.55:1. Higher mass ratios (e.g., greater than about 6.1:1) and lower mass ratios (e.g., less than about 0.6:1) are also considered.

[0083] Certain relative amounts of magnetic agents and crosslinking agents in pH-responsive self-healing microgels have also been shown to contribute their surprisingly useful properties to the microgels disclosed herein. The mass ratio of magnetic agents to crosslinking agents in the microgels can be, for example, from about 10:1 to about 300:1, e.g., from about 10:1 to about 77:1, from about 14:1 to about 110:1, from about 20:1 to about 150:1, from about 28:1 to about 210:1, or from about 39:1 to about 300:1. At the upper limit, the mass ratio of magnetic agents to crosslinking agents in the microgels can be, for example, less than about 300:1, e.g., less than about 210:1, less than about 150:1, less than about 110:1, less than about 77:1, less than about 55:1, less than about 39:1, less than about 28:1, less than about 19:1, or less than about 14:1. With regard to the lower limit, the mass ratio of magnetic agent to crosslinking agent in the microgel can be, for example, greater than about 10:1, such as greater than about 14:1, greater than about 20:1, greater than about 28:1, greater than about 39:1, greater than about 55:1, greater than about 77:1, greater than about 110:1, greater than about 150:1, or greater than about 210:1. Higher mass ratios (e.g., greater than about 300:1) and lower mass ratios (e.g., less than about 10:1) are also considered.

[0084] Certain relative amounts of magnetic agents and developers in pH-responsive self-healing microgels have also been shown to provide the microgels disclosed herein with their surprisingly useful properties. The mass ratio of magnetic agents to developers in the microgel can be, for example, from about 0.6:1 to about 6.1:1, such as from about 0.6:1 to about 3.9:1, from about 1.15:1 to about 4.45:1, from about 1.7:1 to about 5:1, from about 2.25:1 to about 5.55:1, or from about 2.8:1 to about 6.1:1. At the upper limit, the mass ratio of magnetic agents to developers in the microgel can be, for example, less than about 6.1:1, such as less than about 5.55:1, less than about 5:1, less than about 4.45:1, less than about 3.9:1, less than about 3.35:1, less than about 2.8:1, less than about 2.25:1, less than about 1.7:1, or less than about 1.15:1. With regard to the lower limit, the mass ratio of magnetic agent to developer in the microgel can be, for example, greater than about 0.6:1, such as greater than about 1.15:1, greater than about 1.7:1, greater than about 2.25:1, greater than about 2.8:1, greater than about 3.35:1, greater than about 3.9:1, greater than about 4.45:1, greater than about 5:1, or greater than about 5.55:1. Higher mass ratios (e.g., greater than about 6.1:1) and lower mass ratios (e.g., less than about 0.6:1) are also considered.

[0085] Certain relative amounts of the developer and crosslinker in the pH-responsive self-healing microgel have also been shown to provide the microgel disclosed herein with its surprisingly useful properties. The mass ratio of developer to crosslinker in the microgel can be, for example, from about 5:1 to about 150:1, e.g., from about 5:1 to about 38:1, from about 7.1:1 to about 54:1, from about 9.9:1 to about 76:1, from about 14:1 to about 110:1, or from about 19:1 to about 150:1. At the upper limit, the mass ratio of developer to crosslinker in the microgel can be, for example, less than about 150:1, e.g., less than about 110:1, less than about 76:1, less than about 54:1, less than about 38:1, less than about 27:1, less than about 19:1, less than about 14:1, less than about 9.9:1, or less than about 7:1. With regard to the lower limit, the mass ratio of developer to crosslinker in the microgel can be, for example, greater than about 5:1, such as greater than about 7:1, greater than about 9.9:1, greater than about 14:1, greater than about 19:1, greater than about 27:1, greater than about 38:1, greater than about 54:1, greater than about 76:1, or greater than about 110:1. Higher mass ratios (e.g., greater than about 150:1) and lower mass ratios (e.g., less than about 5:1) are also considered.

[0086] The size of the provided pH-responsive self-healing microgel can be configured or selected to have a size suitable for a specific desired application. For example, when the microgel is used for embolization therapy, the size of the microgel can be configured or selected to facilitate the delivery or guidance of the microgel to a targeted intravascular site and the ability of the microgel to form an embolism (i.e., blockage) at that site. The equivalent sphere diameter of the microgel can be, for example, from about 30 μm to about 300 μm, such as from about 30 µm to about 120 µm, from about 38 µm to about 150 µm, from about 48 µm to about 190 µm, from about 60 µm to about 240 µm, or from about 75 µm to about 300 µm. At the upper limit, the equivalent sphere diameter of the microgel can be, for example, less than about 300 μm, such as less than about 240 μm, less than about 190 μm, less than about 150 μm, less than about 120 μm, less than about 95 μm, less than about 75 μm, less than about 60 μm, less than about 48 μm, or less than about 38 μm. With regard to the lower limit, the equivalent sphere diameter of the microgel can be, for example, greater than about 30 μm, such as greater than about 38 μm, greater than about 48 μm, greater than about 60 μm, greater than about 75 μm, greater than about 95 μm, greater than about 120 μm, greater than about 150 μm, greater than about 190 μm, or greater than about 240 μm. Larger diameters (e.g., greater than about 300 μm) and smaller diameters (e.g., less than about 30 μm) are also considered. In some embodiments, the microgel has a substantially spherical shape.

[0087] A population of pH-responsive self-healing microgels disclosed herein is also provided. The population may comprise multiple microgels, each a member of the same provided microgel species, i.e., each having similar or identical composition and properties. Alternatively, the population may comprise multiple microgels, including two or more different species of members of the provided microgels, i.e., microgels with different compositions and properties. The average equivalent sphere diameter of the microgels in the provided population may be, for example, from about 30 μm to about 300 μm, e.g., from about 30 µm to about 120 µm, from about 38 µm to about 150 µm, from about 48 µm to about 190 µm, from about 60 µm to about 240 µm, or from about 75 µm to about 300 µm. Regarding the upper limit, the average equivalent sphere diameter of the microgels in the population can be, for example, less than about 300 μm, such as less than about 240 μm, less than about 190 μm, less than about 150 μm, less than about 120 μm, less than about 95 μm, less than about 75 μm, less than about 60 μm, less than about 48 μm, or less than about 38 μm. Regarding the lower limit, the average equivalent sphere diameter of the microgels in the population can be, for example, greater than about 30 μm, such as greater than about 38 μm, greater than about 48 μm, greater than about 60 μm, greater than about 75 μm, greater than about 95 μm, greater than about 120 μm, greater than about 150 μm, greater than about 190 μm, or greater than about 240 μm. Larger average diameters (e.g., greater than about 300 μm) and smaller average diameters (e.g., less than about 30 μm) are also considered.

[0088] IV. System

[0089] Another aspect of this disclosure relates to systems comprising a group of pH-responsive self-healing microgels. The microgels can be any of those disclosed in Part III. For example, the microgels of the provided system can each be independently pH-responsive self-healing microgels comprising a magnetic agent, an imaging agent, and a polymerization product of two or more polymer precursors and crosslinking agents. The magnetic agent of the system microgel can comprise, for example, nanoparticles containing a transition metal, such as magnetite nanoparticles. The imaging agent of the system microgel can comprise, for example, a contrast agent, such as tantalum nanoparticles. The polymerization product of the system microgel can comprise, for example, multiple side chains containing amide groups and / or carboxyl groups, such as 1-oxo-1-(5-carboxyl)pentanaminomethyl side chains. Because the system comprises the group of specific microgels disclosed herein, the system benefits from the advantageous features of the microgels described in Part III. Therefore, the system offers particular advantages when used to treat subjects requiring embolization at a targeted intravascular location.

[0090] The provided system typically also includes a magnetron control module. The magnetron control module can be configured or selected to interact with magnetic agents within a population of pH-responsive self-healing microgels in the system, allowing the module to guide the microgel population within a subject requiring embolization treatment, for example. This remote control of the microgel population using the magnetron control module can be used to guide the microgel population to, for example, a targeted intravascular location. The magnetron control module may include, for example, a spherical permanent magnet. Including a spherical permanent magnet advantageously allows the system to easily establish a localized magnetic field in an omnidirectional manner. The magnetron control module may include, for example, an electric motor and / or a robotic arm. These components of the magnetron control module can, for example, be configured to adjustably position the spherical permanent magnet at various locations relative to the subject to guide the microgel population within the subject.

[0091] The provided system typically also includes an imaging module. The imaging module can be configured or selected to detect an imaging agent capable of detecting populations of pH-responsive self-healing microgels in the system, such that the imaging module can provide location information of the microgel populations, for example, information indicating the location of the microgel populations within the body of a subject requiring embolization treatment. The imaging module may include a fluorescence microscopy module, for example, a module configured or selected to detect a fluorescence imaging agent of the microgel population, or a combination thereof. The imaging module may include a positron emission tomography (PET) module, for example, a module configured or selected to detect a radioactive imaging agent of the microgel population, or a combination thereof. The imaging module may include an ultrasound imaging module, for example, a module configured or selected to detect an ultrasound contrast imaging agent of the microgel population, or a combination thereof. The imaging module may include a fluoroscopy module, for example, a module configured or selected to detect an X-ray contrast imaging agent of the microgel population, or a combination thereof. The imaging module may include a confocal microscopy module, or a combination thereof. In some embodiments, the system's imaging module includes an ultrasound imaging module and a fluoroscopy module, or a combination thereof.

[0092] The provided system may optionally include a catheter. The catheter may be configured or selected to administer a microgel population to a subject requiring embolization therapy. The catheter may additionally or optionally be configured or selected to administer an acidic solution (e.g., an acidic buffered aqueous solution) to the subject, thereby triggering the pH-responsive self-healing properties of the microgel. The system may include a first catheter designed for administering the microgel population and a second catheter designed for administering the acidic solution. Optionally, the system may include a single catheter for administering both the microgel population and the acidic solution.

[0093] The provided system may optionally include one or more other components configured or selected for use with an operating system, and / or a computer system for performing one or more steps of any of the methods disclosed herein. The computer system may include, for example, a logic system that receives one or more data signals from and / or transmits one or more data signals to and / or to a magnetocontrol module and / or an imaging module. The logic system may include a display (e.g., a monitor, LED display, etc.) and user input devices (e.g., a mouse, keyboard, buttons, etc.), or connected to the foregoing. The logic system and other components of the system may be part of a stand-alone or network-connected computer system, or they may be directly attached to or integrated into the device. The logic system may also include software that executes in a processor. The logic system may include a computer-readable medium storing instructions for use with one or more other components of an operating system, and / or for performing one or more steps of any of the methods disclosed herein.

[0094] Any of the computer systems provided herein can utilize any suitable number of subsystems. In some embodiments, the computer system includes a single computer device, wherein the subsystem may be a component of the computer device. In other embodiments, the computer system may include multiple computer devices, each of which is a subsystem with internal components. The computer system may include desktop and laptop computers, tablet computers, mobile phones, and other mobile devices.

[0095] Subsystems can be interconnected via a system bus. Additional subsystems may be included, such as printers, keyboards, storage devices, monitors (e.g., displays, such as LEDs) connected to the display adapter. Peripheral devices and input / output (I / O) devices connected to the I / O controller can be connected via any number of methods known in the art (e.g., input / output (I / O) ports (e.g., USB, Firewall)). ® The system connects to the computer system. For example, I / O ports or external interfaces (e.g., Ethernet, Wi-Fi, etc.) can be used to connect the computer system to a wide area network (e.g., the Internet), a mouse input device, or a scanner. Interconnection via the system bus allows the central processing unit to communicate with each subsystem and control the execution of multiple instructions from system memory or storage devices (e.g., a fixed disk, such as a hard disk drive or optical disk), as well as the exchange of information between subsystems. System memory and / or storage devices can be embodied in computer-readable media. Additional subsystems can be data acquisition devices, such as cameras, microphones, accelerometers, etc. Any data mentioned herein can be output from one component to another and can be output to the user.

[0096] A computer system may include multiple identical components or subsystems, for example, connected together via an external interface, an internal interface, or via a removable storage device that can be connected and removed between components. In some embodiments, the computer system, subsystem, or device may communicate via a network. In such a case, one computer may be considered a client, and another computer may be considered a server, where each computer may be part of the same computer system. Clients and servers may each include multiple systems, subsystems, or components. In various embodiments, the method may involve a variety of numbers of clients and / or servers, including at least 10, 20, 50, 100, 200, 500, 1,000, or 10,000 devices. The method may include a variety of numbers of communications between devices, including at least 100, 200, 500, 1,000, 10,000, 50,000, 100,000, 500,000, or one million communications. Such communication can involve at least 1 MB, 10 MB, 100 MB, 1 GB, 10 GB, or 100 GB of data.

[0097] Aspects of the embodiments can be implemented in a modular or integrated manner as control logic using hardware circuitry (e.g., application-specific integrated circuits or field-programmable gate arrays) and / or computer software stored in memory, with a general-purpose programmable processor. Therefore, the processor may include memory storing software instructions for configuring the hardware circuitry, and an FPGA or ASIC having configuration instructions. As used herein, the processor may include a single-core processor, a multi-core processor on the same integrated chip, or multiple processing units on a single circuit board or networked, as well as dedicated hardware. Based on the disclosure and teachings provided herein, those skilled in the art will know and understand other ways and / or methods of implementing embodiments of this disclosure using hardware and combinations of hardware and software.

[0098] Any software component or function described in this application can be implemented as software code executed by a processor using any suitable computer language (such as, for example, Java, C, C++, C#, Objective-C, Swift) or scripting language (such as Perl or Python), using, for example, conventional or object-oriented techniques. The software code can be stored as a series of instructions or commands on a computer-readable medium for storage and / or transmission. Suitable non-transitory computer-readable media may include random access memory (RAM), read-only memory (ROM), magnetic media (e.g., hard disk drive or floppy disk) or optical media (e.g., optical disc (CD) or DVD (Digital Versatile Optical Disc) or Blu-ray disc), flash memory, etc. The computer-readable medium can be any combination of such means. Furthermore, the order of operations can be rearranged. A process can terminate when its operations are complete, but may also have additional steps not otherwise described herein. A process can correspond to a method, function, program, subroutine, subroutines, etc. When a process corresponds to a function, its termination can correspond to the function returning to the calling function or the main function.

[0099] Such programs can also be encoded and transmitted using carrier signals suitable for transmission over wired, optical, and / or wireless networks conforming to various protocols, including the Internet. Thus, computer-readable media can be created using data signals encoded with such programs. Computer-readable media encoded with program code can be packaged with compatible devices or provided separately from other devices (e.g., downloaded via the Internet). Any such computer-readable media can reside on or within a single computer product (e.g., a hard drive, CD, or an entire computer system) and can exist on or within different computer products within a system or network. The computer system may include monitors, printers, or other suitable displays for providing the user with any of the results mentioned herein.

[0100] V. Treatment methods

[0101] Another aspect of this disclosure relates to a treatment method, such as a method for treating a subject requiring embolization. The method typically includes the step of applying a microgel population to the subject, wherein the population can be any of those disclosed in Part IV. This application can be performed via any suitable means. In a particular embodiment, the microgel population is applied to the subject using a catheter. Because the treatment method therefore uses the pH-responsive self-healing microgels of Part III, the method benefits from the relevant advantages described in that part. For example, the method has the advantage of using the microgel population as a swarm of remotely controllable and detectable microrobots, particularly for embolization treatment.

[0102] Groups of patients applying pH-responsive self-healing microgels to a subject may also include making an incision in the subject and inserting the distal end of a catheter through the incision. Application may include anesthetizing the subject's skin area prior to making the incision. The incision may be made to access a blood vessel in the subject, such as an artery, for example, the femoral artery, allowing the catheter to be inserted into the artery. In some instances, the proximal end of the catheter may be mounted on a pump (e.g., an infusion pump), which is used to drive the flow of the microgel through the catheter and into the subject.

[0103] The provided treatment method typically includes, after the microgel population has been applied to the subject, applying a magnetic field to at least a portion of the subject (e.g., a region of the subject's body that coincides with or is close to the location of the microgel population). The method typically also includes the step of guiding the microgel population within the subject's body using the applied magnetic field. Typically, this method involves guiding the microgel population to an intravascular location within the subject, where the intravascular location is a target site for embolization with the microgel population. As an example, the target intravascular location could be within, adjacent to, or near an aneurysm of the subject. The application and guidance of the magnetic field can be performed, for example, using a magnetic control module. The magnetic control module can be any of those described in Part IV, for example. For example, the magnetic control module may include a spherical permanent magnet, an electric motor, and / or a robotic arm.

[0104] The provided treatment method may optionally include determining the location information of a microgel population within the subject by imaging the population. This location information can be advantageously used during the guidance of the microgel population with an applied magnetic field. In a particularly useful example of the provided method, the imaging for determining the location information includes real-time imaging, thereby allowing guidance of the microgel population with knowledge of its current location. For example, an imaging module can be used to image the population within the subject. The imaging module can be any of those described, for example, in Part IV. For example, the imaging module can be an imaging module configured or selected to provide, for example, ultrasound and fluoroscopic imaging of the microgel population.

[0105] The treatment methods provided typically also include the introduction of an acidic solution into the subject, for example, into a targeted intravascular location within the subject's body. Typically, the acidic solution is applied to the subject after the microgel population has been directed to the targeted intravascular location. By altering the pH environment of the microgel population, the applied acidic solution induces the formation of hydrogen bonds within the population. This hydrogen bond formation, as described in Part III, is due to the advantageous pH-responsive self-healing characteristics of the provided microgels, causing different microgels within the population to adhere to each other, thereby forming aggregates (i.e., blockages) in a therapeutic manner that can substantially fill the targeted intravascular location. The hydrogen bonds formed during this method may include face-to-face hydrogen bonds between different polymer side chains of the microgels, interleaved hydrogen bonds between different polymer side chains of the microgels, or combinations thereof. The introduction of the acidic solution can be carried out in any suitable manner. In a particular embodiment, a catheter is used to introduce the acidic solution. The catheter may be the same catheter also used for applying the microgel population, or it may be a different catheter. The acidic solution may be, for example, a buffer solution, an aqueous solution, or a buffered aqueous solution.

[0106] The amount and pH of the acidic solution introduced into the provided treatment method can be selected to effectively induce the formation of hydrogen bonds between different microgels within the microgel population. The pH of the acidic solution can be, for example, less than about 6, such as less than about 5.75, less than about 5.5, less than about 5.25, less than about 5, less than about 4.75, less than about 4.5, less than about 4.25, less than about 4, or less than about 3.75. The pH of the acidic solution can be, for example, from about 3.5 to about 6, such as from about 3.5 to about 5, about 3.75 to about 5.25, about 4 to about 5.5, about 4.25 to about 5.75, or about 4.5 to about 6.

[0107] The treatment method provided is highly effective in essentially filling the target intravascular site to provide embolization. The filling rate of the target intravascular site after treatment can be, for example, greater than about 90%, such as greater than about 91%, greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. This high filling rate can be advantageously achieved even when the target intravascular site is in, adjacent to, or near a dynamic blood environment with a high average inlet blood flow velocity. For example, the treatment method can provide effective embolization even when the average inlet blood flow velocity in, adjacent to, or near the target intravascular site is about 2 cm / s to about 60 cm / s, such as about 2 cm / s to about 15 cm / s, about 2.8 cm / s to about 22 cm / s, about 3.9 cm / s to about 30 cm / s, about 5.5 cm / s to about 43 cm / s, or about 7.8 cm / s to about 60 cm / s. Regarding the lower limit, the average inlet blood flow velocity in the dynamic blood environment before the introduction of acid solution can be greater than about 2 cm / s, for example, greater than about 2.8 cm / s, greater than about 3.9 cm / s, greater than about 5.5 cm / s, greater than about 7.8 cm / s, greater than about 11 cm / s, greater than about 15 cm / s, greater than about 22 cm / s, greater than about 30 cm / s, or greater than about 43 cm / s.

[0108] The treatment methods provided also advantageously lead to robust and durable embolization. For example, the high filling rate at the targeted intravascular site after treatment can be stably maintained for a long time under typical physiological conditions. As an indicator of this stability, the occlusions formed by the microgel aggregates can continue to exhibit self-adhesion in the blood environment at 37°C for more than 2 months after the completion of treatment. Furthermore, the shape and compressive modulus of the occlusions independently showed changes of less than 30% after more than 2 months in the blood environment at 37°C following the completion of treatment.

[0109] Another advantage of the treatment method offered is the excellent biocompatibility of the multiple microgels and the occlusions formed by the aggregates of microgels in the patient, without causing significant side effects. For example, during the first 48 hours after occlusion formation, the occlusion does not reduce the viability of endothelial cells near the target vessel by more than 10%. Furthermore, during the first 24 hours after occlusion formation, the occlusion does not cause more than 10% erythrolysis near the target vessel. As another benefit of biocompatibility, during the first 24 hours after occlusion formation, the occlusion does not increase procoagulant or anticoagulant levels in the blood near the target vessel by more than 10%.

[0110] VI. Exemplary Implementation Scheme

[0111] The following implementation schemes were considered. All combinations of features and implementation schemes were considered.

[0112] Implementation Scheme 1: pH-responsive self-healing microgel comprising: a polymerization product of two or more polymer precursors and a crosslinking agent; a magnetic agent; and a developer.

[0113] Implementation Scheme 2: According to the implementation scheme of Implementation Scheme 1, at least one of the two or more polymer precursors comprises an acryloyl group, an acrylamide group, or a combination thereof.

[0114] Implementation Scheme 3: According to the implementation scheme of Implementation Scheme 2, the two or more polymer precursors include optionally substituted N-acryloyl-2-glycine, optionally substituted N-acryloyl-4-aminobutyric acid, optionally substituted N-acryloyl-6-aminohexanoic acid, optionally substituted N-acryloyl-8-aminooctanoic acid, optionally substituted N-acryloyl-11-aminoundecanoic acid, optionally substituted N-isopropylacrylamide, optionally substituted acrylamide, optionally substituted acrylic acid, or combinations thereof.

[0115] Implementation Scheme 4: According to any one of Implementation Schemes 1-3, the polymerization product comprises a plurality of dangling side chains, each of which independently comprises an amide group, a carboxyl group, or a combination thereof.

[0116] Implementation Scheme 5: According to the implementation scheme of Implementation Scheme 4, the plurality of suspension side chains include suspension side chains having the following structure: .

[0117] Implementation Scheme 6: According to the implementation scheme of Implementation Scheme 4 or 5, wherein the plurality of suspended side chains form hydrogen bonds at the interface of the pH-responsive self-healing microgel.

[0118] Implementation Scheme 7: According to the implementation scheme of Implementation Scheme 6, wherein the hydrogen bonds are formed when the pH-responsive self-healing microgel is exposed to a pH less than or equal to about 6.

[0119] Implementation Scheme 8: According to the implementation scheme of Implementation Scheme 6 or 7, wherein the formed hydrogen bonds are maintained in 0.9wt% brine at 37°C for at least about 24 h.

[0120] Implementation Scheme 9: According to any one of Implementation Schemes 1-6, wherein the crosslinking agent comprises an acrylamide group, an acrylate group, a methacrylate group, a vinyl ether group, or a combination thereof.

[0121] Implementation Scheme 10: According to the implementation scheme of Implementation Scheme 9, wherein the crosslinking agent comprises optionally substituted N,N'-methylenebisacrylamide, optionally substituted poly(ethylene glycol) diacrylate, optionally substituted 1,4-cyclohexanediethanol diethylene ether, optionally substituted trimethylolpropane triacrylate, optionally substituted methacrylamide gelatin, or combinations thereof.

[0122] Implementation Scheme 11: According to the implementation scheme of Implementation Scheme 10, wherein the crosslinking agent comprises N,N'-methylenebisacrylamide.

[0123] Implementation Scheme 12: According to any one of Implementation Schemes 1-11, wherein the magnetic agent comprises a transition metal.

[0124] Implementation Scheme 13: According to the implementation scheme of Implementation Scheme 12, the magnetic agent includes nickel microparticles, iron microparticles, iron nanoparticles, iron oxide microparticles, iron oxide nanoparticles, cobalt oxide nanoparticles, iron-platinum nanoparticles, or combinations thereof.

[0125] Implementation Scheme 14: According to the implementation scheme of Implementation Scheme 13, the magnetic agent comprises magnetite nanoparticles.

[0126] Implementation Scheme 15: According to any one of Implementation Schemes 1-14, wherein the developing agent comprises a contrast agent.

[0127] Implementation Scheme 16: According to the implementation scheme of Implementation Scheme 15, the developer includes barium sulfate nanoparticles, tantalum microparticles, iodine, or a combination thereof.

[0128] Implementation Scheme 17: According to the implementation scheme of Implementation Scheme 16, the developer includes tantalum microparticles.

[0129] Implementation Scheme 18: According to any one of Implementation Schemes 1-17, wherein the pH-responsive self-healing microgel comprises about 10% to about 30% of the two or more polymer precursors.

[0130] Implementation Scheme 19: According to any one of Implementation Schemes 1-18, wherein the pH-responsive self-healing microgel comprises about 0.1% to about 1% of the crosslinking agent.

[0131] Implementation Scheme 20: According to any one of Implementation Schemes 1-19, wherein the pH-responsive self-healing microgel comprises about 10% to about 30% of the magnetic agent.

[0132] Implementation Scheme 21: According to any one of Implementation Schemes 1-20, wherein the pH-responsive self-healing microgel comprises about 5% to about 15% of the imaging agent.

[0133] Implementation Scheme 22: According to any one of Implementation Schemes 1-21, wherein the pH-responsive self-healing microgel has an equivalent sphere diameter of less than about 300 μm.

[0134] Implementation Scheme 23: According to any one of Implementation Schemes 1-21, wherein the pH-responsive self-healing microgel has a substantially spherical shape.

[0135] Implementation Scheme 24: A group of pH-responsive self-healing microgels comprising any one of Implementation Schemes 1-23.

[0136] Implementation Scheme 25: A system for treating subjects requiring embolization at a targeted intravascular location, the system comprising: a population of pH-responsive self-healing microgels as described in Implementation Scheme 24; a magnetron sputtering module; and an imaging module.

[0137] Implementation Scheme 26: According to the implementation scheme of Implementation Scheme 25, the magnetron module is configured to guide a plurality of the pH-responsive self-healing microgels to the target intravascular location.

[0138] Implementation Scheme 27: According to the implementation scheme of Implementation Scheme 25 or 26, the magnetic control module includes a spherical permanent magnet, an electric motor and a robotic arm.

[0139] Implementation Scheme 28: According to any one of Implementation Schemes 25-27, wherein the imaging module is configured to image multiple pH-responsive self-healing microgels within the subject body.

[0140] Implementation Scheme 29: According to any one of Implementation Schemes 25-28, the imaging module includes a fluorescence microscope module, a magnetic resonance imaging module, a positron emission tomography module, an ultrasound imaging module, a fluoroscopy module, a confocal microscope module, or a combination thereof.

[0141] Implementation Scheme 30: According to the implementation scheme described in Implementation Scheme 29, the imaging module includes an ultrasound imaging module and a fluoroscopy module.

[0142] Implementation Scheme 31: An implementation scheme according to any one of Implementation Schemes 25-30, wherein the system further includes a conduit.

[0143] Implementation Scheme 32: According to the implementation scheme of Implementation Scheme 31, wherein the catheter is configured to apply a plurality of the pH-responsive self-healing microgels to the object.

[0144] Implementation Scheme 33: A method for treating a subject requiring embolization at a targeted intravascular location, the method comprising: applying a population of pH-responsive self-healing microgels as described in Implementation Scheme 24 to the subject; applying a magnetic field to at least a portion of the subject; using the magnetic field to guide the population of pH-responsive self-healing microgels to the targeted intravascular location; and introducing a quantity of acidic solution into the targeted intravascular location, wherein the quantity effectively induces the formation of hydrogen bonds between pH-responsive self-healing microgels within the population of pH-responsive self-healing microgels.

[0145] Implementation Scheme 34: According to the implementation scheme of Implementation Scheme 33, the method further includes determining the location information of the pH-responsive self-healing microgel population by imaging the population of pH-responsive self-healing microgels in the object.

[0146] Implementation Scheme 35: The implementation scheme according to Implementation Scheme 34, wherein the guidance is based on the location information.

[0147] Implementation Scheme 36: The implementation scheme according to Implementation Scheme 34 or 35, wherein the imaging includes real-time imaging.

[0148] Implementation Scheme 37: According to any one of Implementation Schemes 34-36, wherein the imaging includes fluorescence microscopy imaging, magnetic resonance imaging, positron emission tomography imaging, ultrasound imaging, fluoroscopic imaging, confocal microscopy imaging, or a combination thereof.

[0149] Implementation Scheme 38: According to the implementation scheme of Implementation Scheme 37, wherein the imaging includes ultrasound imaging and fluoroscopic imaging.

[0150] Implementation Scheme 39: According to any one of Implementation Schemes 33-38, the magnetic field is applied using a magnetic control module comprising a spherical permanent magnet, an electric motor, and a robotic arm.

[0151] Implementation Scheme 40: An implementation scheme according to any one of Implementation Schemes 33-39, wherein a catheter is used to apply the pH-responsive self-healing microgel to a population.

[0152] Implementation Scheme 41: According to any one of Implementation Schemes 33-40, wherein the acidic solution has a pH of less than about 6.

[0153] Implementation Scheme 42: According to any one of Implementation Schemes 33-41, wherein the target intravascular location is within, adjacent to or near the aneurysm of the object.

[0154] Implementation Scheme 43: An implementation scheme according to any one of Implementation Schemes 33-42, wherein prior to the introduction of the acidic solution, the target intravascular location is within, adjacent to or near a dynamic blood environment with an average inlet blood flow velocity of about 2 cm / s to about 60 cm / s.

[0155] Implementation Scheme 44: According to any one of Implementation Schemes 33-43, wherein after the introduction of the acidic solution, the target intravascular site has a filling rate of more than about 90%.

[0156] Example

[0157] The present disclosure will be better understood in light of the following non-limiting embodiments. The following embodiments are for illustrative purposes only and do not limit the scope of the present disclosure in any way.

[0158] Example 1. pH-responsive self-healing properties of the provided microgel

[0159] exist Figure 5 In the experiment shown, several hydrogel segments, distinguished by red and blue staining, were prepared and stored in saline solution. Upon immersion in an acidic aqueous environment (ascorbic acid buffer solution at pH 5), the two hydrogels rapidly bonded to each other within 10 s, exhibiting a strong interface capable of withstanding manual stretching. By repeating this process, multiple hydrogels could be easily assembled into a ring structure, demonstrating the excellent pH-responsive self-healing behavior of the provided hydrogel. Furthermore, after removing the acidic buffer and immersing the hydrogel rings in saline solution at 37°C, adhesion between adjacent segments remained effective for at least 24 h, indicating that the prepared hydrogel material possesses stable healing properties in a biofluid-simulated environment (SBF).

[0160] Example 2. Mechanical properties of the provided microgel

[0161] The healing properties of the provided hydrogel were further quantitatively evaluated by mechanical tensile testing. First, a hydrogel cylinder was fabricated using a tubular mold and then fixed onto a universal tensile testing machine. The results showed an initial fracture stress of 57.1 kPa and an elastic modulus of 15.9 kPa. Subsequently, the hydrogel was cut at the midpoint and allowed to heal in an acidic buffer for 5 min, followed by incubation in saline solution at 37°C for 24 h. Figure 6As shown, the maximum stress required for the hydrogel to rupture after this healing process was approximately 29.2 kPa, indicating an effective recovery of over 50% of the tensile strength within a short time. Further incubation of the healed hydrogel in SBF only resulted in a slight deterioration of the fracture stress to approximately 21.7 kPa, rather than a complete failure of the healing behavior. These results demonstrate the suitability of the provided material for practical biomedical applications in a biological environment.

[0162] The time dependence of the hydrogel healing process was also studied. Figure 6 The results plotted show that the adhesion properties continuously improve with increasing healing time, then gradually stabilize after 30 min of healing. Particularly for hydrogels incubated in SBF for 24 h, the average fracture stress only changed from 20.9 kPa to 23.3 kPa when the healing time was extended from 5 min to 1 h. Notably, the hydrogel exposed to acidic buffer for only 30 s exhibited an interfacial adhesion strength as high as 14.6 kPa, demonstrating the rapid healing capability of the provided hydrogel material.

[0163] Example 3. Characterization of hydrogen bonds in the provided microgel

[0164] To confirm the regulation and control of hydrogen bond formation in self-healing behavior, Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR) and Raman spectroscopy were performed. Figure 7 As shown, when the hydrogel was treated with an acidic buffer solution, at 1704 cm⁻¹... -1 (FTIR-ATR) and 1714 cm -1 A new prominent peak appears at (Raman), indicating the presence of a hydrogen-bonded terminal carboxylic acid group. Additionally, a peak at 1640 cm⁻¹ attributed to the amide I group... -1 The FTIR-ATR band at 1638 cm -1 The Raman bands at the locations shifted downwards to 1624 cm. -1 and 1621 cm -1 This indicates enhanced H-bonding with the amide group. Such spectroscopic analysis suggests the formation of two types of hydrogen bonds in the polymer matrix under acidic conditions: face-to-face interactions between relative carboxyl groups and cross-bonding between carboxyl and amide groups. Figure 4Without being bound by any specific theory, the results show that these hydrogen bond types constitute the fundamental self-healing mechanism of the provided hydrogel. No significant differences were observed in FTIR-ATR and Raman spectroscopy after the hydrogel was thoroughly rinsed and incubated in 37°C saline for 24 h. These findings are consistent with the stable welding properties in SBF described above, demonstrating the advantages of the provided hydrogel for developing embolization microrobots for on-demand embolization therapy of aneurysms.

[0165] Example 4. Physical stability of the provided microgel

[0166] Figure 8 The morphology of the prepared microgels is shown, confirming the successful batch fabrication of microrobots with regular and spherical shapes. Quantitative statistics indicate that the provided microgels can have an average diameter of approximately 110 μm. This average size can be easily tuned by adjusting the stirring rate or the viscosity of the aqueous phase during the emulsification process, thus facilitating specific and customizable embolization of vascular sacs of different sizes. Furthermore, due to the presence of a self-healing hydrogel matrix, the microgels exhibit favorable self-adhesive properties in a pH-responsive manner. Figure 9 As shown, once an acidic buffer solution is injected into the suspension, a group of microgels can rapidly (e.g., within seconds) adhere to each other to weld into aggregates. This observed behavior also works in the blood environment.

[0167] For use in long-term embolization therapy, the embolization microrobot should advantageously possess physical stability and compatibility with the surrounding biological environment within the body. To facilitate the study of these stability and biocompatibility properties, the provided embolization material, consisting of a self-healing hydrogel matrix, a magnetic agent, and a developer, was molded into a small disc (10 mm in diameter). Figure 10 The study showed that hydrogel discs immersed in anticoagulated pig blood for different time periods did not exhibit significant shape changes even after 6 months. Figure 10 Quantitative analysis of the area and compressive modulus of the immersed disk was also presented. After long-term storage in blood, the area decreased by only about 5.5%. Due to the exchange of blood into the hydrogel matrix, the corresponding modulus decreased to approximately 82.5% of its initial value on the first day, and then remained almost stable over the following 180 days. These results demonstrate that the material provided for embolization microrobots can maintain substantially constant shape, size, and mechanical properties over long periods, thus exhibiting excellent physical stability.

[0168] Example 5. Biocompatibility and detectability of the provided microgel

[0169] In further testing, blood cells were centrifuged from pig blood and incubated with microgels in phosphate-buffered saline solution. After 24 hours, the supernatant was collected and characterized to verify whether hemolysis occurred. The results showed that the hemolysis rate was consistently below 5% regardless of the microgel concentration, indicating that the provided microrobots did not have a harmful effect on blood cells.

[0170] Because the embolization microrobots used for embolization therapy operate in blood vessels and maintain constant contact with blood, the materials provided should be biocompatible and blood-compatible. Figure 11 The effect of the provided microrobot on blood coagulation was demonstrated. Disc-shaped embolic material was immersed in pig blood, followed by the addition of calcium ions to induce blood coagulation. Compared to the control group, the blood state in contact with the embolic hydrogel showed a similar trend, and there was no significant difference in blood clotting time. These results confirm that the provided microrobot does not induce either procoagulant or anticoagulant effects. Microgels were also prepared and co-cultured with different types of normal cells for 48 h. Figure 12 As shown, even at concentrations as high as 1.0 mg / mL, the addition of the microgel did not induce any changes in the viability of stem cells, 3T3 cells, and human umbilical vein endothelial cells (HUVECs) compared to the control group. These results demonstrate the negligible cytotoxicity of the provided microrobot. In conclusion, the provided microrobot can be successfully deployed via clinical catheters. Figure 13 It exhibits long-term physical stability and excellent biocompatibility and blood compatibility with the physiological blood environment.

[0171] Also advantageously, after incorporating Ta particles into the provided microgel, a transmission imaging contrast proportional to the Ta concentration was detected. Figure 14 Perspective images indicating the feasibility of using this method for imaging and tracking microrobots provided in vivo (e.g., within a subject treated with a microrobot). For this additional reason, the disclosed materials and manufacturing methods provide spherical embolic microrobots capable of pH-responsive self-adhesion and in vivo imaging. These advantageous properties further demonstrate the suitability of the disclosed materials and methods for providing embolic agents.

[0172] Example 6. Formation of occlusion in an aneurysm using the provided microgel

[0173] Figure 15This study demonstrates the on-demand embolization process provided in an aneurysm replica and a dynamic fluid environment. The average inlet flow velocity was set to 20 cm / s, and a clinical catheter was first inserted via a branch cannula with its tip positioned at the aneurysm neck (Phase I). A dynamic external magnetic field was then applied via a robotic magnet, subsequently deploying clusters of microgels, resulting in magnetically guided aggregation of the embolization microrobots within the aneurysm sac (Phase II). After sufficient microgel accumulation, an acidic buffer solution was released via the catheter to trigger the pH-responsive self-adhesive behavior of the microgels, causing the clusters of microrobots to weld together to occlude the sac (Phase III). Finally, the catheter and robotic magnet were removed (Phase IV), indicating completion of on-demand aneurysm embolization. Following embolization, the aneurysm replica was dissected, and the occluded material welded by the embolization microrobots was removed and preserved in saline at 37°C. No significant morphological differences were observed even after 6 months, confirming the long-term stability of the embolization effect.

[0174] The applicability of the provided microrobot embolization strategy for aneurysm treatment was further validated in a blood setting. Due to the opacity of blood, ultrasound (US) imaging was used instead of optical imaging to monitor the embolization process first. Figure 16 Relevant ultrasound images from this study are presented. In addition to standard B-mode imaging, US Doppler imaging (a non-invasive medical imaging strategy compatible with magnetic fields) was applied to estimate blood flow status. In this way, US imaging not only allows for monitoring of immediate operational progress but also visualizes the blood occlusion status within the aneurysm sac, thus serving as a useful tool for evaluating embolization performance. Two US imaging planes (I and II) were used to reflect the real-time status of the horizontal and vertical cross-sections of the aneurysm sac, respectively. Before the deployment of the clustered microgels, distinct Doppler red and blue signals, corresponding to red blood cells moving towards and away from the US source, were observed distributed throughout the aneurysm sac and branch vessels, indicating robust blood circulation in the aneurysm replica. When the clustered microgels were released via catheter and magnetically aggregated, a B-mode acoustic shadowing signal (i.e., the area enclosed by the dashed line) appeared and continuously pushed the boundaries of the Doppler signal, indicating attenuation of blood flow within the aneurysm sac. After injection of acidic buffer to achieve microgel bonding of the clusters, the intraluminal Doppler signal completely disappeared for both US imaging planes I and II, indicating no further blood flow into the aneurysm.

[0175] To further extend the provided microrobot embolization strategy to in vivo settings, C-arm fluoroscopy (a universal medical imaging method for interventional procedures) was used to test the embolization process. Figure 17The experimental setup used in this study is depicted. By controlling a rotating magnet integrated into a robotic arm, deployed clusters of microgels were concentrated within the aneurysm sac without unintentional leakage, even in a dynamic blood environment with an average flow rate of 20 cm / s. Figure 18 As shown, the controlled concentration of the deployed microgels can be clearly monitored via fluoroscopy. These results demonstrate that the provided clustered self-adhesive microgels function in a physiological blood environment for real-time imaging-guided aneurysm embolization.

[0176] Figure 19 This demonstrates further experimental validation of the magnetic aggregation performance of the swarming microrobots in an aneurysm model under flowing conditions. Figure 19 As shown in Region I, when the z-coordinate is sufficiently small (i.e., the robotic magnet is sufficiently close to the aneurysm), the aneurysm sac can be completely filled, even when an inlet mean flow rate as high as approximately 20 cm / s is applied. As the z-coordinate increases, the maximum flow rate that the clustered microgels can tolerate gradually decreases. When the actual flow rate exceeds a critical value, some microgels may no longer remain stable within the sac, leading to incomplete aneurysm filling, as shown in Region II. Further removal of the robotic magnet from the aneurysm causes a significant deterioration in aggregation performance. Cases with filling rates below 50% (Region III) are classified as failures. The observed results are scalable to magnetostatic systems with varying magnetic field strengths and gradients; larger and stronger magnets generally contribute to better magnetic aggregation.

[0177] Example 7. Formation of a blockage within the placenta using the provided microgel.

[0178] The effectiveness of the provided microrobot strategy in blood vessels was further validated by performing an embolization procedure in an ex vivo human placenta under the guidance of ultrasound and fluoroscopic imaging. Figure 20 A schematic diagram and experimental setup used in this study are shown. The placenta, filled with flowing blood, was chosen to simulate the vascular system due to its rich blood supply, such as... Figure 20 As illustrated in the illustration, a clinical catheter mounted on an infusion pump is inserted into a blood vessel for microgel deployment. A robotic arm-integrated rotating magnet controls the magnetic field, and peristaltic pumps connected to four arterial vessels are responsible for building dynamic blood circulation within the placenta. The average blood flow velocity in the inlet vessels is set at 5 cm / s because higher flow velocities and pressures could cause rupture of blood vessels within the placenta. Figure 21 Real-time US B-type images show the entire embolization process in a specific blood artery, including catheter insertion, microgel aggregation under a magnetic field, on-demand embolization via injection of acidic buffer, catheter removal, and magnetic field shutdown. Figure 22US Doppler images during the procedure are shown, revealing the disappearance of the Doppler signal in the blood flowing in the distal vessel (blood outlet I) after the embolization process, indicating effective occlusion of the targeted artery. Figure 23 The images confirm that the inherent X-ray imaging contrast of the provided microgel allows for clear monitoring of such procedures via C-arm fluoroscopy within biological tissue. Figure 24 As shown, dissection of the obstructed blood artery following embolization revealed a blockage welded by self-adhesive microgels clustered within the vessel. Strong adhesion was achieved between the provided microgels, allowing the blockage to be grasped with forceps without fragmentation. In summary, these results demonstrate the practicality of the provided microrobotic embolization platform for on-demand occlusion of real blood vessels in ex vivo human organs, and the suitability of the provided ultrasound and fluoroscopic imaging strategies for monitoring and evaluating the performance of the provided procedures.

[0179] While the foregoing disclosure has been described in detail by way of illustration and example for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be practiced within the spirit and scope of this disclosure, for example, within the scope of the appended claims. It should also be understood that aspects of this disclosure and portions of the various described embodiments and features may be combined or interchanged, in whole or in part. In the foregoing description of the various embodiments, as will be understood by those skilled in the art, those embodiments relating to another embodiment may be suitably combined with other embodiments. Furthermore, those skilled in the art will understand that the foregoing description is merely illustrative and not intended to limit this disclosure. In addition, each reference provided herein is incorporated by reference in its entirety for all purposes, to the same extent that each reference is individually incorporated herein by reference.

Claims

1. A pH-responsive self-healing microgel comprising: a polymerization reaction product of two or more polymer precursors and a crosslinking agent; a magnetic agent; and an imaging agent.

2. The pH-responsive self-healing microgel of claim 1, wherein the polymerization reaction product comprises a plurality of pendant side chains having the following formula: 。 3. The pH-responsive self-healing microgel of claim 1, wherein the crosslinking agent comprises N,N'-methylenebisacrylamide.

4. The pH-responsive self-healing microgel of claim 1, wherein the magnetic agent comprises magnetite nanoparticles.

5. The pH-responsive self-healing microgel of claim 1, wherein the imaging agent comprises tantalum microparticles.

6. The pH-responsive self-healing microgel of claim 1, wherein the pH-responsive self-healing microgel comprises about 10% to about 30% of the two or more polymer precursors.

7. The pH-responsive self-healing microgel of claim 1, wherein the pH-responsive self-healing microgel comprises about 0.1% to about 1% of the crosslinking agent.

8. The pH-responsive self-healing microgel of claim 1, wherein the pH-responsive self-healing microgel comprises about 10% to about 30% of the magnetic agent.

9. The pH-responsive self-healing microgel of claim 1, wherein the pH-responsive self-healing microgel comprises about 5% to about 15% of the imaging agent.

10. The pH-responsive self-healing microgel of claim 1, wherein the pH-responsive self-healing microgel has an equivalent spherical diameter of less than about 300 μιη.

11. A population of pH-responsive self-healing microgels comprising the pH-responsive self-healing microgel of claim 1.

12. A system for treating a subject in need of embolization at a targeted intravascular location, the system comprising: a population of pH-responsive self-healing microgels of claim 11; a magnetically controlled module; and an imaging module.

13. The system of claim 12, wherein the magnetically controlled module is configured to direct a plurality of the pH-responsive self-healing microgels to the targeted intravascular location.

14. The system of claim 12, wherein the magnetically controlled module comprises a spherical permanent magnet, an electric motor, and a robotic arm.

15. The system of claim 12, wherein the imaging module is configured to image a plurality of pH-responsive self-healing microgels within the subject.

16. The system of claim 12, wherein the imaging module comprises an ultrasound imaging module and a fluoroscopy module.

17. A method of treating a subject in need of embolization at a targeted intravascular location of the subject, the method comprising: administering to the subject a population of pH-responsive self-healing microgels of claim 11; applying a magnetic field to at least a portion of the subject; using the magnetic field to direct the population of pH-responsive self-healing microgels to the targeted intravascular location; and and introducing an amount of an acidic solution to the targeted intravascular location, wherein the amount is effective to induce formation of hydrogen bonds between pH-responsive self-healing microgels in the population of pH-responsive self-healing microgels.

18. The method of claim 17, wherein the method further comprises determining location information of the population of pH-responsive self-healing microgels by imaging the population of pH-responsive self-healing microgels in the subject.

19. The method of claim 18, wherein the directing is based on the location information.

20. The method of claim 18, wherein the imaging comprises real-time imaging.

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