Injectable shear-thinned self-assembled hydrogels

Abstract

In some aspects, the disclosure relates to an injectable hydrogel comprising (a) one or more types of polymeric hydrogen bond donors, (b) one or more types of polymeric hydrogen bond acceptors, and (c) water. Other aspects of the present disclosure relate to kits comprising a delivery device and one or more containers containing an injectable hydrogel comprising one or more types of polymeric hydrogen bond donors, one or more types of polymeric hydrogen bond receptors, and water. Other aspects of the present disclosure relate to a medical procedure comprising administering to a subject an injectable hydrogel comprising one or more types of polymeric hydrogen bond donors, one or more types of polymeric hydrogen bond receptors, and water.

Description

[0001] Cross-references to related applications This application claims the benefit of US Provisional Patent Application No. 63 / 518,165, filed on August 8, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to injectable, shear-thinning, self-assembling hydrogels. These hydrogels can be used in, for example, a variety of medical applications. Background Technology

[0003] It is known that hydrogels with shear-thinning properties undergo a reversible gel-sol transition when shear stress is applied. J. Pushpamalar, et al., “Development of a polysaccharide-based hydrogel drug delivery system (DDS): An update.” Gels, 2021, 7(4), p. 153. Shear-thinning hydrogels are increasingly used in drug delivery systems because they can conform to the shape of the injection lumen, maximizing contact with the target tissue for local drug delivery. Ibid. Hydrogels with shear-thinning properties have been reported to provide smooth injection without clogging the injection needle, and the hydrogels return to their original properties after the mechanical load (shear stress) is removed. MHChen, et al., “Methods to assess shear-thinning hydrogels for application as injectable biomaterials.” ACS Biomater. Sci. Eng. 2017, 3, 3146-3160. It has been noted that doxorubicin-containing hydrogels assembled by physically crosslinking polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) are capable of deforming under high shear and subsequently retaining their original shape after the high shear is removed, exhibiting both shear-thinning and self-healing properties. (NK Prasad et al., “Discerning the self-healing, shear-thinning characteristics and therapeutic efficacy of hydrogel drug carriers migrating through constricted microchannel resembling blood microcapillary,” Colloids Surf. A Physiochem. Eng. Asp. 2021, 626, 127070.) Figure 1 on page 5 of J. Pushpamalar et al. schematically illustrates the shear-thinning and self-healing properties of doxorubicin-loaded polyvinyl alcohol / polyvinylpyrrolidone hydrogels. A shear-thinning hydrogel containing gelatin and laponite for local drug delivery was also reported, along with chitosan and poly(N-isopropylacrylamide-co-acrylic acid) particles to make the hydrogel pH responsive.S. Gharaie, et al., “Smart shear-thinning hydrogels as injectable drugdelivery systems.” Polymers, 2018, 10(12), p. 1317.

[0004] This disclosure provides other shear-thinning hydrogels with unique properties, as well as a variety of novel applications of shear-thinning hydrogels beyond drug delivery. Summary of the Invention

[0005] In some aspects, this disclosure provides an injectable hydrogel comprising (a) one or more types of polymeric hydrogen bond donors, (b) one or more types of polymeric hydrogen bond acceptors, and (c) water.

[0006] In some embodiments that can be used in conjunction with the above aspects, the one or more types of polymer hydrogen bond donors are selected from polyvinyl alcohol, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), polyvinylphenol, and polysaccharides.

[0007] In some embodiments that can be used in conjunction with the above aspects and embodiments, the one or more types of polymeric hydrogen bond acceptors are selected from polyvinylpyrrolidone, poly(4-vinylpyridine), poly(ethylene oxide), polyacrylamide, polymethyl methacrylate, polycaprolactone, poly(vinyl acrylate), and poly(2-alkyl-2-oxazoline).

[0008] In some embodiments that can be used in conjunction with the above aspects and embodiments, the weight-average molecular weight of the one or more types of polymeric hydrogen bond donors and the one or more types of polymeric hydrogen bond acceptors ranges from 1 to 150 kDa.

[0009] In some embodiments that can be used in conjunction with the above aspects and embodiments, the one or more types of polymeric hydrogen bond donors or the one or more types of polymeric hydrogen bond acceptors are in particulate form.

[0010] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the injectable hydrogel comprises (a) 0.25 to 25 wt% of one or more of the aforementioned polymeric hydrogen bond donors, (b) 0.25 to 25 wt% of one or more of the aforementioned polymeric hydrogen bond acceptors, and (c) 30 to 99 wt% water.

[0011] In some embodiments that can be used in conjunction with the above aspects and implementations, the injectable hydrogel further comprises one or more types of radiopaque atoms.

[0012] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the one or more types of polymeric hydrogen bond donors include iodinated polymeric hydrogen bond donors, and / or the one or more types of polymeric hydrogen bond acceptors include iodinated polymeric hydrogen bond acceptors.

[0013] In some embodiments, the iodinated polymer hydrogen bond donor and / or the iodinated polymer hydrogen bond acceptor comprises a covalently linked iodinated aromatic group. In some of these embodiments, the covalently linked iodinated aromatic group is staggered with the hydrogen bond donor group along the backbone of the iodinated polymer hydrogen bond donor, or the covalently linked iodinated aromatic group is located in a first polymer block of the iodinated polymer hydrogen bond donor and the hydrogen bond donor group is located in a second polymer block of the iodinated polymer hydrogen bond donor. In some of these embodiments, the covalently linked iodinated aromatic group is staggered with the hydrogen bond acceptor group along the backbone of the iodinated polymer hydrogen bond acceptor, or the covalently linked iodinated aromatic group is located in a first polymer block of the iodinated polymer hydrogen bond acceptor and the hydrogen bond acceptor group is located in a second polymer block of the iodinated polymer hydrogen bond acceptor. In some of these embodiments, the covalently linked iodinated aromatic groups are connected to the iodinated polymer hydrogen bond donor via ester or cyclic acetal bonds, and / or the covalently linked iodinated aromatic groups are connected to the iodinated polymer hydrogen bond acceptor via ester or cyclic acetal bonds.

[0014] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the injectable hydrogel has a radiation impermeability greater than 100 Hounsfield units.

[0015] In some embodiments that can be used in conjunction with the foregoing aspects and embodiments, the injectable hydrogel further comprises one or more other agents selected from the group consisting of: therapeutic agents, imaging agents, coloring agents, tension modifiers, suspending agents, wetting agents, and pH adjusters.

[0016] In some embodiments that can be used in conjunction with the above aspects and implementations, the injectable hydrogel is a sterile composition.

[0017] In some embodiments that can be used in conjunction with the foregoing aspects and implementations, the injectable hydrogel is disposed in a container. For example, the injectable hydrogel may be disposed in a pre-loaded syringe.

[0018] In other respects, this disclosure relates to a kit comprising (a) a container holding one or more injectable hydrogels according to any of the foregoing aspects and embodiments, and (b) a delivery device. In some embodiments, the delivery device comprises a syringe loaded with the injectable hydrogel according to the foregoing aspects and embodiments.

[0019] In other respects, this disclosure relates to medical procedures that include the administration of an injectable hydrogel to a subject in accordance with any of the foregoing aspects and implementation methods.

[0020] In some embodiments, the method includes injecting the injectable hydrogel into a subject. For example, it can be administered parenterally, via a catheter or syringe, and / or image-guided.

[0021] Potential benefits associated with this disclosure include one or more of the following: providing a hydrogel that can be smoothly injected by a healthcare professional who can pause the injection without the risk of needle clogging during product injection, and that can be injected using a single syringe.

[0022] Other benefits associated with this disclosure include the ability to transform a hydrogel having a first shape (e.g., the shape of a container (e.g., a syringe barrel)) into a viscous liquid during injection, after which the viscous liquid is transformed back into a hydrogel having a new shape reflecting the new environment. The ability of the viscous liquid to transform back into the hydrogel improves material retention and restores the mechanical properties of the hydrogel. Such properties can be used, for example, to create spacers for radiotherapy and other cancer treatments, and for injectable embolization applications.

[0023] The above and other aspects, implementations, features and benefits of this disclosure will become apparent from the following detailed description. Attached Figure Description

[0024] Figure 1A The self-assembly of an injectable hydrogel formed from a polymeric hydrogen bond donor (poly(hydroxyethyl methacrylate)) and a polymeric hydrogen bond acceptor (polyvinylpyrrolidone) is illustrated schematically according to one embodiment of the present disclosure.

[0025] Figure 1B Schematic illustration Figure 1A The shear thinning (disassembly) and self-assembly properties of the hydrogel.

[0026] Figure 2A The synthesis of a radiopaque polymeric hydrogen bond donor (iodinated poly(hydroxyethyl methacrylate)) according to one embodiment of the present disclosure is illustrated schematically.

[0027] Figure 2B The schematic illustration shows one embodiment of the present disclosure. Figure 2A Self-assembly of hydrogels formed by radiopaque polymer hydrogen bond donors and polymer hydrogen bond acceptors (polyvinylpyrrolidone).

[0028] Figure 3AThe synthesis of a radiopaque polymeric hydrogen bond donor (iodinated polyvinyl alcohol) according to another embodiment of this disclosure is illustrated schematically.

[0029] Figure 3B The schematic illustration shows one embodiment of the present disclosure. Figure 3A Self-assembly of hydrogels formed by radiopaque polymer hydrogen bond donors and polymer hydrogen bond acceptors (polyvinylpyrrolidone).

[0030] Figure 4 A catheter and syringe loaded with injectable hydrogel are schematically shown according to one embodiment of the present disclosure. Detailed Implementation

[0031] This disclosure provides shear-thinning, self-assembling, injectable hydrogels. The shear-thinning properties of such hydrogels allow for efficient injectability because the hydrogels exhibit viscous flow under shear. The self-assembling properties (also known as self-healing properties) of such hydrogels allow the hydrogels to reform and stabilize upon removal of shear stress. As used herein, self-assembly and self-healing refer to the spontaneous formation of new bonds within a material after the breaking of old bonds. As used herein, a hydrogel refers to a hydrophilic three-dimensional network of a cross-linked polymer.

[0032] In various embodiments, the injectable hydrogel of this disclosure comprises (a) one or more types of hydrogen bond donors, (b) one or more types of hydrogen bond acceptors, and (c) water.

[0033] Such hydrogels contain hydrogen-bonded crosslinks that dissociate upon application of shear stress and spontaneously self-assemble upon removal of shear stress. For example, such dissociation can occur when shear stress is applied during injection via a syringe. After the dissociation of the hydrogen-bonded crosslinks, the hydrogel becomes a viscous liquid that can be delivered to a target site using a suitable delivery device, such as a tube (e.g., a catheter / microcatheter) or a needle. Upon delivery to the target site, the shear stress decreases, and the hydrogen bonds spontaneously recombine (i.e., self-assemble), reforming the hydrogel at the target site. This transformation from a viscous liquid back to a hydrogel results in improved material retention and mechanical properties.

[0034] In some embodiments, the injectable hydrogels of this disclosure exhibit yielding behavior. For example, after being subjected to a threshold yield strain, the injectable hydrogels may exhibit a sharp decrease in storage modulus and loss modulus, which recover at low strain after shear cessation.

[0035] Hydrogen bond acceptors used in this disclosure include one or more types of polymeric hydrogen bond donors, examples of which include polyvinyl alcohol, poly(hydroxy-C1-C6-alkyl acrylates) (e.g., poly(hydroxymethyl acrylate), poly(hydroxyethyl acrylate), poly(hydroxypropyl acrylate), poly(hydroxybutyl acrylate), etc.), poly(hydroxy-C1-C6-alkyl methacrylates) (e.g., poly(hydroxymethyl methacrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl methacrylate), poly(hydroxybutyl methacrylate), etc.), polyvinylphenol, polyacrylic acid, polysaccharides, and polystyrene sulfonic acid, poly(vinylphosphonic acid), poly(vinyl methyl ether), and poly(maleic acid).

[0036] Hydrogen bond acceptors used in this disclosure include one or more types of polymeric hydrogen bond acceptors, examples of which include polyvinylpyrrolidone, poly(4-vinylpyridine), poly(ethylene oxide), polyacrylamide, polymethyl methacrylate, polycaprolactone, poly(vinyl acrylate), poly(2-C1-C6-alkyl-2-oxazoline) (e.g., poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), etc.) and waterborne polyurethanes.

[0037] Polymer hydrogen bond acceptors or polymer hydrogen bond donors can be in particulate form, in which many polymer molecules are bonded together, or in non-particulate form, in which polymer molecules are not bonded together and are separated from each other or are capable of separation.

[0038] For example, in some embodiments, the hydrogel of this disclosure may contain polymeric hydrogen bond acceptors in a non-partic form and polymeric hydrogen bond donors in a non-partic form. In some embodiments, the hydrogel may contain both non-partic polymeric hydrogen bond acceptors and polymeric hydrogen bond donors in a particulate form. In some embodiments, the hydrogel may contain both polymeric hydrogen bond acceptors in a particulate form and polymeric hydrogen bond donors in a non-particulate form.

[0039] When polymeric hydrogen bond acceptors or donors are in particulate form, multiple polymeric hydrogen bond donor molecules or multiple polymeric hydrogen bond acceptor molecules are linked together, preventing them from dissociating from each other under the shear stress associated with injection. For example, polymeric hydrogen bond donor molecules or polymeric hydrogen bond acceptor molecules can maintain their particulate form through covalent crosslinking or interpenetrating networks.

[0040] The size of the polymer hydrogen bond donor or polymer hydrogen bond acceptor particles can vary, for example, the maximum cross-sectional size (e.g., the diameter of spherical particles, the length of rod-shaped particles, the maximum width of sheet-like particles, etc.) ranges from 1 nm to 300 micrometers, for example, 1 nm, 3 nm to 10 nm to 30 nm to 100 nm to 300 nm to 1 micrometer to 3 micrometers to 10 micrometers to 30 micrometers to 100 micrometers to 300 micrometers (i.e., between any two of the aforementioned values), and the size range is typically 50 nm to 1250 nm.

[0041] When the polymeric hydrogen bond acceptor or polymeric hydrogen bond donor is in a non-partic form, the molecules of the polymeric hydrogen bond acceptor or polymeric hydrogen bond donor are not connected to each other and can dissociate from each other under the shear stress associated with injection.

[0042] The lengths of the polymeric hydrogen bond donor and acceptor molecules according to this disclosure can vary, for example, their weight-average molecular weight (Mw) can range from 2.5 kDa or less to 200 kDa or greater, for example, any range from 1 kDa to 2.5 kDa to 5 kDa to 10 kDa to 25 kDa to 50 kDa to 100 kDa to 250 kDa (i.e., between any two of the foregoing values), etc. The polydispersity values ​​of the polymeric hydrogen bond acceptor and polymeric hydrogen bond donor molecules can vary, but are generally less than 8, more generally less than 2, and even more generally less than 1.5.

[0043] The concentration of one or more types of hydrogen bond donors in the injectable hydrogels of this disclosure can vary over a wide range, but is typically in the range of 0.25 wt% or less to 25 wt% or more, for example, in any range from 0.25 to 0.5 to 1 to 2.5 to 5 to 10 to 25 wt%. Similarly, the concentration of one or more types of hydrogen bond acceptors in the injectable hydrogels of this disclosure can vary over a wide range, but is typically in the range of 0.25 or less to 25 wt% or more, for example, in any range from 0.25 to 0.5 to 1 to 2.5 to 5 to 10 to 25 wt%.

[0044] The water in the injectable hydrogel disclosed herein can be in the form of ultrapure water, water for injection, saline, phosphate-buffered saline, or water with high ion content.

[0045] In some embodiments, the injectable hydrogel of this disclosure contains 0.25 wt% or less up to 30 wt% or more of water, for example, in any range from 0.25 to 0.5 to 1 to 2.5 to 5 to 10 to 20 to 30 wt%.

[0046] In some embodiments, the injectable hydrogel of this disclosure may also contain other reagents, examples of which will be discussed further below.

[0047] exist Figure 1A In one specific embodiment, illustrated schematically, a non-particulate polyvinylpyrrolidone hydrogen bond acceptor molecule (112) and a non-particulate poly(hydroxyalkyl acrylate) hydrogen bond donor molecule, specifically a poly(2-hydroxyethyl methacrylate) hydrogen bond donor molecule (114), are mixed, and then assembled into a shear-thinning hydrogel (116) via hydrogen bond-induced self-assembly. Figure 1A In this context, n is an integer. For polyvinylpyrrolidone molecules (112), n is typically 20 or less to 1000 or more (e.g., any range from 20 to 50 to 100 to 200 to 500 to 1000). For poly(2-hydroxyethyl methacrylate) molecules (114), n is typically 20 or less to 1000 or more (e.g., any range from 20 to 50 to 100 to 200 to 500 to 1000). like Figure 1B As illustrated, when subjected to mechanical shear, the shear-thinning hydrogel (116) disassembles into individual polyvinylpyrrolidone (112) molecules and poly(2-hydroxyethyl methacrylate) molecules (114). Then, when the mechanical shear conditions are removed, the individual polyvinylpyrrolidone (112) molecules and poly(2-hydroxyethyl methacrylate) molecules (114) reassemble into the shear-thinning hydrogel (116).

[0048] The result of this behavior is an injectable hydrogel that can be disintegrated (shear-thinned) during injection via a syringe, providing smooth injection, and then reassembled at the target site when the shear forces associated with the injection are removed. Furthermore, the shape of the hydrogel deforms during injection due to its self-assembly properties, forming a new shape at the targeted injection site.

[0049] In some embodiments, the injectable hydrogel of this disclosure further comprises one or more radiopaque atoms, which may be selected from, for example, Br, I, Bi, Ba, Gd, Ta, Zn, W and Au.

[0050] In some embodiments, one or more radiopaque atoms are iodine atoms, which may be in the form of a covalently linked iodide moiety. In some of these embodiments, the iodide moiety includes an iodinated aromatic group. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as phenyl iodide, naphthyl iodide, anthraceneyl iodide, phenanthrene iodide, or tetraphenyl iodide. The iodinated aromatic group may be substituted with one, two, three, four, five, six, or more iodine atoms. In some of these embodiments, the aromatic group may also be substituted with one or more hydrophilic groups, for example, one, two, three, four, five, six, or more hydrophilic groups. The hydrophilic group may be a hydroxyl-containing group, selected from, for example, hydroxyl and hydroxyalkyl (e.g., hydroxyalkyl containing one, two, three, four, or four carbons), amide-containing groups (e.g., amide groups containing two, three, four, or five carbons), and sulfonamide groups, etc. The hydrophilic group can be directly or through any suitable linker to the monocyclic or polycyclic aromatic structure, and the linker can be selected from, for example, ether, ester, amide, amine or carbonate groups.

[0051] In one exemplary embodiment, the hydroxyl groups of the precursor polymer hydrogen bond donor react with the carboxyl groups of the radiopaque precursor compound in an ester coupling reaction. This reaction step forms a radiopaque polymer hydrogen bond donor comprising a plurality of hydroxyl groups providing hydrogen bonds and a plurality of radiopaque groups interleaved along the backbone of the radiopaque polymer hydrogen bond donor.

[0052] exist Figure 2A In the specific example shown, the hydroxyl group of the precursor polymer hydrogen bond donor, specifically poly(hydroxyethyl methacrylate) (211) (where n is an integer from, for example, 20 to 1000), reacts with the carboxyl group of the radiopaque precursor compound, specifically 2,3,5-triiodobenzoic acid (213), to form a radiopaque polymer hydrogen bond donor, specifically iodine-substituted poly(hydroxyethyl methacrylate) (214), wherein the 2,3,5-triiodobenzene moiety is linked to the poly(hydroxyethyl methacrylate) backbone via an ester bond. Such ester coupling reactions can be carried out using suitable coupling agents (e.g., carbodiimide coupling agents, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC)). Figure 2AIn this context, x and y are integers representing the number of unsubstituted hydroxyl monomers and iodine-substituted monomers in iodine-substituted poly(hydroxyethyl methacrylate) (214), respectively. Note that the ratio of integers x and y in iodine-substituted poly(hydroxyethyl methacrylate) (214) is adjustable; a larger amount of x provides a larger number of hydrogen bond donors, and a larger amount of y provides stronger radiation opacity. Typically, x will be 60 to 99% of the n value in the precursor poly(hydroxyethyl methacrylate) (211), while y will typically be 1 to 40% of the n value in the precursor poly(hydroxyethyl methacrylate) (211).

[0053] although Figure 2A Medium-sized poly(2-hydroxyethyl methacrylate) is used as a precursor polymer hydrogen bond donor, but other hydroxylated polymers (including other poly(hydroxyalkyl methacrylate), poly(hydroxyalkyl acrylate), polyvinyl alcohol, polyvinylphenol, or polysaccharides) can also be used as precursor polymer hydrogen bond donors.

[0054] Furthermore, despite Figure 2A Triiodobenzoic acid is used as a radiopaque precursor compound, but other radiopaque precursor compounds can also be used, including... Diatrizoic acid, CAS# 117-96-4 5-Formyl-2-iodobenzenesulfonamide, CAS# 1289167-85-6 N-acetyl-3,5-diiodo-L-tyrosine, CAS# 1027-28-7 N-acetyl-3-diiodo-L-tyrosine, CAS# 1023-47-8 and N-acetyl-thyroxine, CAS# 26041-51-0, etc.

[0055] exist Figure 2B In a specific embodiment illustrated schematically, polyvinylpyrrolidone molecules (212) and iodine-substituted poly(2-hydroxyethyl methacrylate) molecules (214) are mixed, and then they self-assemble into a shear-thinning hydrogel (216) via hydrogen bond-induced self-assembly.

[0056] In another exemplary embodiment, typically under acidic conditions, a portion of the diol group of a precursor polymer hydrogen bond donor having 1,2-diol or 1,3-diol groups reacts with the aldehyde group of a radiopaque precursor compound in a cyclic acetal coupling reaction. This reaction step forms a radiopaque polymer hydrogen bond donor comprising a plurality of hydroxyl groups providing hydrogen bonds and a plurality of radiopaque groups, which are covalently linked to the backbone of the polymer hydrogen bond donor via cyclic acetal groups.

[0057] exist Figure 3AIn the specific example shown, the precursor polymer hydrogen bond donor, specifically the 1,3-diol group of polyvinyl alcohol (311) (where n can range, for example, from 20 to 1500), reacts with the aldehyde group of an opaque precursor compound, specifically 2,3,5-triiodobenzaldehyde (313), to form an opaque polymer hydrogen bond donor, specifically iodinated polyvinyl alcohol (314) (where the 2,3,5-triiodobenzene moiety is linked to the polyvinyl alcohol backbone via a cyclic acetal bond). Such coupling reactions are typically carried out under acidic conditions. Note that the ratio of integer x to y in iodinated polyvinyl alcohol (314) is adjustable, with a larger amount of x providing a larger number of hydrogen bond donors and a larger amount of y providing stronger radiopaqueness. Typically, x will be 1 to 40% of the n value in the precursor polyvinyl alcohol (311), while y will typically be 60 to 99% of the n value in the precursor polyvinyl alcohol (311). Although polyvinyl alcohol in Figure 3A 2,3,5-triiodobenzaldehyde is used as a hydrogen bond donor in precursor polymers, but other diols (including ethylene-vinyl alcohol copolymers or glycerol-2-acrylates) can also be used as hydrogen bond donors in precursor polymers. Furthermore, although 2,3,5-triiodobenzaldehyde is used as a hydrogen bond donor in precursor polymers... Figure 3A It is used as a radiopaque precursor compound, but other aldehydes (including 2,3,5-triiodobenzaldehyde, 2,3,4,6-tetraiodobenzaldehyde and 2-(2,4,6-triiodophenoxy)acetaldehyde) can also be used as radiopaque precursor compounds.

[0058] exist Figure 3B In a specific embodiment illustrated schematically, polyvinylpyrrolidone molecules (312) and iodine-substituted polyvinyl alcohol molecules (314) are mixed, and then they self-assemble into a shear-thinning hydrogel (316) via hydrogen bond-induced self-assembly.

[0059] In some embodiments, an iodinated block copolymer is provided, comprising, for example, polymeric hydrogen bond donor blocks selected from the aforementioned polymeric hydrogen bond donors and iodinated polymeric blocks. In some embodiments, an iodinated block copolymer is provided, comprising, for example, polymeric hydrogen bond acceptor blocks selected from the aforementioned polymeric hydrogen bond acceptors and iodinated polymeric blocks. Examples of iodinated polymeric blocks include iodinated polystyrene blocks. In these embodiments, the length of the polymeric hydrogen bond donor blocks can range, for example, from 20 to 1500 monomers, the length of the polymeric hydrogen bond acceptor blocks can range, for example, from 20 to 1500 monomers, and the length of the iodinated polymeric blocks can range, for example, from 1 to 50 monomers.

[0060] In various embodiments, the hydrogel of this disclosure is visible under fluorescence fluoroscopy. In various embodiments, the hydrogel has a radiation opacity greater than 100 Hounsfield units (HU), advantageously any value in the range of 100 HU to 250 HU to 500 HU to 750 HU to 1000 HU to 2000 HU or higher (in other words, within the range between any two of the aforementioned values).

[0061] The injectable hydrogel of this disclosure can be formed using a variety of methods. One or more types of hydrogen bond donors, one or more types of hydrogen bond acceptors, and water can be mixed in any order. For example, one or more types of hydrogen bond donors and one or more types of hydrogen bond acceptors can be mixed first, and then mixed with water. As another example, one or more types of hydrogen bond donors and water can be mixed first, and then mixed with one or more types of hydrogen bond acceptors. As another example, one or more types of hydrogen bond acceptors and water can be mixed first, and then mixed with one or more types of hydrogen bond donors. As another example, a first composition containing one or more types of hydrogen bond donors and water can be formed, a second composition containing one or more types of hydrogen bond acceptors and water can be formed, and then the first and second compositions can be mixed. As another example, one or more types of hydrogen bond acceptors, one or more types of hydrogen bond donors, and water can be mixed simultaneously. Mixing can be performed using any suitable mixing technique, including, for example, centrifugal mixing, manual mixing, high-shear dispersion, vacuum mixing, vortexing, and / or syringe-to-syringe mixing.

[0062] The compositions disclosed herein can be sterilized using any suitable method, such as heating (e.g., dry heat, moist heat, etc.), sterile filtration, supercritical CO2, gamma ray irradiation, X-ray irradiation, or electron beam irradiation. The compositions disclosed herein can be sterilized in hydrogel or powder form (to which a sterile liquid such as water, saline, etc., may be added). The compositions can be sterilized in a reservoir (e.g., syringe, vial, or ampoule).

[0063] In various embodiments, the injectable hydrogel of this disclosure also contains one or more reagents in addition to one or more types of hydrogen bond donors, one or more types of hydrogen bond acceptors, and water. Examples of such other reagents include therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters.

[0064] Examples of therapeutic agents include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antibodies, anticancer drugs, antiproliferative agents, anti-inflammatory agents, proliferative inhibitors, anti-restenosis agents, steroids, anti-allergic agents, hemostatic agents, smooth muscle cell inhibitors, antibiotics, antibacterial agents, antifungal agents, analgesics, anesthetics, immunosuppressants, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T-cell agonists, and STING (interferon gene stimulator) agonists, etc.

[0065] Examples of imaging agents include (a) fluorescent dyes, such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, and blue-green fluorescent proteins), and (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd. (III) Mn (II) Fe (III) (c) Contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in increased reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that result in decreased reflected ultrasound energy), and (d) contrast agents used in conjunction with near-infrared (NIR) imaging, which may be selectively used to impart near-infrared fluorescence to the injectable hydrogel of this disclosure, thereby allowing deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derived with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles (e.g., dye-doped nanofibers and dye-encapsulated nanoparticles), and semiconductor quantum dots, etc., and NIR-sensitive dyes (e.g., cyanine dyes). (e) Imageable radioisotopes, including dyes), squaraines, phthalocyanines, porphyrin derivatives, and borodipyrrole methylene (BODIPY) analogs, etc. 99m Tc, 201 Th、 51 Cr 67 Ga, 68Ga 111 In、 64 Cu、 89 Zr、 59 Fe、 42 K, 82 Rb、 24 Na、 45 Ti、 44 Sc、 51Cr and 177Lu, etc., and (f) radioactive contrast agents, such as metal particles, for example, particles of tantalum, tungsten, rhenium, niobium, molybdenum and their alloys, which may be spherical or non-spherical. Other examples of radioactive contrast agents include non-ionic radioactive contrast agents such as iohexol, iodixanol, ioflufenicol, iopamidol, ioxilan, or iopromide; ionic radioactive contrast agents such as diatrizoate, iothalamate, metrizoate, or ioxaglate; and iodized oils, including ethiodized poppyseed oil (which can be used as Lipiodol). ® get).

[0066] Examples of colorants include brilliant blue (e.g., brilliant blue FCF, also known as FD&C blue 1), indigocarmine (also known as FD&C blue 2), indigocarmine lake, FD&C blue 1 lake, and methylene blue (also known as methylene blue chloride), etc.

[0067] Examples of other reagents include tension modifiers such as sugars (e.g., glucose, lactose, etc.), polyols (e.g., glycerol, propylene glycol, mannitol, sorbitol, etc.) and inorganic salts (e.g., potassium chloride, sodium chloride, etc.), suspending agents including various surfactants, wetting agents and polymers (e.g., albumin, PEO, polyvinyl alcohol, block copolymers, etc.), and pH adjusters including various buffer solutes.

[0068] The injectable hydrogel disclosed herein can be stored and transported in a sterile manner. The injectable hydrogel can be transported, for example, in syringes, catheters, vials, ampoules, or other containers.

[0069] In various embodiments, kits are provided that may include one or more containers of an injectable hydrogel as described herein, as well as other components. For example, the kit may include one or more delivery devices, such as syringes, catheters, or tubing devices, for delivering the injectable hydrogel to a subject. In some embodiments, the kit may contain an injectable hydrogel as described herein pre-loaded in a catheter and / or syringe barrel and / or container (e.g., vial or ampoule). Optionally or additionally, kits may be provided that include one or more auxiliary devices (e.g., guidewires). Optionally or additionally, kits may be provided that include one or more containers of liquid material (e.g., contrast agents, sterile water for injection, physiological saline, phosphate-buffered saline, etc.). Optionally or additionally, the kit may also contain other therapeutic agents, selected from, for example, those described above. Kits provided herein may also include instructions (in insert or label form) describing the amount of composition to be administered and / or administration guidelines. In some embodiments, the instructions include instructions for performing one or more methods provided herein.

[0070] The injectable hydrogel described herein can be administered via a variety of routes, depending on the desired medical outcome. In some embodiments, administration includes injecting the injectable hydrogel. In some embodiments, the injectable hydrogel is administered via parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion. In some embodiments, administration includes an image-guided procedure in which the composition is delivered using computed tomography, fluoroscopy, or ultrasound imaging. In some embodiments, administration includes injecting the injectable hydrogel into the vascular system of a subject. In some embodiments, administration includes injecting the injectable hydrogel into a tumor of a subject or into the vascular system supplying the tumor. In some embodiments, administration is performed using a catheter or syringe.

[0071] Figure 4 An exemplary syringe 10 is shown, providing a reservoir for the injectable hydrogel described herein. The syringe 10 may include a tube 12, a plunger 14, and one or more stoppers 16. The tube 12 may include, for example, a Luer adapter (or other suitable adapter / connector) at its distal end 18 for attachment to an injection needle 50 via a flexible conduit 29. The proximal end of the conduit 29 may include a suitable connector 20 for receiving the tube 12. In other instances, the tube 12 may be directly connected to the injection needle 50. The syringe tube 12 may serve as a reservoir containing injectable hydrogel 15 for injection via the needle 50.

[0072] The injectable hydrogel described in this article can be applied to patients to achieve a variety of medical effects.

[0073] The injectable hydrogels described herein can be visualized using any suitable method during and / or after application (e.g., in mammals). For example, imaging techniques such as ultrasound, computed tomography, magnetic resonance imaging, and / or fluorescence fluoroscopy can be used to visualize the injectable hydrogels provided herein.

[0074] The injectable hydrogel disclosed herein can be used in a variety of medical procedures, including: procedures for injecting the injectable hydrogel into a feeding artery to embolize tissue (including benign tumors, malignant tumors and other abnormal tissues); procedures for introducing the injectable hydrogel between a first tissue and a second tissue to separate the first tissue from the second tissue; procedures for implanting a reference marker containing the injectable hydrogel (e.g., in the form of a bubble); procedures for implanting a tissue regeneration scaffold containing the injectable hydrogel; procedures for implanting a tissue support containing the injectable hydrogel; procedures for implanting a tissue filler containing the injectable hydrogel; procedures for implanting a depot containing the injectable hydrogel and a therapeutic agent; procedures for tissue enlargement including implantation of the injectable hydrogel; and procedures for controlling bleeding.

[0075] Injectable hydrogels can be injected for tissue enlargement or regeneration, can be injected as fillers or substitutes for soft tissues, can be injected to provide mechanical support for damaged tissues, can be injected as scaffolds, and / or can be injected as carriers of therapeutic agents for the treatment of diseases and cancers, as well as for tissue repair and regeneration, and other uses.

[0076] Injectable hydrogels can be injected in conjunction with a variety of medical procedures, including: septal injections between the prostate or vagina and rectum in radiotherapy for rectal cancer; septal injections between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injections for palliative treatment of prostate cancer; transurethral or submucosal injections for female stress urinary incontinence; intravesical injections for urinary incontinence; intrauterine injections for Asherman's syndrome; submucosal injections for anal incontinence; percutaneous injections for heart failure; intramyocardial injections for heart failure and dilated cardiomyopathy; transendocardial injections for myocardial infarction; intra-articular injections for osteoarthritis; spinal injections for spinal fusion and spinal, maxillofacial, and orthopedic trauma surgery; and spinal injections for posterolateral lumbar fusion. Intradiscal injection for degenerative disc diseases; inter-pancreatic and duodenal injection for pancreatic cancer imaging; resection bed injection for oropharyngeal cancer imaging; peritumoral injection for bladder cancer imaging; submucosal injection for gastrointestinal tumors and polyps; visceral pleural injection for lung biopsy; renal injection for type 2 diabetes and chronic kidney disease; renal cortical injection for chronic kidney disease with congenital abnormalities from the kidneys and urethra; intravitreal injection for neovascular age-related macular degeneration; intratympanic injection for sensorineural hearing loss; correction of wrinkles, creases and folds; signs of facial fat loss; volume reduction; superficial to deep contour defects; correction of depressed skin scars; perioral wrinkles; lip augmentation; facial fat atrophy; dermal injection to stimulate natural collagen production.

[0077] Injectable hydrogels can be used for permanent or temporary occlusion of blood vessels, thus enabling the control of a variety of diseases and conditions. For example, injectable hydrogels can be used for controlled selective blockage of blood supply to benign and malignant tumors, including solid tumors such as kidney cancer, bone cancer, brain cancer, liver cancer, breast cancer, prostate cancer, benign prostatic hyperplasia, esophageal cancer, colon cancer, endometrial cancer, bladder cancer, uterine cancer, uterine fibroids (leiomyomas), ovarian cancer, lung cancer, sarcoma, pancreatic cancer, and gastric cancer. The principle behind this treatment is that the blood flow supplying nutrients to the tumor is blocked, leading to tumor shrinkage. Embolization can be used as an enhancement to chemotherapy or radiotherapy. In this disclosure, treatment can be enhanced by including therapeutic agents (e.g., antitumor agents / antiproliferative agents / antimitotic agents, toxins, ablatives, etc.) in the injectable hydrogel.

[0078] The injectable hydrogel according to this disclosure can also be used to treat a variety of other diseases, conditions, and symptoms, including the treatment of arteriovenous fistulas and malformations (including, for example, aneurysms (e.g., neurovascular aneurysms and aortic aneurysms), pulmonary pseudoaneurysms, intracerebral arteriovenous fistulas, cavernous sinus dural arteriovenous fistulas, and arteriovenous fistulas), varicose veins, chronic venous insufficiency, varicocele, abscesses, pelvic congestion syndrome, gastrointestinal bleeding, renal hemorrhage, urinary tract bleeding, varicose vein bleeding, venous congestion disorders, bleeding (including uterine bleeding), severe epistaxis (nosebleeds), and preoperative embolization (to reduce bleeding during surgery) and occlusion of collateral branches of the great saphenous vein in great saphenous vein bypass surgery, among other uses. As described elsewhere herein, in this disclosure, treatment can be enhanced by including therapeutic agents in the particulate composition.

[0079] The injectable hydrogels according to this disclosure can also be used for tissue filling applications, for example, as reinforcing materials for treating urinary incontinence, vesicoureteral reflux, fecal incontinence, intrinsic sphincter defect (ISD), or gastroesophageal reflux disease, or as reinforcing materials for aesthetic improvement. For example, a common method for treating patients with urinary incontinence is to inject the filling material perineally or transurethrally. In this regard, the method of injecting the filling typically requires placing a needle in the treatment area, such as perineally or transurethrally. With visual assistance, the filling is injected into multiple sites to close the urethral mucosa. In some cases, additional application of the filling may be necessary. Treatment can be enhanced by including therapeutic agents (e.g., pro-inflammatory agents, sclerosing agents, etc.) in the injectable hydrogel.

[0080] The injectable hydrogel according to this disclosure can be used for hemostasis, for example, by applying it directly to the bleeding site or by injecting it into a blood vessel leading to the bleeding site.

[0081] The injectable hydrogel according to this disclosure can be injected into the left atrial appendage during left atrial appendage occlusion. In some embodiments, the injectable hydrogel can be injected into the left atrial appendage after the introduction of an occlusion device (such as the Watchman® left atrial appendage occlusion device purchased from Boston Scientific Corporation).

[0082] The injectable hydrogel according to this disclosure can be used to treat aneurysms. For example, the injectable hydrogel can be introduced into the aneurysm alone or together with an embolization device (e.g., an embolization coil or a liquid embolization).

[0083] Although various embodiments have been specifically shown and described herein, it should be understood that modifications and variations of this disclosure are covered by the foregoing teachings and are within the scope of any of the appended claims without departing from the spirit and intended scope of this disclosure.

Claims

1. An injectable hydrogel comprising (a) one or more types of polymeric hydrogen bond donor, (b) one or more types of polymeric hydrogen bond acceptor, and (c) water.

2. The injectable hydrogel of claim 1, wherein the one or more types of polymeric hydrogen bond donor is selected from polyvinyl alcohol, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), polyvinyl phenol, and polysaccharide.

3. The injectable hydrogel of any one of claims 1-2, wherein the one or more types of polymeric hydrogen bond acceptor is selected from polyvinylpyrrolidone, poly(4-vinylpyridine), poly(ethylene oxide), polyacrylamide, polymethyl methacrylate, polycaprolactone, poly(ethyl vinyl acrylate), and poly(2-alkyl-2-oxazoline).

4. The injectable hydrogel of any one of claims 1-3, wherein the one or more types of polymeric hydrogen bond donor or the one or more types of polymeric hydrogen bond acceptor is in particulate form.

5. The injectable hydrogel of any one of claims 1-4, comprising (a) 0.25 to 25 wt% of the one or more types of polymeric hydrogen bond donor, (b) 0.25 to 25 wt% of the one or more types of polymeric hydrogen bond acceptor, and (c) 30 to 99 wt% of water.

6. The injectable hydrogel of any one of claims 1-5, further comprising one or more types of radio-opaque atoms.

7. The injectable hydrogel of any one of claims 1-5, wherein the one or more types of polymeric hydrogen bond donor comprises an iodinated polymeric hydrogen bond donor, and / or wherein the one or more types of polymeric hydrogen bond acceptor comprises an iodinated polymeric hydrogen bond acceptor.

8. The injectable hydrogel of claim 7, wherein the iodinated polymeric hydrogen bond donor and / or the iodinated polymeric hydrogen bond acceptor comprises a covalently attached iodinated aromatic group.

9. The injectable hydrogel of claim 8, (a) wherein the covalently attached iodinated aromatic group is interspersed with hydrogen bond donor groups along the main chain of the iodinated polymeric hydrogen bond donor, or the covalently attached iodinated aromatic group is in a first polymeric block of the iodinated polymeric hydrogen bond donor and the hydrogen bond donor groups are in a second polymeric block of the iodinated polymeric hydrogen bond donor, and / or (b) wherein the covalently attached iodinated aromatic group is interspersed with hydrogen bond acceptor groups along the main chain of the iodinated polymeric hydrogen bond acceptor, or the covalently attached iodinated aromatic group is in a first polymeric block of the iodinated polymeric hydrogen bond acceptor and the hydrogen bond acceptor groups are in a second polymeric block of the iodinated polymeric hydrogen bond acceptor.

10. The injectable hydrogel of claim 8 or 9, wherein the covalently attached iodinated aromatic group is attached to the iodinated polymeric hydrogen bond donor via an ester linkage or a cyclic acetal linkage, and / or wherein the covalently attached iodinated aromatic group is attached to the iodinated polymeric hydrogen bond acceptor via an ester linkage or a cyclic acetal linkage.

11. The injectable hydrogel of any one of claims 6-10, wherein the injectable hydrogel has a radiopacity greater than 100 Hounsfield units.

12. The injectable hydrogel of any one of claims 1-11, wherein the injectable hydrogel further comprises one or more additional agents selected from the group consisting of a therapeutic agent, an imaging agent, a colorant, a tonicity adjusting agent, a suspending agent, a wetting agent, and a pH adjusting agent.

13. The injectable hydrogel of claim 12, wherein the injectable hydrogel is disposed in a pre-loaded syringe.

14. A kit comprising (a) one or more containers containing the injectable hydrogel of any one of claims 1-13, and (b) a delivery device.

15. The kit of claim 14, wherein the delivery device comprises a syringe loaded with the injectable hydrogel.

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