Polymer electrolyte hydrogel preparation, method of manufacturing the same, and method of use.

Abstract

This specification describes polyelectrolyte (PE) hydrogels having properties suitable for many medical applications. A polyelectrolyte hydrogel is composed of one or more water-soluble polycationic polyelectrolytes, one or more water-soluble polyanionic polyelectrolytes, and a mixture of monovalent and / or divalent ions. Depending on the selection and amount of the polycationic and polyanionic polyelectrolytes, monovalent and / or divalent ions, the charge ratio, and the addition of any additives or components, mechanical properties, durability, delivery, occluded vessel size, and coagulation ability can be adjusted to suit the intended application. PE hydrogels maintain dimensional stability and water-insoluble properties under physiological conditions.

Description

[Background technology]

[0001] (Cross-reference of related applications) This application claims the benefits and priority of concurrently pending U.S. Provisional Patent Application No. 63 / 535,727, filed on 31 August 2023, and U.S. Provisional Patent Application No. 63 / 584,982, filed on 25 September 2023, all of which are incorporated herein by reference.

[0002] Vascular embolization is a common endovascular procedure that involves placing an occlusive agent via a catheter to block blood flow. Embolization is performed to treat a variety of diseases, from blocking blood vessels in tumors to controlling gastrointestinal bleeding and benign prostatic hyperplasia. These procedures are usually performed under fluoroscopy, with radiopaque markers on the guidewire and catheter providing feedback to the physician to navigate to the target site. While many embolizing agents are currently available for these applications, they have drawbacks such as the use of harmful solvents, undesirable polymerization that can trap the catheter and guidewire, and lack of visibility during placement that can lead to off-target embolization. [Overview of the project]

[0003] This specification describes polyelectrolyte (PE) hydrogels having properties suitable for many medical applications. A polyelectrolyte hydrogel is composed of one or more water-soluble polycationic polyelectrolytes, one or more water-soluble polyanionic polyelectrolytes, and a mixture of monovalent and / or divalent ions. Depending on the selection and amount of the polycationic and polyanionic polyelectrolytes, monovalent and / or divalent ions, the charge ratio, and the inclusion of any additives or components, mechanical properties, durability, delivery, occluded vessel size, and coagulation ability can be tailored to the intended application. PE hydrogels maintain dimensional stability and water-insoluble properties under physiological conditions.

[0004] Other systems, methods, features, and advantages of this disclosure will become apparent to those skilled in the art by examining the following drawings and detailed description. All such additional systems, methods, features, and advantages are incorporated herein, within the scope of this disclosure, and intended to be protected by the appended claims. Furthermore, all optional and preferred features and modifications of the embodiments described herein are available for use in all embodiments of this disclosure taught herein. Moreover, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the embodiments described herein, are combinable and interchangeable with each other. [Brief explanation of the drawing]

[0005] Many aspects of this disclosure can be better understood by referring to the following drawings. The parts in the drawings are not necessarily to scale, but rather the emphasis is on clearly illustrating the principles of this disclosure. Furthermore, in the drawings, the same reference numerals indicate corresponding parts through several figures.

[0006] [Figure 1A-1D] This study characterizes the effect of charge ratio on the performance of PE hydrogel composed of protamine sulfate and xanthan gum. The weight percentage of PE hydrogel is fixed at 5%, and the molar concentration of the added salt is fixed at 1 mole. (A) Viscosity curves as a function of shear rate for positive-negative charge ratios of 1:4, 1:1, and 2:1 are shown. (B) Injection force through a catheter with an inner diameter of 0.0235 inches and a length of 130 cm is shown as a function of charge ratio. (C) Temperature stability of elastic modulus (G') with respect to changes in charge ratio is shown. (D) It is shown that the elastic modulus (G') recovers to 100% after repeated deformation for charge ratios of 1:4 and 2:1. Samples were subjected to 100% strain for 1 minute, followed by a 6-second relaxation period, and then 1% strain for 1 minute, after which the elastic modulus (G') and loss elastic modulus (G") were measured.

[0007] [Figure 2A-2D]Shows characterization of the effect of molar concentration of added sodium chloride on the performance of PE hydrogels composed of protamine sulfate and xanthan gum. The weight percentage of PE solids is fixed at 5%, and the charge ratio is fixed at 1:1. (A) shows viscosity curves as a function of shear rate when 0.5 M, 1.0 M, and 1.5 M sodium chloride preparations are added, with 5 wt% PE solids. (B) shows injection force through a catheter with an inner diameter of 0.0235 inches and a length of 130 cm as a function of sodium chloride molar concentration for 5 wt% PE solids. (C) shows temperature stability of storage modulus (G') when 0.5 M, 1.0 M, and 1.5 M sodium chloride preparations are added, with 5 wt% PE solids. (D) shows that for 0.5 M and 1.0 M preparations with 9% polyelectrolyte concentration, storage modulus (G') recovers to 100% after repeated deformation. The sample was subjected to 100% strain for 1 minute, after a relaxation period of 6 seconds, 1% strain was applied for 1 minute, and storage modulus (G') and loss modulus (G'') were measured.

[0008] [Figure 3] (A) shows that the PE hydrogel added with 0.5 M sodium chloride, containing protamine sulfate and xanthan at a charge ratio of 1:1 and having 5% PE solids, forms an opaque white self-standing gel; (B) shows that the PE hydrogel added with 1.0 M sodium chloride, containing protamine sulfate and xanthan at a charge ratio of 1:1 and having 5% PE solids, forms a translucent self-standing gel; (C) shows that the PE hydrogel added with 1.5 M sodium chloride, containing protamine sulfate and xanthan at a charge ratio of 1:1 and having 5% PE solids, forms a transparent self-standing gel. Based on the added sodium chloride and counterions in xanthan gum, the total sodium concentration is estimated to be about 0.56, 1.06, and 1.56, respectively.

[0009] [Figure 4A-4D]This paper characterizes the effect of solid percentage on the performance of PE hydrogels composed of protamine sulfate and xanthan gum. The molar concentration of added sodium chloride is fixed at 1 mole, and the charge ratio is fixed at 1:1. (A) Viscosity curves as a function of shear rate for formulations with 5% and 9% PE solid percentages are shown. (B) Injection force with a catheter of 0.0235 inches inner diameter and 130 cm length is shown as a function of solid percentage. (C) Temperature stability of elastic modulus (G') for formulations with 5%, 7.5%, and 9% PE solid percentages is shown. (D) For formulations with 5% and 9% solid percentages, it is shown that the elastic modulus (G') recovers to 100% after repeated deformation. Samples were subjected to 100% strain for 1 minute, followed by a 6-second relaxation period, and then 1% strain for 1 minute, after which the elastic modulus (G') and loss elastic modulus (G") were measured.

[0010] [Figures 5A-5D] This study characterizes the effect of added sodium chloride molar concentration on the performance of PE hydrogels composed of poly(guanidinyl-propyl-methacrylamide)pGPMA and xanthan gum. The weight percentage of the PE solid is fixed at 5%, and the charge ratio is fixed at 1:1. (A) Viscosity curves as a function of shear rate when 1.0 mol and 1.5 mol sodium chloride formulations are added are shown. (B) Injection force through a catheter with an inner diameter of 0.027 inches and a length of 130 cm is shown as a function of the molar concentration of sodium chloride. (C) Temperature stability of the elastic modulus (G') of the formulations when 1.0 mol and 1.5 mol sodium chloride are added is shown. (D) For the 1.0 mol and 1.5 mol formulations, it is shown that the elastic modulus (G') recovers to 100% after repeated deformation. The sample was subjected to a 100% strain for 1 minute, followed by a 6-second relaxation period, and then a 1% strain for 1 minute. The modulus of elasticity (G') and loss modulus of elasticity (G") were then measured.

[0011] [Figures 6A-6D]This paper characterizes the effect of solid percentage on the performance of PE hydrogels composed of pGPMA and xanthan gum. The molar concentration of added sodium chloride is fixed at 1 mole, and the charge ratio is fixed at 1:1. (A) Viscosity curves as a function of shear rate for formulations with solid percentages of 5, 7, and 12 are shown. (B) Injection force with a catheter of 0.027 inches inner diameter and 130 cm length is shown as a function of solid percentage. (C) Temperature stability of elastic modulus (G') for formulations with solid percentages of 5, 7, and 12 is shown. (D) For PE solid percentage formulations of 5% and 9%, it is shown that the elastic modulus (G') recovers to 100% after repeated deformation. Samples were subjected to 100% strain for 1 minute, followed by a 6-second relaxation period, and then 1% strain for 1 minute, after which the elastic modulus (G') and loss modulus (G") were measured.

[0012] [Figures 7A-7D] This study characterizes the effect of adding cross-linked gelatin fibers on the performance of PE hydrogels composed of protamine sulfate and xanthan gum. The weight percentage of the solid is fixed at 7%, the added sodium chloride is fixed at 0.5 moles, and the charge ratio is fixed at 1:1. (A) Viscosity curves as a function of shear rate for formulations with fiber content of 0%, 1%, and 2% are shown. (B) Injection force through a catheter with an inner diameter of 0.0235 inches and a length of 130 cm is shown as a function of fiber content. (C) Temperature stability of elastic modulus (G') for formulations with fiber content of 0%, 1%, and 2% is shown. (D) For formulations with fiber content of 1% and 2%, it is shown that the elastic modulus (G') recovers to 100% after repeated deformation. Samples were subjected to 100% strain for 1 minute, followed by a 6-second relaxation period, and then 1% strain for 1 minute, after which the elastic modulus (G') and loss modulus (G") were measured.

[0013] [Figure 8] This image shows a fiber made from cross-linked gelatin, magnified 100 times against the light.

[0014] [Figure 9A-9B](A) Shows the case where a PE hydrogel composed of protamine and xanthanum, with a charge ratio of 1:1, with 0.5 moles of sodium chloride added, 7% solid, and 25% tantalum added for radiopaqueness, is placed in an equilibrium salt solution via a 0.0235-inch catheter. (B) Shows the case where a PE hydrogel composed of protamine and xanthanum, with a charge ratio of 1:1, with 0.5 moles of sodium chloride added, 7% solid, and iohexol of iodine at a concentration of 200 mg per mL added for radiopaqueness, is placed in an equilibrium salt solution via a 0.027-inch catheter. In this embodiment, the PE hydrogel maintains the shape of the catheter and forms a stable coil that can be injected through the catheter to occlude a blood vessel.

[0015] [Figure 10A-10D] This study characterizes the effect of radiopaque contrast agents on the performance of PE hydrogel composed of protamine sulfate and xanthan gum. The weight percentage of the PE solid is fixed at 7%, and the molar concentration of the added salt is fixed at 0.5 mol. (A) Viscosity curve as a function of shear rate for iohexol 200 mgI / mL and tantalum 25%. (B) Injection force through a catheter with an inner diameter of 0.027 inches and a length of 130 cm for iohexol 200 mgI / mL and tantalum 25%. (C) Temperature stability of elastic modulus (G') for iohexol 200 mgI / mL and tantalum 25%. (D) Recovery of elastic modulus (G') to 100% after repeated deformation for iohexol 200 mgI / mL and tantalum 25%. The sample was subjected to a 100% strain for 1 minute, followed by a 6-second relaxation period, and then a 1% strain for 1 minute. The modulus of elasticity (G') and loss modulus of elasticity (G") were then measured.

[0016] [Figure 11]This document describes the in vitro characterization of the occlusive effect of PE hydrogels composed of protamine sulfate and xanthanum, with 25 wt% tantalum or 200 mgI / mL iohexol added to achieve radiopaqueness. Both PE hydrogels contained 7 wt% PE solid and 0.5 mol of sodium chloride, with a charge ratio of 1:1. Figure 11 shows the pressure at which the embolic preparation could maintain a constant tapered vascular diameter for more than 5 minutes. As a worst-case test of the mechanical ability of the PE hydrogel to create occlusion, the liquid used in the in vitro model to simulate ionic and chemical conditions without coagulation factors was a heparinized equilibrium salt solution.

[0017] [Figures 12A-12B] (A) An angiographic image of a pig before placement, showing the anatomy of the kidney before injection of embolic PE hydrogel using contrast agent. (B) Shows the formation of a proximal plug at the cranial pole of the pig kidney by injection of embolic PE hydrogel. The tantalum in the PE hydrogel provides visibility without obstructing the catheter tip. In this placement, no adhesion to the catheter was observed despite some reflux.

[0018] [Figure 13A] This image shows the injection of 0.15 mL ± 0.025 mL of embolic PE hydrogel into a gelatin mold prepared in a 3 mL syringe. Gelatin allows for the exchange of soluble compounds, mimicking diffusion in vascular walls and embolic materials in vivo. [Figure 13B]The elimination rate of iohexol from an embolic PE hydrogel containing protamine and xanthanum in a 1:1 charge ratio, with 0.75 mol of sodium chloride added, and containing 7% PE solids, was measured using UV-Vis spectroscopy. The intensity of the absorption peak at 245 nm correlated with the time-dependent elimination rate of iohexol from the PE hydrogel. The initial concentration of iohexol in the PE hydrogel was 200 mgI / mL, which is within the range of contrast agent concentrations used in peripheral vascular surgery. After 5 minutes, the PE hydrogel was faintly visible, and after 20 minutes, it was almost invisible. Due to this gradual elimination of the contrast agent, the PE hydrogel is highly visible upon placement, unlike currently commonly used embolic particles or gelatin, and does not produce artifacts in future CT images like liquids or coils containing tantalum or platinum.

[0019] [Figure 14A] This shows the viscosity of a hyaluronic acid-protamine polyelectrolyte (PE) hydrogel with 0 moles of sodium chloride added, a positive-to-negative charge ratio of 1.5:1, and a solid polymer electrolyte concentration of 9%. The decrease in viscosity with increasing shear rate indicates the feasibility of catheter delivery with this combination. [Figure 14B] This shows the elastic modulus G' of the same hyaluronic acid-protamine PE hydrogel recovering after multiple 100% strains.

[0020] [Figure 15] The gel exhibits wrapping behavior and shape memory. When placed under simulated use conditions, the embolic PE hydrogel material spontaneously wrapped around the gel when the flow slowed due to downstream occlusion, demonstrating its ability to fill more effectively. Over time, the wrapped material compresses, forming an occlusion with a filling density far higher than that achievable with typical embolic coils, thus ensuring successful occlusion regardless of blood clot formation.

[0021] [Figure 16] This specification shows the filling of the left atrial appendage with the polymer electrolyte hydrogel described herein.

[0022] [Figures 17A-17D] This shows the effect of adding salt (potassium chloride) to a PE hydrogel containing 4.5% XG and 4.0% chitosan hydrochloride to the level necessary for ionically shielding. The upper panel shows the PE hydrogel under backlighting, with the potassium chloride concentration shown in mg / mL. The lower panel shows the gel with the corresponding molar concentration of potassium chloride added under top light. (A) At low salt concentrations, a viscous colloidal liquid is formed with a heterogeneous distribution of small particles of ionically bonded components. (Figure 17B) A semi-solid gel that can retain its shape begins to form, but the backlighting image shows that it is still heterogeneous. (C) A nearly homogeneous gel is formed. Adding more salt at this point helps to prevent phase separation and ensure an increase in the elastic modulus of xanthan gum. (D) This shows the transparency of the XG-CS hydrogel in a completely ionically shielded state after autoclaving. A slight amber color change was observed after autoclaving.

[0023] [Figures 18A-18C] This shows the insolubility of PE hydrogels with XG-CS compared to hydrogels containing only xanthan gum. (A) From left to right, the images show an opaque white PE hydrogel with XG-CS having a charge ratio of 3:1 with 1.0 M NaCl added, a clear PE hydrogel with XG-CS having a charge ratio of 3:1 with 0.36 M CaCl2 added, and a clear hydrogel with 4% xanthan gum in a petri dish against a black background for contrast. (B) The images show the PE hydrogels on a white background and the hydrogels containing only XG before the addition of BSS. (C) After adding the equilibrium salt solution to the petri dish and waiting 2 minutes, the xanthan gum gel almost dissolved, while the chitosan-salt-xanthan gum PE hydrogel remained insoluble in water. This is an important property of the gel, namely, that it reduces viscosity under shear conditions, recovers, and maintains insolubility due to electrostatic interactions.

[0024] [Figures 19A-19F]This shows the effects of salt type, concentration, and temperature on the solubility of chitosan hydrochloride (4.0%, pH 5.1). (A) Shows a backlit image taken 1 hour after initial salt dissolution at 23°C. The salt type is shown in the row, and the salt concentration (mg / mL) is shown in the column. Opaque images indicate the insolubility of chitosan hydrochloride. (B) Shows the same result as in (A), but after 10 minutes in a freezer at -20°C. (C) Shows a backlit image obtained at 23°C in the same order as above, and a backlit image taken after 10 minutes at -20°C with the total charge molar concentration fixed at 0.85 M. (D) Shows the absorbance data at 600 nm for the plate shown in Figure 19A. Higher absorbance indicates more salt elution from the chitosan. (E) Shows the absorbance at 600 nm for the plate shown in Figure 19B. (F) Shows the absorbance data corresponding to the image in Figure 19C.

[0025] [Figures 20A-20D] The results of zeta potential measurements for carboxymethyl chitosan (CMC) at pH 7.1, 4% chitosan hydrochloride (G0) without added salt, 4% chitosan hydrochloride with added 0.85M potassium chloride, and 4% chitosan hydrochloride with added 0.45M potassium chloride at pH 5.1 are shown. (A) Zeta potential measurement. (B) Conductivity measurement. (C) Transmittance measurement. The decrease in solubility and increase in salt molar concentration at 0.85M contribute to the decrease in zeta potential in (A). In the case of the 0.45M sample, the solubility does not appear to decrease, and the decrease in zeta potential in (A) is likely due to the thinning of the interfacial bilayer from ions in the salt.

[0026] [Figures 21A-21B]This shows the range of action of each chloride salt in a PE hydrogel containing chitosan and xanthan gum. (A) This shows the range of action with respect to the total charge molar concentration, which is normalized to the same as the total chloride ion molar concentration for the divalent cationic salt. The gelation point is the minimum amount of salt required to ionically shield the polyelectrolyte and is the lower limit or minimum amount of salt for forming the PE hydrogel. The maximum amount of salt is governed by the solubility of chitosan, with the solid line showing the complete solubility at room temperature and the dotted line showing the point where solubility decreases and the concentration at which the PE hydrogel eventually no longer maintains its ideal properties for use as an embolizer. The ideal range of action is indicated by the dashed circle. (B) This shows the same data as (A) expressed in mg / mL concentrations.

[0027] [Figures 22A-22D] This shows the effect of polyelectrolyte concentration on the behavior of XG-CS PE hydrogel, which is fixed at a concentration of 0.27 M, with CaCl2 added and pH adjusted to 5.80-5.95. Concentrations are shown in mg / mL, where XG50 indicates a xanthan gum concentration of 50 mg / mL. (A) Shows the stepwise flow viscosity curve showing the peak viscosity and shear viscosity reduction behavior of the PE hydrogel. (B) Shows the viscosity range over 1 minute when the shear rate is 100 s⁻¹. (C) Shows the initial modulus of elasticity (G') when the strain is 1% and the frequency is 1 Hz, and the recovery modulus of elasticity over 1 minute when the strain is 100% and the frequency is 1 Hz. (D) Shows the ratio of recovery G' to the shear viscosity reduction viscosity at 100 s⁻¹. Higher values ​​are desirable, as they allow us to understand the initial strength of the embolic agent when it exits the delivery conduit in response to the force with which the embolic agent is injected through a delivery conduit such as a catheter.

[0028] [Figures 23A-23F]The images show CS-XG polymer electrolyte hydrogels with different charge ratios. The left image shows a charge ratio (CR) of 2:3, the center shows a charge ratio of 1:2, and the right shows a charge ratio of 1:1. (A) Shows the PE hydrogel delivered to the bottom of a glass petri dish. (B) Shows the appearance 30 seconds after adding the equilibrium salt solution (BSS) to the petri dish. (C) Shows the appearance 5 minutes after adding the BSS. When the CR is 1:1, the opacity is significantly higher. (D) Shows the appearance 30 minutes after adding the BSS. (E) Shows the appearance 24 hours after adding the BSS. The sample with a charge ratio of 1:2 swells significantly and tends to break. (F) Shows the appearance 24 hours after adding the BSS under backlighting.

[0029] [Figures 24A-24C] This study demonstrates the ability of CS-XG PE hydrogels with different ranges of polyelectrolyte concentrations and different types of salts to continue strengthening in a physiological medium. All measurements shown were performed on samples prepared by placing the PE hydrogel in BSS for 30 minutes before measurement, as described in the Methods section. (A) Shows the peak viscosity of the stepwise flow test. (B) Shows the modulus of elasticity at a strain of 1% and a frequency of 1 Hz. (C) Shows the yield stress curve, with the point considered to be the yield point magnified for emphasis.

[0030] [Figures 25A-25B] The results of the flow model tests and model details are shown. (A) Shows the pressure held by the exemplary formulation for three different terminal vascular diameters. (B) Shows an example of the flow model used, where the terminal vascular diameter is up to 500 μm or narrows to 100 μm. "1" is where the hemostatic valve is connected and the catheter is inserted into the model. "2" is where the peristaltic pump is connected, "3" is the outflow bypass channel to control the pressure increase during embolus formation, and "4a-4c" are outflow channels that filter the BSS back into the pump reservoir and capture the embolic material that has passed through the terminal channel. To evaluate the behavior of the PE hydrogel under different flow conditions, delivery was made from points labeled "D" for distal and "P" for proximal.

[0031] [Figures 26A-26C] This study demonstrates the use of a PE hydrogel predjet with a CS-XG formulation consisting of 4.0% chitosan hydrochloride, 4.5% xanthan gum, 32.5% tantalum, 1.0% gelatin fiber, and 0.27 M CaCl2 at pH 5.70. (A) This shows how to cleanly inject 0.10 mL of PE predjet into the catheter lumen with sterile saline, without leaving any residue in the catheter hub (Merit Maestro, 2.4 Fr, 150 cm microcatheter). (B) This shows exemplary injection force curves for three different injection rates of 0.10 mL of PE predjet. (C) This shows the behavior in a flow model. The predjet exited the catheter in a coiled state, rapidly compressed, and formed the indicated occlusion with a flow rate of 160 mL / min and a mean arterial pressure of 100 mmHg (±6 mmHg). After delivery, the pressure rose to 37 kPa (277 mmHg), and the degree of distal penetration into the model was quantified.

[0032] [Figures 27A-27F] An example of a delivery system for delivering the pre-jet PE hydrogel described herein is shown. Additional advantages of the present invention are some described below, some become apparent from the description, and some are acquired through the practice of the invention. The advantages of the present invention are realized and achieved by the elements and combinations specifically pointed out in the appended claims. It should be understood that both the above general description and the following detailed description are illustrative and descriptive only and do not limit the claimed invention. [Modes for carrying out the invention]

[0033] Many modifications and other embodiments disclosed herein will be recognizable to those skilled in the art who benefit from the teachings presented in the foregoing description and the accompanying drawings of the disclosed compositions and methods. Therefore, it should be understood that the disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the embodiments described herein. These variations and adaptations are included in the teachings of this disclosure and are intended to be included within the scope of the claims herein.

[0034] Certain terms are used in this specification, but these terms are used only in a general and descriptive sense and not for restrictive purposes.

[0035] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has separate components and features that are readily separable from or readily combined with any of the features of several other embodiments without departing from the scope or spirit of this disclosure.

[0036] Any of the listed methods shall be performed in the order of the listed events, or in any other logically possible order. In other words, unless otherwise specifically stated, no method or embodiment described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Accordingly, no order is ever intended to be inferred in any respect unless the claims or specification specifically state that the steps are limited to a particular order. This is also true of any possible implicit grounds for interpretation, including logical matters relating to the arrangement or flow of operations of the steps, obvious meanings derived from grammatical construction or punctuation, or the number or type of embodiments described in the specification.

[0037] All publications referenced herein are incorporated herein by reference to disclose and describe the manner and / or materials by which the publications are cited. Publications discussed herein are provided solely for disclosure prior to the filing date of this application. Nothing herein shall be construed as admitting that the present invention has no prior authority over such publications based on prior inventions. Furthermore, the dates of publications provided herein may differ from the actual publication dates and may require individual verification.

[0038] The aspects of this disclosure are described and claimed as specific legal classes, such as system legal classes, but this is for convenience only, and those skilled in the art will understand that each aspect of this disclosure may be described and claimed in any legal class.

[0039] Furthermore, it should be understood that the technical terms used herein are for the purpose of describing specific embodiments and are not intended to limit them. All technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the disclosed compositions and methods belong, unless otherwise specified. In addition, terms as defined in commonly used dictionaries should be interpreted as having the meaning consistent with their meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0040] Before describing the various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms are defined elsewhere in this disclosure. definition

[0041] As used herein, “comprising” is interpreted as identifying the presence of the feature, integer, step, or component described as mentioned, but does not exclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in an open, non-restrictive sense and are interchangeable. Furthermore, the term “comprising” is intended to include examples and aspects that are encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples that are encompassed by the term “consisting of.”

[0042] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise. Thus, for example, a reference to "excipients" includes, but is not limited to, mixtures or combinations of two or more such excipients.

[0043] It should be noted that in this specification, ratios, concentrations, quantities, and other numerical data are expressed in range form. Furthermore, it will be understood that each endpoint of a range is important in relation to other endpoints, and also important independently of other endpoints. Also, in this specification, several values ​​are disclosed, and each value is disclosed not only as the value itself, but also "about" that particular value. For example, if the value "10" is disclosed, "about 10" is also disclosed. In this specification, ranges can be expressed as "about" from one particular value and / or "about" to another particular value. Similarly, when a value is expressed as an approximation by the use of the antecedent "about," it will be understood that the particular value forms further aspects. For example, if the value "about 10" is disclosed, 10 is also disclosed.

[0044] When expressing a range, further embodiments include including a range from one specific value and / or to another specific value. For example, if a range described includes one or both of limit values, the range excluding one or both of those limit values ​​is also included in this disclosure. For example, the phrase "x to y" includes not only the range "x" to "y" but also the range greater than "x" and less than "y". A range can also be expressed as an upper limit, for example, "about x, y, z, or less," and should be interpreted as including not only the specific ranges "about x," "about y," and "about z," but also the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted as including not only the specific ranges "about x," "about y," and "about z," but also the ranges "greater than x," "greater than y," and "greater than z." Also, the phrase "about "x" to "y"" (where "x" and "y" are numerical values) includes "about "x" to about "y."

[0045] It should be understood that such range formats are used for convenience and conciseness, and should be interpreted flexibly to include not only the numbers explicitly listed as range limits, but also all individual numbers or subranges within that range, as if each number and subrange were explicitly listed. For example, the numerical range "approximately 0.1% to 5%" should be interpreted to include not only the explicitly listed values ​​of approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., approximately 1%, approximately 2%, approximately 3%, and approximately 4%) and subranges (e.g., approximately 0.5% to approximately 1.1%, approximately 5% to approximately 2.4%, approximately 0.5% to approximately 3.2%, and approximately 0.5% to approximately 4.4%, as well as other possible subranges). Therefore, for example, if the amount of a component is approximately 1%, 2%, 3%, 4%, or 5% (any value may be the lower and upper limits of the range), then any range of 1% to 5% (e.g., 1% to 3%, 2% to 4%, etc.) is assumed.

[0046] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect as described in the claims or taught herein. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics may not be exact, and do not need to be exact, but may be approximate values ​​and / or greater or less than values ​​that reflect tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art, as necessary, so as to provide an equivalent result or effect. In some situations, a value that provides an equivalent result or effect may not be reasonably determined. In such cases, as used herein, the terms “about” and “at or about” are generally understood to mean a variation of ±10% of the nominal value shown, unless otherwise indicated or inferred. In general, quantities, sizes, proportions, parameters, or other quantities or characteristics are "about," "approximate," or "at or about," whether or not they are explicitly stated to be so. When "about," "approximate," or "at or about" is used before a quantitative value, it will be understood that the parameter also includes the specific quantitative value itself, unless otherwise specified.

[0047] As used herein, the term “alkyl group” refers to a branched or unbranched saturated hydrocarbon group having 1 to 25 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, and tetracosyl. Longer-chain alkyl groups include, but are not limited to, palmitate groups. “Lower alkyl” groups are alkyl groups containing 1 to 6 carbon atoms.

[0048] As used herein, the term "cycloalkyl group" refers to a non-aromatic carbon ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0049] As used herein, the term “treatment” is defined as maintaining or reducing the symptoms of a pre-existing disease compared to the same symptoms as when the PE hydrogel described herein is not administered. As used herein, the term “prevention” refers to the ability of the PE hydrogel described herein to completely eliminate or reduce activity compared to the same activity as when the gel is not present. As used herein, the term “inhibition” refers to the ability of the PE hydrogel described herein to slow down or prevent a process.

[0050] "Subjects" refers to mammals (humans, non-human primates, sheep, dogs, rodents (e.g., mice, rats, guinea pigs, etc.)) and non-mammals (including, but not limited to, vertebrates, birds, fish, amphibians, and reptiles).

[0051] As used herein, the term "salt" is defined as the dry solid form of a water-soluble compound having cations and anions. When a salt is placed in water, it dissociates into cations and anions. A polycationic salt is a compound having multiple cationic groups and an anionic counterion. A polyanionic salt is a compound having multiple anionic groups and a cationic counterion.

[0052] As used herein, the term “polyelectrolyte” is defined as a polymer having an ionizable functional group, which may be located in the polymer backbone, polymer side chains, or a combination thereof. When a polycationic salt or polyanionic salt is dissolved in water, polycations and polyanions are produced.

[0053] As used herein, the term “ionic” is defined as any charged element. For example, an ion may be a positively charged ionic species containing a monovalent cation (e.g., sodium or potassium) or a divalent cation (e.g., calcium or magnesium). An ion may also be a negatively charged ionic species containing a monovalent anion (e.g., chloride).

[0054] As used herein, the term “molecular weight” refers to the average molecular weight of a collection of synthetic polymers, including their molecular weight distribution. Unless otherwise specified, the values ​​reported herein are weight-average molecular weights (Mw).

[0055] As used herein with respect to contrast agents, the term “transient” is defined as the ability of a contrast agent to diffuse or leak from the PE hydrogel described herein over time.

[0056] As used herein, the term “transient contrast agent” arises when the majority of the transient contrast agent diffuses from the PE hydrogel described herein, making it undetectable in the subject by imaging techniques such as fluoroscopy or CT.

[0057] "Physiological conditions" refer to conditions such as osmotic pressure, ion concentration, pH, and temperature within a specific range of a subject. For example, the normal range of sodium concentration in human blood is 135 mMol / L to 145 mMol / L.

[0058] Where used herein, multiple (i.e., two or more) items, structural elements, compositional elements, and / or materials may be presented in common lists for convenience. However, these lists should be interpreted as each member of the list being identified individually as a distinct and unique member. Therefore, no individual member of such a list should be interpreted as a de facto equivalent of any other member of the same list, merely on the basis of being presented in a common group, unless otherwise indicated.

[0059] As used herein, the term "multimodal polymer" refers to a polymer having a molecular weight distribution curve that is the sum of at least two or more monomodal molecular weight distribution curves. For example, polyanionic polyelectrolytes can be mixed to form a multimodal molecular weight distribution in order to modify the flow behavior of a polyelectrolyte hydrogel under shear.

[0060] As used herein, the term "polymer electrolyte (PE) hydrogel" refers to a composition in which the cohesive force of the hydrogel is due to electrostatic interactions between oppositely charged polymer electrolytes, and in which the elastic modulus is greater than the viscosity when no shear is applied. Polymer electrolyte hydrogels are dimensionally stable and insoluble in water and physiological fluids.

[0061] In this specification, concentrations, quantities, and other numerical data may be expressed and presented in range form. Since such range forms are used solely for convenience and conciseness, it should be understood that they should be interpreted flexibly to include not only the numbers explicitly listed as range limits, but also all individual numbers or subranges contained within that range, as if each number and subrange were explicitly listed. For example, a numerical range of "approximately 1" to "approximately 5" should be interpreted to include not only the explicitly listed values ​​of approximately 1 to approximately 5, but also the individual values ​​and subranges within the indicated range. Therefore, this numerical range includes individual values ​​such as 2, 3, and 4, as well as subranges such as 1 to 3, 2 to 4, 3 to 5, approximately 1 to approximately 3, 1 to approximately 3, and approximately 1 to 3, as well as individually 1, 2, 3, 4, and 5. The same principle applies to ranges that list only one number as the minimum or maximum value. Furthermore, such interpretations should apply regardless of the width of the range or characteristic described.

[0062] Disclosed are materials and components, or products thereof, that can be used for, in combination with, or for the preparation thereof, of the disclosed compositions and methods. These materials and other materials are disclosed herein, and where combinations, subsets, interactions, groups, etc., of these materials are disclosed, specific references to various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, but it will be understood that each is specifically assumed and described herein. For example, when a class of molecules A, B, and C is disclosed, along with a class of molecules D, E, and F, and an example of a combined molecule, A+D, each is individually and collectively assumed, even if not described individually. Therefore, in this example, each combination of A+E, A+F, B+D, B+E, B+F, C+D, C+E, and C+F should be considered specifically assumed and disclosed from the disclosure of examples of combinations of A, B and C, D, E and F, and A+D. Similarly, any subset or combination of these is also specifically assumed and disclosed. Accordingly, for example, the subgroups A+E, B+F, and C+E should be considered as specifically envisioned and disclosed in the disclosure of examples of combinations of A, B and C, D, E and F, and A+D. This concept applies to all aspects of this disclosure, including but not limited to steps in a method for producing and using the disclosed compositions. Accordingly, where there are various additional steps that can be performed in any particular embodiment or combination of embodiments of the disclosed method, each of such combinations should be considered specifically envisioned and disclosed.

[0063] Polymer electrolyte hydrogel preparations This specification describes polyelectrolyte (PE) hydrogels having properties suitable for delivery to a target. The polyelectrolyte hydrogels consist of one or more water-soluble polycationic polyelectrolytes, one or more water-soluble polyanionic polyelectrolytes, and a mixture of monovalent and / or divalent ions. Depending on the selection and amounts of the polycationic and polyanionic polyelectrolytes, monovalent and / or divalent ions, the charge ratio, and the inclusion of any additives or components, the mechanical properties, durability, delivery capabilities, and occluded vessel size can be adjusted to suit the intended application.

[0064] PE hydrogels maintain stability and water-insoluble properties under physiological conditions. Typical hydrogels swell in water. The hydrogels described herein possess dimensional stability under physiological conditions. In one embodiment, when introduced under physiological conditions, the hydrogels will not swell or shrink at concentrations of 10.0% or higher, or at 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, or 9.0% (or any range such as 0.5% to 9.0%). While we do not wish to be bound by theory, the stability of the hydrogels described herein is due to the electrostatic interaction between the polyanionic and polycationic polymer electrolytes.

[0065] In one embodiment, the PE hydrogel exhibits a reversible decrease in elastic modulus and viscosity under shear flow during delivery via a conduit (e.g., a needle or catheter). The elastic modulus and viscosity of the PE hydrogel decrease during delivery via the conduit, and when the material exits the conduit at the target site, the shear force decreases, and the elastic modulus and viscosity recover to near their initial values. The degree of decrease and recovery of elastic modulus and viscosity can be adjusted by the selection of the polyelectrolyte, the charge ratio between the polyelectrolyte components, the polyelectrolyte concentration, the concentration of monovalent and / or divalent ions, and the inclusion of additional components as described herein.

[0066] In one embodiment, after being delivered to a physiological medium (e.g., a subject), the modulus and viscosity of the polymer electrolyte hydrogel continue to increase. In one embodiment, after 30 minutes in the physiological medium, the modulus of the polymer electrolyte hydrogel is 200 Pa to 25000 Pa. In another embodiment, after 30 minutes in the physiological medium, the modulus of the polymer electrolyte hydrogel is 200 Pa, 500 Pa, 1000 Pa, 1500 Pa, 2000 Pa, 2500 Pa, 3000 Pa, 3500 Pa, 4000 Pa, 4500 Pa, 5000 Pa, 5500 Pa, 6000 Pa, 10000 Pa, 15000 Pa, 20000 Pa, or 25000 Pa, where any value may be the lower and upper limits of the range (e.g., 3000 Pa to 8000 Pa).

[0067] In another embodiment, the modulus of elasticity of the polymer electrolyte hydrogel remains greater than its viscosity. In another embodiment, after delivery to a physiological medium, the modulus of elasticity continues to increase. In another embodiment, after delivery to a physiological medium, the modulus of elasticity of the PE hydrogel is within ±10% of the initial modulus of elasticity before delivery.

[0068] In another embodiment, the PE hydrogel can be exposed to an ionic liquid to alter one or more properties of the hydrogel before being delivered to the target. In one embodiment, the polymer electrolyte hydrogel is exposed to a liquid with a lower ion content than the polymer electrolyte hydrogel in order to increase its elastic modulus before delivery.

[0069] In another embodiment, the viscosity of the polymer electrolyte hydrogel decreases under shear such that the injection force through the catheter is less than 20 lbf, or 2 lbf, 4 lbf, 6 lbf, 8 lbf, 10 lbf, 12 lbf, 14 lbf, 16 lbf, 18 lbf, or 20 lbf, with any value being the lower and upper limits of the range (e.g., 4 lbf to 12 lbf).

[0070] The shear viscosity reduction properties of the hydrogel can be altered depending on the selection and amount of polycationic and polyanionic polymer electrolytes. In one embodiment, the polyanionic polymer electrolyte has 10 mol% to 90 mol% ionized side chains when the pH is greater than 4.5. In another embodiment, the polyanionic polymer electrolyte has only anionic charged groups, i.e., no cationic groups. In another embodiment, the molecular weight of the polyanion is about 20 kDa to about 10,000 kDa. In another embodiment, the polyanionic polymer electrolyte is linear or branched. In another embodiment, the polyanionic polymer electrolyte contains multiple molecular weight polymers to form a multimodal molecular weight distribution. Examples of suitable polyanionic polymer electrolytes are described in more detail below.

[0071] In another embodiment, the polycationic polymer electrolyte has 85.0 mol% to 100 mol% ionized side chains when the pH is less than 6.3. In yet another embodiment, the polycationic polymer electrolyte has only cationic charged groups, i.e., no anionic groups. Examples of suitable polycationic polymer electrolytes are described in more detail below.

[0072] When polyelectrolytes dissolve together in water, oppositely charged sites attract each other. Monovalent and / or divalent ions provide ion shielding, preventing polycations and polyanions from completely binding. Monovalent and divalent ions each have advantages depending on the polyelectrolyte containing the hydrogel. For example, monovalent and / or divalent ions can control the homogeneity of the PE hydrogel and can themselves be used as levels to adjust the mechanical properties of the gel. The concentration of added monovalent and / or divalent ions is selected depending on the chosen polyelectrolyte, the concentration of the polyelectrolyte, and the desired hydrogel properties.

[0073] In one embodiment, the ions include monovalent cations (e.g., sodium and / or potassium) and monovalent anions (e.g., chloride) having concentrations of about 0.10 M to about 2.5 M. In another embodiment, the monovalent ions are sodium ions and chloride ions having concentrations of about 0.10 M, 0.25 M, 0.50 M, 0.75 M, 1.00 M, 1.25 M, 1.50 M, 1.75 M, 2.00 M, 2.25 M, or 2.5 M, where any values ​​may be the lower and upper limits of the range (e.g., 0.50 M to 1.50 M).

[0074] In one embodiment, the ions include divalent cations (e.g., calcium and / or magnesium) and monovalent anions (e.g., chloride) having concentrations of about 0.10 M to about 2.5 M. In another embodiment, the monovalent ions are sodium ions and chloride ions having concentrations of about 0.10 M, 0.25 M, 0.50 M, 0.75 M, 1.00 M, 1.25 M, 1.50 M, 1.75 M, 2.00 M, 2.25 M, or 2.5 M, where any values ​​may be the lower and upper limits of the range (e.g., 0.50 M to 1.50 M).

[0075] In addition to the selection of polyelectrolytes and monovalent and / or divalent ions, the charge ratio of the polyelectrolytes at a particular pH is another factor in generating and modifying the properties of the hydrogels described herein. The charge density of each polyelectrolyte can be expressed as the mass per mole of charge. For example, in protamine sulfate (salmin), the arginine groups are positively charged, and there are 21 arginine groups per protamine molecule. Using this information and molecular weight, the mass per mole of charge can be calculated. For example, the molecular weight of salmin is 4236 Da, and the mass per mole of positive charge is 201.7 g. If the charge densities of polycations and polyanions are known, the charge ratio can be selected. In one embodiment, when the pH is about 4.5 to about 8, the charge ratio of polycationic polyelectrolytes to polyanionic polyelectrolytes is 6:1 to 1:6. In another embodiment, the charge ratio is 1:1 or about 1:1, but this ratio can be adjusted to modify the properties of the hydrogel.

[0076] The initial modulus of elasticity of the PE hydrogel can be changed depending on the selection and amount of polycationic and polyanionic polymer electrolytes. In one embodiment, the initial modulus of elasticity of the hydrogel is 200 Pa or more, and at least twice the viscosity.

[0077] PE hydrogels are useful in several medical applications, such as embolizing agents, due to their ability to recover their elastic modulus after administration to a target. In one embodiment, the recovered elastic modulus of a polymer electrolyte hydrogel under physiological conditions is at least 80% of its initial elastic modulus. In another embodiment, the recovered elastic modulus of a polymer electrolyte hydrogel under physiological conditions is at least 80%, 85%, 90%, 95%, or 100% of its initial elastic modulus. In yet another embodiment, the hydrogel has an elastic modulus under physiological conditions greater than its initial elastic modulus. In yet another embodiment, the elastic modulus recovers to a level sufficient to provide occlusion or fill a cavity.

[0078] The weight percentage of total solids in the hydrogel is selected based on the solubility of the polymer electrolyte and the desired properties of the hydrogel; generally, a higher weight percentage results in improved modulus of elasticity and viscosity. The mass of each component added is calculated based on the desired batch size, the concentration of the selected polymer electrolyte, the charge ratio, and the concentration of the added monovalent and / or divalent ions. The total concentration of monovalent and / or divalent ions in the PE hydrogel includes the concentration of the counterions of the polymer electrolyte and the concentration of the added monovalent and / or divalent ions.

[0079] The components used to prepare the polymer electrolyte hydrogel, their manufacturing methods, and methods of use are described in detail below. Polycationic polymer electrolytes

[0080] A polycationic polymer electrolyte is a compound having multiple cationic groups, or groups that can be easily converted to cationic groups by adjusting the pH. In one embodiment, a polycationic polymer electrolyte is a polymer having multiple cationic groups and pharmaceutically acceptable anionic counterions. In one embodiment, when the pH is greater than 6, the polycationic polymer electrolyte has about 10 mol% to about 90 mol% cationicity (i.e., ionized side chains), or about 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, or 90 mol%, where any value may be the lower and upper limits of the range (e.g., 30 mol% to 70 mol%). In another embodiment, the polycation has only cationic charged groups, i.e., no anionic groups.

[0081] In one embodiment, the polycationic polymer electrolyte is a polymer having a polymer backbone with a plurality of cationic groups and pharmaceutically acceptable anionic counterions. The cationic groups may be pendanted from and / or incorporated into the polymer backbone.

[0082] In one embodiment, a polycationic polymer electrolyte is obtained by dissolving a polycationic salt in water. In one embodiment, the polycationic salt is a polycationic hydrochloride salt, which, when mixed with water, produces a polycationic polymer electrolyte and chloride ions. In another embodiment, the polycationic salts described herein can be produced by combining a polymer having multiple basic groups (e.g., amino groups) with an acid to produce the corresponding cationic groups. In various embodiments, the acid used to form a pharmaceutically acceptable polycationic salt includes inorganic acids such as hydrochloric acid, acetic acid, glutaric acid, or other monovalent carboxylic acids.

[0083] Furthermore, basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides like methyl chloride, ethyl chloride, propyl chloride, butyl chloride, bromide, and iodide; dialkyl sulfates like dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long-chain halides like decyl chloride, lauryl chloride, myristyl chloride, stearyl chloride, bromide, and iodide; and aralkyl halides like benzyl bromide and phenethyl bromide.

[0084] In another embodiment, when the polycationic polymer electrolyte is a polymer, the polycation can be produced by polymerization of one or more monomers, each monomer having one or more cationic groups with corresponding counterions. In one embodiment, once the polycation is prepared, excess ions can be removed from the polycation by filtration or dialysis before drying (e.g., freeze-drying) to produce a polycationic salt having a stoichiometric amount of anionic counterions relative to the number of cationic groups.

[0085] In one embodiment, the counterion of the polycationic polymer electrolyte is a monovalent ion, such as chloride ions, pyruvate ions, acetate ions, tosylate ions, benzenesulfonate ions, benzoate ions, lactate ions, salicylate ions, glucuronate ions, galacturonate ions, nitrite ions, mesylate ions, trifluoroacetate ions, nitrate ions, gluconate ions, glycolate ions, formate ions, or any combination thereof. In another embodiment, the counterion of the polycationic polymer electrolyte is a polyvalent ion, such as sulfate ions or phosphate ions.

[0086] In one embodiment, the polycationic polymer electrolyte is a pharmaceutically acceptable salt of a polyamine. The amino groups of the polyamine may be branched or part of the polymer backbone. In one embodiment, the polyamine comprises two or more pendant amino groups, the amino groups comprising primary amino groups, secondary amino groups, tertiary amino groups, quaternary amino groups, alkylamino groups, heteroaryl groups, guanidinyl groups, imidazolyl groups, or aromatic groups substituted with one or more amino groups.

[0087] In one embodiment, a pharmaceutically acceptable salt of a polyamine may contain an aryl group having one or more amino groups directly or indirectly linked to an aromatic group. Alternatively, the amino group may be incorporated into the aromatic ring. For example, the aromatic amino group may be pyrrole, isopyrrole, pyrazole, imidazole, triazole, or indole. In another embodiment, the aromatic amino group may include an isoimidazole group present in histidine. In yet another embodiment, the biodegradable polyamine may be gelatin modified with ethylenediamine.

[0088] Generally, polyamine salts are polymers in which the positive charge is significantly in excess of the negative charge at or near the physiological pH. For example, the polycation may have 10 mol% to 90 mol%, 10 mol% to 80 mol%, 10 mol% to 70 mol%, 10 mol% to 60 mol%, 10 mol% to 50 mol%, 10 mol% to 40 mol%, 10 mol% to 30 mol%, or 10 mol% to 20 mol% of protonated amino groups. In another embodiment, all amino groups of the polyamine are protonated.

[0089] In one embodiment, the polycationic polymer electrolyte may have protonated residues of lysine, histidine, or arginine. For example, arginine has a guanidinyl group, and the guanidinyl group is a suitable amino group that can be converted to a cationic group useful herein.

[0090] In another embodiment, the polyamine may be a biodegradable synthetic polymer or a naturally occurring polymer. The mechanism by which the polyamine can be broken down varies depending on the polyamine used. In the case of natural polymers, they are biodegradable because enzymes are present that can hydrolyze the polymer chains. For example, proteases can hydrolyze natural proteins such as gelatin. In the case of biodegradable synthetic polyamines, they also have chemically unstable bonds. For example, amino esters have hydrolyzable ester groups.

[0091] In one embodiment, polyamines include polysaccharides, proteins, peptides, or synthetic polyamines. Polysaccharides having two or more amino groups may be used as described herein. In one embodiment, the polysaccharide is a natural polysaccharide such as chitosan or chemically modified chitosan. Similarly, the protein may be a synthetic compound or a naturally occurring compound. In another embodiment, the polyamine is a synthetic polyamine such as poly(aminoester), polyesteramine, poly(disulfideamine), mixed poly(ester and amideamine), and peptide-crosslinked polyamines.

[0092] In one embodiment, the polycation is chemically modified chitosan. Chitosan possesses hemostatic, mucosal, and endothelial properties, all of which are useful in embolic polymer electrolyte hydrogels. While we do not wish to be bound by theory, when combined with a suitable anionic polysaccharide, chitosan exhibits hydrogen bonding and polymer chain entanglement in addition to the electrostatic interactions described herein. This synergistic stratification of interactions results in higher cohesiveness of polymer electrolyte hydrogels prepared from chitosan, allowing them to occlude larger blood vessels when used as embolizers.

[0093] In one embodiment, chemically modified chitosan enhances the solubility of chitosan while maintaining only a positive charge. In one embodiment, modified chitosan is a pharmaceutically acceptable salt of chitosan. Examples of pharmaceutically acceptable salts of chitosan include, but are not limited to, chlorides, glutamates, or acetates. In one embodiment, modified chitosan is positively charged only. For example, modified chitosan does not contain negative or amphoteric charges throughout the chitosan polymer.

[0094] In one embodiment, a pharmaceutically acceptable salt of chitosan has a degree of deacetylation (DDA) greater than 85%. In another embodiment, a pharmaceutically acceptable salt of chitosan has a degree of deacetylation (DDA) of 85%, 90%, 95%, 99%, 99.9%, or 100%, where any value may be the lower and upper limits of the range (e.g., 90% to 95%). While we do not wish to be bound by theory, if the degree of deacetylation is less than 85%, the pharmaceutically acceptable salt of chitosan will have reduced solubility, be more easily separated from solution, and have reduced charge density, resulting in reduced gel strength in physiological media.

[0095] In one embodiment, pharmaceutically acceptable salts of chitosan have an average molecular weight of 10 kDa to 130 kDa. In another embodiment, pharmaceutically acceptable salts of chitosan have an average molecular weight of 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, 110 kDa, 120 kDa, or 130 kDa, where any value may be the lower and upper limits of the range (e.g., 20 kDa to 50 kDa). While we do not wish to be bound by theory, if the molecular weight is less than 10 kDa, chitosan does not have sufficient interaction to maintain the cohesiveness of the hydrogel in flowing blood. If the molecular weight is greater than 130 kDa, the material becomes too viscous to be injected.

[0096] In one embodiment, the pharmaceutically acceptable salt of chitosan is approximately 0.70% to approximately 8% by weight of the hydrogel. In another embodiment, the pharmaceutically acceptable salt of chitosan is 0.7%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, or 8.0% by weight of the hydrogel, with any value being the lower and upper limits of the range (e.g., 0.7% to 3.5%). While we do not wish to be bound by theory, if the concentration of the pharmaceutically acceptable salt of chitosan is too low, there will be insufficient charge to produce a non-water-soluble hydrogel. If the concentration is too high, the viscosity of the hydrogel will be too high, limiting the use of the hydrogel.

[0097] In one embodiment, when a pharmaceutically acceptable salt of chitosan is used to produce a PE hydrogel, the hydrogel has a pH of 4.5 to 6.3. In another embodiment, when a pharmaceutically acceptable salt of chitosan is used to produce a PE hydrogel, the hydrogel has a pH of 4.5, 4.75, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, or 6.3, where any value may be the lower and upper limits of the range (e.g., 4.75 to 6.0).

[0098] In one embodiment, the pharmaceutically acceptable salt of the polyamine may be an amine-modified natural polymer. For example, the amine-modified natural polymer may be gelatin modified with one or more alkylamino groups, heteroaryl groups, or aromatic groups substituted with one or more amino groups. Examples of alkylamino groups are shown in formulas IV-VI. (chemical 1) -NR 13 (CH2) S NR 14 R 15 IV [ka] [ka] In the formula, R 13 ~R 22 These are independently hydrogen, alkyl groups, or nitrogen-containing substituents. s, t, u, v, w, and x are integers between 1 and 10. A is an integer between 1 and 50. Alkylamino groups are covalently bonded to natural polymers. In one embodiment, if the natural polymer has carboxyl groups (e.g., acids or esters), the carboxyl groups react with alkyldiamino compounds to form amide bonds, thereby incorporating the alkylamino groups into the polymer. Therefore, referring to formulas IV-VI, the NR of the amino group 13 It is covalently bonded to the carbonyl group of the natural polymer.

[0099] As shown in formulas IV to VI, the number of amino groups may vary. In one embodiment, the alkylamino group is -NHCH2NH2, -NHCH2CH2NH2, -NHCH2CH2CH2NH2, -NHCH2CH2CH2CH2NH2, -NHCH2CH2CH2CH2CH2NH2 -NHCH2NHCH2CH2CH2NH2 -NHCH2CH2NHCH2CH2CH2NH2 -NHCH2CH2CH2NHCH2CH2CH2CH2NHCH2CH2CH2NH2, -NHCH2CH2NHCH2CH2CH2CH2NH2 -NHCH2CH2NHCH2CH2CH2NHCH2CH2CH2NH2 or -NHCH2CH2NH(CH2CH2NH) d The expression is CH2CH2NH2, where d is between 0 and 50.

[0100] In one embodiment, a pharmaceutically acceptable salt of an amine-modified natural polymer may contain an aryl group in which one or more amino groups are directly or indirectly bonded to an aromatic group. Alternatively, the amino group may be incorporated into an aromatic ring. For example, the aromatic amino group may be pyrrole, isopyrrole, pyrazole, imidazole, triazole, or indole. In another embodiment, the aromatic amino group may include an isoimidazole group present in histidine. In yet another embodiment, the biodegradable polyamine may be gelatin modified with ethylenediamine.

[0101] In other embodiments, the polycationic polymer electrolyte may be a dendrimer. The dendrimer may be a branched polymer, a multi-arm polymer, a star polymer, etc. In one embodiment, the dendrimer is a polyalkylimine dendrimer, a mixed amino / ether dendrimer, a mixed amino / amide dendrimer, or an amino acid dendrimer. In another embodiment, the dendrimer is poly(amideamine) or PAMAM. In one embodiment, the dendrimer has 3 to 20 arms, each arm containing an amino group.

[0102] In one embodiment, the polycationic polymer electrolyte comprises a polyacrylate having one or more pendant protonated amino groups. For example, the backbone of the polycationic salt can be derived by polymerization of acrylate monomers, including (but not limited to) acrylates, methacrylates, acrylamides, and methacrylamides. In one embodiment, the backbone of the polycationic salt is derived from polyacrylamide. In another embodiment, the polycationic salt is a random copolymer. In another embodiment, the polycation is a block copolymer, and segments or portions of the copolymer have cationic or neutral groups, depending on the selection of monomers and methods used to produce the copolymer.

[0103] In another embodiment, the polycationic polymer electrolyte may be polyethyleneimine hydrochloride (linear or branched), cation-modified gelatin, cationic guar gum (hydroxypropyltrimonium chloride), poly-L-lysine, poly(amideamine), cation-modified polyvinylpyrrolidone derivative, cation-modified poly(N-isopropylacrylamide), cationic polysaccharide, and cation-modified polysaccharide.

[0104] In another embodiment, the polycationic polyelectrolyte is a pharmaceutically acceptable salt of protamine. Protamine is a polycationic, arginine-rich protein that plays a role in the condensation of chromatin into the sperm head during spermatogenesis. Commercially available protamine, purified from fish sperm as a by-product of fishing, is readily available in large quantities and relatively inexpensive. A non-limiting example of protamine useful herein is salmin. In another embodiment, protamine is clepein.

[0105] In one aspect, the protamine is approximately 0.5% to approximately 15% by weight of the hydrogel. In another aspect, the protamine is 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, or 15.0% by weight of the hydrogel, where any value may be the lower and upper limits of the range (e.g., 3.0% to 8.0%).

[0106] In one embodiment, the polycationic polyelectrolyte is a polymer having multiple guanidinyl groups. In one embodiment, the guanidinyl groups are pendant from the polymer backbone. The number of guanidinyl groups present on the polycation ultimately determines the charge density of the polycation. In one embodiment, the guanidinyl groups may be derived from arginine residues bonded to the polymer backbone.

[0107] Polyguanidinyl polymers may be homopolymers or copolymers having multiple guanidinyl groups. In one embodiment, polyguanidinyl copolymers are synthetic compounds prepared by free radical polymerization of monomers such as acrylates, methacrylates, acrylamides, methacrylamides, or any combination thereof, with guanidinyl monomers of formula I or pharmaceutically acceptable salts thereof.

Chem.

[0108] In one embodiment, in the compound of formula (I), R 1 is methyl, X is NH, and m is 3. In another embodiment, the monomer is methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-[3-(N'-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3-aminopropyl)methacrylamide, N-(1,3-dihydroxypropan-2-yl)methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof.

[0109] In yet another embodiment, the molar ratio of the guanidinyl monomer of formula I to the other monomer is 1:20 to 20:1, or 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1, and any of said ratios may serve as the lower limit endpoint and upper limit endpoint of a range (for example, 2:1 to 5:1). In one embodiment, the molar ratio of the guanidinyl monomer of formula I to the other monomer is 3:1 to 4:1. In another embodiment, the polyguanidinyl polymer is a homopolymer derived from the guanidinyl monomer of formula I.

[0110] Polyguanidinyl copolymers can be synthesized using polymerization techniques known in the literature, such as RAFT polymerization (i.e., reversible addition-cleavage chain transfer polymerization) or other methods such as free radical polymerization. In one embodiment, the polymerization reaction can be carried out in an aqueous solution environment. As described above, polyguanidinyl copolymers can be first prepared as neutral polymers and then treated with acid to produce pharmaceutically acceptable salts.

[0111] In another embodiment, controlled M W Multiple copolymers having a narrow polydispersity index (PDI) can be synthesized by RAFT polymerization. In one embodiment, pharmaceutically acceptable salts of polyguanidinyl copolymers have an average molecular weight (M) of about 1 kDa to about 100 kDa. w ) may have or be approximately 1kDa, 2kDa, 3kDa, 4kDa, 5kDa, 10kDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, 60kDa, 65kDa, 70kDa, 75kDa, 80kDa, 85kDa, 90kDa, 95kDa, or 100kDa, and any value may be the lower and upper endpoints of the range (e.g., 10kDa to 25kDa).

[0112] In another embodiment, a pharmaceutically acceptable salt of a polyguanidinyl copolymer is a multimodal polyguanidinyl copolymer. The term "multimodal polyguanidinyl copolymer" refers to a polyguanidinyl copolymer having a molecular weight distribution curve that is the sum of at least two or more unimodal molecular weight distribution curves. In one embodiment, the polyguanidinyl copolymer has a multimodal distribution of molecular weight, with modes ranging from 5 kDa to 100 kDa, or approximately 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, or 100 kDa, where any value may be the lower and upper limits of the range (e.g., 10 kDa to 30 kDa).

[0113] In another embodiment, the number of guanidinyl side groups in the pharmaceutically acceptable salt of the polyguanidinyl copolymer may vary from about 10 mol% to about 100 mol% of the total polymer side chains, and may be about 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, 60 mol%, 65 mol%, 70 mol%, 75 mol%, 80 mol%, 85 mol%, 90 mol%, 95 mol%, or 100 mol%, with any value being the lower and upper limits of the range (e.g., 60 mol% to 90 mol%). In one embodiment, the guanidinyl side groups constitute about 70 mol% to about 80 mol% of the polyguanidinyl copolymer. Conversely, the concentration of the comonomer may vary from approximately 50 mol% to approximately 0 mol%, and may be approximately 50 mol%, 45 mol%, 40 mol%, 35 mol%, 30 mol%, 25 mol%, 20 mol%, 15 mol%, 10 mol%, 5 mol%, or 0 mol%, and any value may be the lower and upper limits of the range (for example, 10 to 40 mol%). In one embodiment, the M of the copolymer n PDI and structure are determined by size exclusion chromatography (SEC). 1 1H NMR, 13This can be verified by 13C NMR or other common techniques.

[0114] In one embodiment, the polyguanidinyl polymer is present in an amount of about 0.5% to about 15% by weight of the hydrogel. In another embodiment, the polyguanidinyl polymer is present in an amount of 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, or 15.0% by weight of the hydrogel, where any value may be the lower and upper limits of the range (e.g., 3.0% to 8.0%).

[0115] Polyanionic polymer electrolytes Polyanionic polymer electrolytes are compounds having multiple anionic groups or groups that can be readily converted to anionic groups. In one embodiment, a polyanionic polymer electrolyte is a polymer having multiple anionic groups and a pharmaceutically acceptable cationic counterion. In another embodiment, a polyanion has only anionic charged groups, i.e., no cationic groups. In one embodiment, when the pH is greater than 4.5, a polyanionic polymer electrolyte has about 10 mol% to about 90 mol% anionicity (i.e., ionized side chains), or about 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, or 90 mol%, where any value may be the lower and upper limits of the range (e.g., 30 mol% to 70 mol%).

[0116] In one embodiment, the polyanionic polymer electrolyte has a molecular weight of approximately 20 kDa to approximately 10,000 kDa, or 10 kDa, 50 kDa, 100 kDa, 500 kDa, 1,000 kDa, 2,000 kDa, 3,000 kDa, 4,000 kDa, 5,000 kDa, 6,000 kDa, 7,000 kDa, 8,000 kDa, 9,000 kDa, or 10,000 kDa, with any value being the lower and upper limits of the range (e.g., 500 kDa to 6,000 kDa). In another embodiment, the polyanionic polymer electrolyte comprises multiple molecular weight polymers to form a multimodal molecular weight distribution.

[0117] In one embodiment, a polyanionic polymer electrolyte is obtained by dissolving a polyanionic salt in water. In one embodiment, the polyanionic salt described herein can be produced by adjusting the pH of a solution of a compound having multiple acidic groups (e.g., carboxylic acid groups) by adding a base to generate the corresponding anionic groups. In various embodiments, the bases used to form pharmaceutically acceptable polyanionic salts include alkali metal hydroxides, carbonates, acetates, and the like. In one embodiment, once the polyanion is prepared, excess ions can be removed from the polyanion by filtration or dialysis before drying (e.g., freeze-drying) to produce a polyanionic salt having a stoichiometric amount of cationic counterions relative to the number of anionic groups.

[0118] In one embodiment, the cationic counterion of a polyanionic polymer electrolyte is a monovalent cation, such as a sodium ion, potassium ion, or ammonium ion. In another embodiment, the counterion of a polyanionic salt is a polyvalent ion, such as a calcium ion, magnesium ion, or a mixture thereof.

[0119] In one embodiment, a polyanionic salt comprises a polymer backbone having multiple anionic groups and pharmaceutically acceptable cationic counterions. The anionic groups may pendant from and / or be incorporated into the polymer backbone. In certain embodiments (e.g., biomedical applications), the polyanionic polymer electrolyte is any biocompatible polymer having anionic groups.

[0120] In one embodiment, the polyanionic polymer electrolyte may be a synthetic polymer or a pharmaceutically acceptable salt of a naturally occurring polymer. Examples of naturally occurring polyanions include glycosaminoglycans such as chondroitin sulfate, heparin, heparin sulfate, dermatan sulfate, keratin sulfate, and hyaluronic acid. In another embodiment, proteins with a net negative charge at neutral pH, or proteins with a low pI, can be used as naturally occurring polyanions as described herein. The anionic group may be pendanted from and / or incorporated into the polymer backbone.

[0121] When a polyanionic polymer electrolyte is a synthetic polymer, it is generally any polymer having an anionic group or a group that can be ionized into an anionic group. Examples of groups that can be converted into anionic groups include, but are not limited to, carboxylic acids, sulfonic acids, boronic acids, sulfuric acids, boric acids, phosphonic acids, or phosphoric acids.

[0122] In one embodiment, the polyanionic polymer electrolyte comprises a polyacrylate having one or more pendant phosphate groups. For example, the polyanionic salt can be derived by polymerization of acrylate monomers, including (but not limited to) acrylates, methacrylates, acrylamides, and methacrylamides. In another embodiment, the polyanionic salt is a block copolymer, and segments or portions of the copolymer have anionic and neutral groups, depending on the selection of monomers used to produce the copolymer. In one embodiment, the anionic groups may be a plurality of carboxylic acid groups, sulfate groups, sulfonic acid groups, boric acid groups, boronic acid groups, phosphonic acid groups, or phosphate groups. In one embodiment, the polyanionic polymer electrolyte is a polymer having multiple fragments of formula XI. [ka] In the formula, R 4 is hydrogen or alkyl group, n is between 1 and 10. Y is oxygen, sulfur, or NR 30 And here, R 30 is hydrogen, alkyl group, or aryl group, Z' is a pharmaceutically acceptable salt of the anionic group.

[0123] In one embodiment, Z' in formula XI is a carboxylate, sulfate, sulfonate, borate, boronate, substituted or unsubstituted phosphate, or phosphonate. In another embodiment, Z' in formula XI is a sulfate, sulfonate, borate, boronate, substituted or unsubstituted phosphate, or phosphonate, and n in formula XI is 2.

[0124] In one embodiment, the polyanionic polymer electrolyte is a copolymer or homopolymer of acrylic acid. In one embodiment, the copolymer or homopolymer of acrylic acid has a molecular weight of about 100 kDa to about 5000 kDa, or about 100 kDa, 1000 kDa, 1500 kDa, 2000 kDa, 2500 kDa, 3000 kDa, 3500 kDa, 4000 kDa, 4500 kDa, or 5000 kDa, and any value may be the lower and upper limits of the range (e.g., 500 kDa to 3500 kDa).

[0125] In one embodiment, the polyanionic polymer electrolyte comprises a polyanionic polysaccharide. In one embodiment, the polyanionic polysaccharide comprises negatively charged xanthan gum, hyaluronic acid, gellan gum, alginic acid, carrageenan, or any combination thereof.

[0126] In one embodiment, the polyanionic polymer electrolyte is xanthan gum (xanthan) (CAS number: 11138-66-2), which consists of a cellulose backbone and mannose and glucuronic acid side chains. The xanthan side chains interact with water to impart thickening and gelling properties to xanthan in aqueous solutions. The anionic properties mainly arise from the glucuronic acid groups of the side chains, which contain carboxyl groups that ionize in water to produce negatively charged carboxylate groups. The second negative charge arises from the pyruvate group bonded to the terminal mannose of the side chain, which also contains carboxyl groups that ionize in water. The pyruvate content varies depending on the synthesis of xanthan, but a higher pyruvate content results in a higher concentration of negative charge per mole of xanthan, making it suitable for the formation of PE hydrogels. Typically, about half of the side chains contain pyruvate groups, but the pyruvate content can be changed through modifications during or after production. In one embodiment, xanthan gum has a pyruvate content of more than 1.5 weight percent. In another embodiment, xanthan gum has a pyruvate content of less than 8.5 weight percent, or less than 1.5 weight percent, 2.5 weight percent, 3.5 weight percent, 4.5 weight percent, 5.5 weight percent, or 8.5 weight percent, where any value may be the lower and upper limits of the range (e.g., 1.5 weight percent to 5.25 weight percent). Since xanthan gum is produced by fermentation of Gram-negative bacteria, it is necessary to remove endotoxins to less than 100 EU per gram before in vivo administration using a method such as that described in U.S. Patent No. 6,451,772B1. When the pH exceeds 4.5, xanthan is deprotonated and negatively charged. In one embodiment, potassium salts, calcium salts, and sodium salts of xanthan are available for use herein.

[0127] In one embodiment, xanthan gum is low-acetic acid xanthan gum. The first mannose group of the side chain typically contains an acetate group. By removing the acetate group, a xanthan gum with a higher charge density and modified flow properties due to a more flexible chain is obtained, which is useful in polymer electrolyte hydrogels.

[0128] In one embodiment, xanthan gum has a molecular weight of approximately 100 kDa to approximately 10,000 kDa, or approximately 100 kDa, 500 kDa, 1,000 kDa, 1,500 kDa, 2,000 kDa, 2,500 kDa, 3,000 kDa, 3,500 kDa, 4,000 kDa, 4,500 kDa, 5,000 kDa, 5,500 kDa, 6,000 kDa, 6,500 kDa, 7,000 kDa, 7,500 kDa, 8,000 kDa, 8,500 kDa, 9,000 kDa, 9,500 kDa, or 10,000 kDa, with any value being the lower and upper limits of the range (for example, 500 kDa to 7,500 kDa).

[0129] In one embodiment, the xanthan gum is present in an amount of about 1.0 to 15 weight percent of the hydrogel. In another embodiment, the xanthan gum is present in an amount of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, or 15.0 weight percent of the hydrogel, where any value may be the lower and upper limits of the range (e.g., 3.0 to 8.0 weight percent).

[0130] In another embodiment, the polyanionic polymer electrolyte is the linear polysaccharide hyaluronic acid. Hyaluronic acid is composed of monomers of glucuronic acid and N-acetylglucosamine and is available in powder form as sodium hyaluronate, with a molecular weight ranging from less than 50,000 Da to greater than 1,000,000 Da. Molecular weights within this range can be used to achieve the desired properties of the gel. When combined with a suitable polycation, hyaluronic acid with a higher molecular weight forms a stronger PE hydrogel than hyaluronic acid with a lower molecular weight. The charge density of hyaluronic acid at physiological pH is higher than that of xanthan gum, and various molecular weights can be used to produce PE hydrogels that are deliverable by a suitable catheter and are stable under physiological conditions. In one embodiment, a combination of high molecular weight linear hyaluronic acid and medium or low molecular weight xanthan gum can produce a PE hydrogel with a high modulus of elasticity at a low shear rate and improved deliverability compared to using only one type of anionic polysaccharide. In one embodiment, hyaluronic acid has a molecular weight of approximately 100 kDa to approximately 5000 kDa, or approximately 100 kDa, 1000 kDa, 1500 kDa, 2000 kDa, 2500 kDa, 3000 kDa, 3500 kDa, 4000 kDa, 4500 kDa, or 5000 kDa, and any value may be the lower and upper limits of the range (for example, 500 kDa to 3500 kDa).

[0131] In another embodiment, the polyanionic polymer electrolyte is gellan gum (CAS number: 71010-52-1). Gellan gum is composed of repeating units of glucose, rhamnose, and glucuronic acid. Similar to xanthan gum and hyaluronic acid, gellan gum contains carboxyl groups in the glucuronic acid units that are negatively charged at physiological pH. There are two main types of gellan gum: high-acyl gellan gum and low-acyl gellan gum. The type indicates the degree of acetylation, which affects the physical properties. High-acyl gellan gum generally forms a more flexible and elastic structure, while low-acyl gellan gum can form a harder and more brittle gel. Gellan gum has a higher modulus of elasticity than xanthan gum and can be used as a single polyanionic polymer electrolyte. It can also be used in combination with xanthan gum to increase the modulus of elasticity in PE hydrogels, as well as to maintain the delivery properties of PE hydrogels using only xanthan gum as the polyanion.

[0132] In another embodiment, polyanionic polyelectrolytes are derived from carrageenan systems consisting of kappa, iota, and lambda types. The negative charge of these molecules derives from the presence of sulfate groups on repeating galactose units that, along with 3,6-anhydrogalactose, form the backbone of the individual molecules. Lambda carrageenan has the lowest degree of sulfate and does not form a true gel on its own. Both kappa (K) and iota (I) have high degrees of sulfate and form gels, with kappa forming the strongest gel. The charge density of carrageenans is generally higher than that of xanthan gum, but the decrease in viscosity under shear is not as pronounced, and the elastic modulus of PE hydrogels without polycationic counterionic components is higher. Similar to gellan gum, carrageenan polyanions can be used to modify the PE hydrogel properties of other polyanions, such as xanthan gum, by increasing the elastic modulus of the PE hydrogel.

[0133] In another embodiment, the polyanionic polymer electrolyte is alginic acid. Alginic acid is an anionic polysaccharide composed of linear repeating structures of guluronic acid and mannuronic acid, with carboxyl groups in both chains. Similar to xanthanum, the carboxyl groups are completely deprotonated at physiological pH. Furthermore, alginic acid exhibits a decrease in viscosity under shear, but not as much as xanthanum, making it less preferable to xanthanum for this application.

[0134] The amount of polyanionic polymer electrolyte in the hydrogel described herein may vary depending on the application of the hydrogel. In one embodiment, the amount of polyanionic polymer electrolyte used to produce the hydrogel described herein is about 1% to about 12% by weight of the hydrogel, or about 1% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, or 12% by weight, and any value may be the lower and upper limits of the range (e.g., 5% to 8% by weight).

[0135] Monovalent ions and divalent ions In one embodiment, a homogeneous PE hydrogel is produced by adding monovalent ions in the form of salts, such as sodium chloride and potassium chloride. In the absence of monovalent ions, the polyelectrolyte can aggregate to form a phase-separated solution or disintegrate into small particles. Increasing the concentration of monovalent ions increases the transparency of the gel, indicating that larger ionic bonds between polyelectrolytes are shielded. In one embodiment, if the polyanion is xanthan gum, monovalent salt counterions also increase the viscosity and modulus of the gel.

[0136] In one embodiment, divalent cations can be used in combination with polycationic polymer electrolytes. For example, calcium chloride and magnesium chloride have properties useful for the formation and use of hydrogel embolization agents. Divalent cations can form crosslinks between polyanion branches, rather than shielding larger polycations and polyanions like monovalent ions. These properties allow divalent ions to be used to reduce the concentration of larger polycations while maintaining the same charge ratio. This is useful for reducing the overall viscosity and improving the delivery of PE hydrogel embolization agents. Divalent ions can also be used to increase the charge ratio and produce positively charged embolization agents with lower viscosity than PE hydrogels with a net positive charge composed only of larger polycation molecules. Divalent ions such as calcium also help activate the coagulation cascade and are useful for the application of PE hydrogel embolization agents in the treatment of bleeding.

[0137] The selection and concentration of the polyelectrolyte affect the amount of salt counterions required to produce a homogeneous PE hydrogel. In one embodiment, the concentration of salt counterions in the hydrogel is about 0.1 M to about 2.5 M, or about 0.1 M, 0.2 M, 0.4 M, 0.6 M, 0.8 M, 1.0 M, 1.2 M, 1.4 M, 1.6 M, 1.8 M, 2.0 M, 2.2 M, 2.4 M, or 2.5 M, where any value may be the lower and upper limits of the range (e.g., 0.8 M to 1.6 M). In one embodiment, when the polyanionic polyelectrolyte is xanthanum, the molar charge concentrations of monovalent and / or divalent ions required to form a homogeneous PE hydrogel are about 0.35 M to about 2.0 M. In another embodiment, when the polyanionic polymer electrolyte is hyaluronic acid, the concentration of monovalent and / or divalent ions required to form a homogeneous PE hydrogel is approximately 0.1 M to approximately 2.5 M.

[0138] contrast agent The hydrogels described herein may contain one or more contrast agents that enable visualization of the hydrogel after administration to a subject.

[0139] In one embodiment, the contrast agent is an X-ray contrast agent. Furthermore, in this embodiment, the X-ray contrast agent may be tantalum metal particles (Ta), gold particles, or iodide salts (e.g., sodium iodide). In one embodiment, up to 30% (w / w) of Ta may be included in the formulation. In one embodiment, the inclusion of Ta is beneficial to the interventional radiologist in the operating room. In another embodiment, the contrast agent may be a fluoroscopic contrast agent. Furthermore, in this embodiment, the fluoroscopic contrast agent may be tantalum oxide (TaO2, Ta2O5) particles. In one embodiment, the contrast agent may be tantalum particles having particle sizes of 0.5 μm to 50 μm, 1 μm to 25 μm, 1 μm to 10 μm, or 1 μm to 5 μm. In another embodiment, the contrast agent is tantalum particles in amounts of 10% to 60%, 20% to 50%, or 20% to 40%.

[0140] The hydrogels described herein contain one or more transient contrast agents, which, upon administration to a subject, readily diffuse from the hydrogel and provide transient contrast.

[0141] In one embodiment, the transient contrast agent is a nonionic compound. In another embodiment, the transient contrast agent is water-soluble. In one embodiment, the transient contrast agent is an iodized organic compound in which one or more iodine atoms are covalently bonded to the organic compound. Iodized organic contrast agents are a type of iodine-containing organic compound. This series of compounds are derivatives of 2,3,5-triiodobenzoic acid for producing various commercially available compounds, such as iopamidol, iodixanol, iohexol, iopromide, iobitridol, iomeprole, iopentol, iopamilon, ioxiran, iotorol, ioversol, iopanoate, diatrizoic acid, iotalamic acid, ioxagrate, etc., in which various side chains are added to the parent compound. These side chains alter the solubility, toxicity, and osmotic pressure of the compound. Iodixanol is a dimer of the parent compound, producing a molecule with six iodine atoms. The structures of these compounds and the parent compound, 2,3,5-triiodobenzoic acid, are shown in Figure 2. In another embodiment, iodized organic compounds include, for example, iodized poppy oil ethyl ester (lipiodol).

[0142] The concentration of the transient contrast agent in the hydrogel may vary depending on the application. In one embodiment, the concentration of the transient contrast agent in the hydrogel is 10 mgI / mL to 1000 mgI / mL, or 10 mgI / mL, 25 mgI / mL, 50 mgI / mL, 75 mgI / mL, 100 mgI / mL, 125 mgI / mL, 150 mgI / mL, 175 mgI / mL, 200 mgI / mL, 225 mgI / mL, 250 mgI / mL, 275 mgI / mL, 300 mgI / mL, 325 mgI / mL, 350 mgI / mL, 375 mgI / mL, 400 mgI / mL, 425 mgI / mL, 450 mgI / mL, 475 mgI / mL, 500 mgI / mL, 525 mgI / mL, 550 mgI / mL, 575 mgI / mL, 6 The values ​​are 00 mgI / mL, 625 mgI / mL, 650 mgI / mL, 675 mgI / mL, 700 mgI / mL, 725 mgI / mL, 750 mgI / mL, 775 mgI / mL, 800 mgI / mL, 825 mgI / mL, 850 mgI / mL, 875 mgI / mL, 900 mgI / mL, 925 mgI / mL, 950 mgI / mL, 975 mgI / mL, or 1000 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, 100 mgI / mL, and any value may be the lower and upper limits of the range (for example, 400 mgI / mL to 600 mgI / mL).

[0143] In one embodiment, the majority of the transient contrast agent diffusing from the hydrogel becomes undetectable by imaging techniques such as fluoroscopy or CT. In one embodiment, once a solid is formed in situ within the body, up to 70%, 80%, 90%, 95%, or 100% of the transient contrast agent diffuses from the solid for 5 minutes to 48 hours, or for 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours, 2 days, 5 days, 10 days, 15 days, 20 days, 25 days, or 30 days, with any value being the lower limit of the range (e.g., 1 hour to 3 hours).

[0144] Polymer electrolyte hydrogel modifier The properties of the hydrogels described herein can be significantly altered by changing the charge ratio and relative amounts of the polycationic polymer electrolyte and the polyanionic polymer electrolyte, as well as the concentration of monovalent ions. However, the properties of PE hydrogels can be further altered by additional compounds.

[0145] In one embodiment, the modifier includes natural or synthetic fibers, water-insoluble filler particles, nanoparticles, or fine particles added to the hydrogel. When fibers are added to the hydrogel, the fibers may or may not be charged and may have a linear or branched morphology. The fibers reinforce the PE hydrogel and undergo deformation similar to that of polymer chains under shear, causing a more significant decrease in elastic modulus and viscosity under shear during catheter delivery. In one embodiment, the fibers include crushed and sieved thermally crosslinked gelatin foam fibers. An example of such fibers is SURGIFOAM®, manufactured by Ethicon, which is water-insoluble porcine gelatin. In one aspect, the amount of fibers present in the hydrogel is 0.1% to 5% by weight, or approximately 0.1% by weight, 0.1% by weight, 0.5% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, or 5.0% by weight, and any value may be the lower and upper limits of the range (e.g., 1.5% to 4.0% by weight).

[0146] In one embodiment, the modifier includes fibers manufactured from cross-linked gelatin. Gelatin alone does not exhibit shear reduction and has a melting point lower than body temperature but higher than room temperature, so its performance becomes unstable during delivery due to the temperature difference between the catheter outside and inside the body. However, cross-linked gelatin is stable over a wide temperature range and exhibits shear reduction behavior complementary to other components in the PE hydrogel. Furthermore, depending on the size and shape, it can provide a mechanical barrier against flow.

[0147] In one embodiment, the modifier comprises thermocrosslinked gelatin fibers or particles manufactured from type A porcine-derived gelatin having an isoelectric point of pH 6-8. The net charge is positive below the isoelectric point and negative above the isoelectric point. The charge density of gelatin is low and decreases further when crosslinked, but the net charge of the fibers or particles can be selected to optimize the interaction with other components of the polymer electrolyte hydrogel.

[0148] In one embodiment, the modifier comprises heat-crosslinked gelatin fibers or particles manufactured from type B porcine-derived gelatin having an isoelectric point of pH 4.5 to 5.5. The net charge is positive below the isoelectric point and negative above the isoelectric point. The charge density of gelatin is low and decreases further when crosslinked, but the net charge of the fibers or particles can be selected to optimize the interaction with other components of the polymer electrolyte hydrogel. For example, in a PE hydrogel containing chitosan with an excess of positive charge for negatively charged polyanions and a pH of 5.5 to 6.0, the interaction between the chitosan and the negatively charged regions of the crosslinked type B gelatin is weak.

[0149] In one embodiment, the cross-linked gelatin has, on average, a length greater than 100 μm and a width less than 25 μm. In another embodiment, the cross-linked gelatin has a maximum dimension of 100 μm to 500 μm and a minimum dimension of less than 100 μm. This provides an additional barrier against flow in small vessels less than 300 μm in diameter, but does not affect the force for injecting the PE hydrogel. In another embodiment, the cross-linked gelatin has a maximum dimension of 500 μm to 1000 μm and a minimum dimension of less than 500 μm. In another embodiment, the cross-linked gelatin has a maximum dimension of 700 μm to 1100 μm and a minimum dimension of less than 700 μm. In yet another embodiment, the cross-linked gelatin has a maximum dimension greater than 1100 μm and less than 2000 μm.

[0150] In another embodiment, the PE hydrogel modifier comprises a nonionic polysaccharide. Examples of nonionic polysaccharides include, but are not limited to, guar gum, locust bean gum, modified starch, or combinations thereof. The nonionic polysaccharide can enhance the PE hydrogel strength of the composition while maintaining a reversible viscosity reduction during catheter delivery. The molecular weight of the nonionic polysaccharide can be selected to achieve the desired properties. In one embodiment, the amount of nonionic polysaccharide present in the hydrogel is 0.1% to 5% by weight, or about 0.1% by weight, 0.1% by weight, 0.5% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, or 5.0% by weight, where any value may be the lower and upper limits of the range (e.g., 1.5% to 4.0% by weight).

[0151] In another embodiment, the PE hydrogel modifier may consist of organic and / or inorganic materials. In one embodiment, the nanostructure may consist of an organic material such as carbon, or an inorganic material, the inorganic material including, but not limited to, boron, molybdenum, tungsten, silicon, titanium, copper, bismuth, tungsten carbide, aluminum oxide, titanium dioxide, molybdenum disulfide, silicon carbide, titanium diboride, boron nitride, dysprosium oxide, iron(III) oxyhydroxide, iron oxide, manganese oxide, titanium dioxide, boron carbide, aluminum nitride, or any combination thereof. In another embodiment, the PE hydrogel modifier may include a metal oxide, ceramic particles, or a water-insoluble inorganic salt. In one aspect, the amount of organic or inorganic material present in the hydrogel is 0.1% to 5% by weight, or about 0.1% by weight, 0.1% by weight, 0.5% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, or 5.0% by weight, and any value may be the lower and upper limits of the range (e.g., 1.5% to 4.0% by weight).

[0152] In another embodiment, the PE hydrogel modifier includes, but is not limited to, bentonite, kaolinite, montmorillonite, saponite, hectorite, palygorskite, laponite, stevensite, or any combination thereof, synthetic silicate nanoparticles or natural silicate nanoparticles. In one embodiment, the amount of synthetic silicate nanoparticles or natural silicate nanoparticles present in the hydrogel is 0.1% by weight to 5% by weight, or about 0.1% by weight, 0.1% by weight, 0.5% by weight, 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, or 5.0% by weight, where any value may be the lower and upper limits of the range (e.g., 1.5% by weight to 4.0% by weight).

[0153] Bioactive agents The hydrogels described herein may contain one or more bioactive agents. In one embodiment, the bioactive agents are antibiotics, analgesics, immunomodulators, growth factors, enzyme inhibitors, hormones, messenger molecules, cell signaling molecules, receptor agonists, oncolytic viruses, chemotherapeutic agents, anti-angiogenic agents, receptor antagonists, nucleic acids, or any combination thereof.

[0154] In one embodiment, the bioactive agent may be a nucleic acid. The nucleic acid may be an oligonucleotide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) including mRNA, or peptide nucleic acid (PNA). The nucleic acid in question may be from any source, for example, nucleic acid obtained from naturally occurring cells, nucleic acid produced by recombinant DNA, chemically synthesized nucleic acid, or chemically modified nucleic acid. For example, the nucleic acid may be cDNA, genomic DNA, or DNA synthesized to have a nucleotide sequence corresponding to the nucleotide sequence of naturally occurring DNA. The nucleic acid may also be a mutant or modified form of nucleic acid (for example, DNA that differs from naturally occurring DNA due to modification, deletion, substitution, or addition of at least one nucleic acid residue), or a nucleic acid that does not exist in nature.

[0155] In one embodiment, a bioactive agent is an anti-angiogenic agent approved by the FDA. In one embodiment, an anti-angiogenic agent is a tyrosine kinase inhibitor (TKI). While we do not wish to be bound by theory, angiogenesis is initiated and maintained primarily by cellular signaling mediated by receptor tyrosine kinases (RTKs). In one embodiment, RTKs include receptors for several pro-angiogenic agents, including VEGF, which stimulates vascular permeability, proliferation, and migration of vascular endothelial cells; PDGF, which recruits pericytes and smooth muscle cells to support budding endothelial cells; and FGF, which stimulates the proliferation of vascular endothelial cells, smooth muscle cells, and fibroblasts. In one embodiment, an anti-angiogenic agent is a TKI such as sunitinib malate (SUN), pazopanib hydrochloride (PAZ), sorafenib tosylate (SOR), vandetanib (VAN), cabozantinib, or any combination thereof.

[0156] In another embodiment, the bioactive agent may be humanized anti-VEGF and anti-VEGFR Fab' fragments. In this embodiment, electrostatic interactions can control the release motion. In one embodiment, the intrinsic charge of the Fab' fragment is sufficient to interact with the polymer electrolyte component in the injectable composition. In another embodiment, the intrinsic charge of the Fab' fragment is insufficient to interact with the polymer electrolyte component in the injectable composition, and the Fab' fragment is modified to increase the charge density by attaching short polymer electrolytes to the reactive sulfidyl groups using maleimide conjugation chemistry.

[0157] In one embodiment, the anti-angiogenic agent is an anti-VEGF antibody. In another embodiment, the anti-VEGF antibody is bevacizumab, a biosimilar anti-VEGF antibody, or an anti-VEGF antibody derivative such as ranibizumab.

[0158] The release rate can be controlled by the selection of materials used to prepare the hydrogel, and if the bioactive agent has ionizable groups, it can also be controlled by the charge of the bioactive agent. Thus, in this embodiment, the hydrogel can function as a locally controlled drug release depot when administered to a subject.

[0159] Preparation of polymer electrolyte hydrogels The preparation of PE hydrogels described herein can be carried out using several techniques and procedures. Exemplary techniques for generating hydrogels are provided in the examples. In one embodiment, an aqueous solution containing a polyanionic polymer electrolyte is added to an aqueous solution containing a polyanionic polymer electrolyte and monovalent ions, and the mixture is mixed with sufficient intensity for a sufficient time to produce a homogeneous gel. The intensity and duration of the mixing depend on the selection and amount of components used to produce the hydrogel.

[0160] When additional components (e.g., contrast agents, PE hydrogel modifiers, bioactive agents) are incorporated into the hydrogel, in one embodiment, these components are added before and / or during the mixing of polycationic and polyanionic polymer electrolytes with monovalent ions. In other embodiments, these components may be added to the hydrogel after it has been formed.

[0161] In one embodiment, the pH of the hydrogel is 4.5–6, 6–9, 6.5–8.5, 7–8, or 7–7.5. In another embodiment, the pH of the composition is 7.4, which is the normal physiological pH of blood.

[0162] Applications of polymer electrolyte hydrogels The polymer electrolyte hydrogels described herein have many advantages and biomedical applications. As described above, the hydrogels can be easily injected through small-diameter devices, catheters, needles, cannulas, or tubes. Because the hydrogels are aqueous, they eliminate the need for potentially toxic solvents.

[0163] The ability to modify or fine-tune the properties of the PE hydrogels described herein makes them suitable for occluding blood vessels of a wide range of diameters and sizes. In one embodiment, the polymer electrolyte PE hydrogel is suitable for occluding flow in blood vessels with a minimum inner diameter greater than 500 μm (e.g., 500 μm to 1000 μm). In another embodiment, if the inner diameter of the distal tip portion of a tapered blood vessel is less than 1000 μm, the PE hydrogel can be filled from distal to proximal in a tapered blood vessel with an inner diameter greater than 1000 μm and less than 3000 μm to occlude the flow in the proximal vessel. In another embodiment, the hydrogel is suitable for occluding flow in blood vessels with an inner diameter of approximately 30 μm to approximately 100 μm. In another embodiment, the hydrogel is suitable for occluding flow in blood vessels with an inner diameter of 100 μm to 300 μm. In another embodiment, the hydrogel is suitable for occluding flow in blood vessels with an inner diameter of approximately 300 μm to 700 μm. In yet another embodiment, the hydrogel is suitable for occluding flow in blood vessels with an inner diameter of 700 μm to 2000 μm.

[0164] In practice, the embolizing agent is selected based on the size of the catheter to which it can be delivered and the inner diameter of the blood vessel to be occluded. When using the PE hydrogels described herein, the same approach can be used by preparing a hydrogel with an appropriate low shear viscosity and modulus G' for occluding blood vessels of a certain size, combined with the acceptable injection force level by the desired catheter. The following table provides non-limiting and exemplary parameters of hydrogels for use with desired catheter sizes and blood vessel inner diameters. The values ​​provided in the table are based on the maximum acceptable injection force for a given catheter size, not exceeding the minimum published burst pressure of a commercially available catheter. The injection force can be reduced by reducing the polyelectrolyte concentration, altering the charge ratio to favor lower viscosity polyelectrolyte components, reducing the molar concentration of salt counterions, and including an appropriate amount of fiber in addition to or instead of viscous polymers. The injection force decreases as the size of the blood vessel decreases, particularly at the arteriole level, starting at about 300 μm. Therefore, a lower modulus is required to effectively occlude blood vessels in that range, and the embolizing agent should be able to reliably fill the space while maintaining cohesiveness and non-water solubility. To effectively occlude larger blood vessels, the charge ratio and concentration of the polymer electrolyte can be adjusted to achieve higher cohesive force and higher elastic modulus. Furthermore, by balancing the size, shape, and concentration of nonionic modifiers, cross-linked gelatin, or other fibers, coagulation promotion, and endothelial cell adhesion, the desired level of occlusion can be achieved. [Table 1] *When delivering with less than half the dead volume of the delivery catheter and pushing it in with a low-viscosity fluid such as 0.9% physiological saline.

[0165] In one embodiment, the PE hydrogel described herein forms right-handed or left-handed coils during delivery by a catheter, needle, or other delivery device. The PE hydrogel can maintain the shape of the delivery catheter under physiological conditions, which offers several advantages when using PE hydrogel as an embolizing agent. The catheter can be selected to create the desired gel coil diameter. Furthermore, depending on the size of the catheter, flow conditions, vascular tapering, and the amount of material delivered, a wide range of vascular sizes can be occluded. The greater the amount of material delivered to the vascular, the denser the coiled mass formed, and the larger the vascular, the more occludable it is.

[0166] Another advantage of coil formation is that the shape of the catheter tip can be designed to deliver or influence the behavior of materials of a specific shape or size. For example, an angled catheter tip increases the cross-sectional area of ​​delivery, introducing the material into the vascular wall and initiating the wrapping process. A catheter tip design that splits the lumen divides the embolic agent into two coil streams, which are delivered simultaneously. Thus, a wide range of custom behaviors can be achieved through the combination of PE hydrogel properties and catheter design.

[0167] In another embodiment, the PE hydrogel initially maintains the shape of the catheter while being delivered into the blood vessel, but subsequently forms an amorphous mass of PE hydrogel material that conforms to the anatomical structure of the blood vessel.

[0168] In one embodiment, the PE hydrogel described herein can be delivered in small quantities by first introducing a desired amount (e.g., 0.10 mL) from a syringe into a delivery device, and then pushing a small amount of PE hydrogel through a catheter or needle together with a second fluid.

[0169] A unique aspect of the PE hydrogel described herein is that, after exposure to a physiological medium, the cohesive force of the hydrogel is enhanced, allowing a small amount of PE hydrogel to be delivered to the target embolization site by being inflated via a catheter along with one of the liquids described below, without diluting or weakening the hydrogel portion in contact with the liquid. This approach has several advantages.

[0170] (1) The force during delivery is reduced, and PE hydrogel prejet can be pushed in with catheters with an inner diameter of less than 0.20 inches and a maximum length of 220 cm. This means that PE hydrogel is not limited to applications including use in prostatic artery embolization, genitourinary artery embolization, or neurological applications where long catheters with small inner diameters are often used.

[0171] (2) The catheter lumen remains empty after injection without any residue of PE hydrogel, allowing the catheter to be used for additional contrast agents for imaging. Furthermore, by saving catheters, the cost of complex procedures requiring multiple injections can be reduced. Existing tantalum-containing liquid or hydrogel embolizers can be diluted and lose strength, coagulate and block the catheter, or leave residue of coagulated material inside the catheter, which carries the risk of extratarget embolization if the catheter is used continuously.

[0172] (3) PE hydrogels function as coils, predettes, or plugs. The PE hydrogels emerge from the catheter in a coiled form but self-compress to achieve nearly 100% filling density, similar to plugs or predettes. In contrast to conventional predettes made from cross-linked gelatin or similar materials, these PE hydrogels can be filled with tantalum or other contrast agents to enhance visibility. They are permanent, more coil-like than gelatin predettes, and do not have difficulty achieving the desired filling density, exhibiting nearly immediate occlusion without relying on coagulation.

[0173] (4) By increasing the concentration of the polymer electrolyte component and reinforcing the PE hydrogel along the contact area with the aqueous extrusion medium, larger blood vessels can be blocked.

[0174] In one embodiment, first, a polymer electrolyte hydrogel is introduced into the target by a delivery system, and subsequently, a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof is introduced into the target by a syringe connected to the delivery system. This embodiment is shown in Figures 27A to 27F. As shown in Figures 27A to 27B, the delivery system 1 includes a housing 2 having a first end 3 and a second end 4, an internal chamber 5 containing the polymer electrolyte hydrogel within the housing, a male Luer connector 6 at the first end of the housing, and a female Luer connector 7 at the second end of the housing. In one embodiment, a needle or catheter 8 is attached to the male Luer connector 6.

[0175] In one embodiment, the female Luer connector 7 can receive a syringe 9 (Figure 27E) containing a liquid to be injected together with a polymer electrolyte hydrogel. When the liquid from the syringe 9 is injected into the delivery system 1 containing the polymer electrolyte hydrogel, the polymer electrolyte hydrogel is extruded through a catheter or needle 8 (Figure 27E) and administered to the subject.

[0176] In one embodiment, the liquid injected with the polymer electrolyte hydrogel is a low-viscosity liquid. Examples of low-viscosity liquids include, but are not limited to, physiological saline (e.g., less than 2%), nonionic iodinated contrast agents in water, glucose (5% or D5W), or distilled water for injection. For example, when delivering a small amount (e.g., 0.020 mL to 0.40 mL) of hydrogel with 0.9% physiological saline or aqueous contrast agent, the elastic modulus can be improved by the diffusion of salt into the extrusion medium. The PE hydrogel maintains high cohesiveness without being diluted at the proximal end in contact with the extrusion medium. The extrusion medium can extrude the proximal end of the PE hydrogel during delivery, thereby promoting ion diffusion along the longer length of the PE hydrogel, stretching the hydrogel before delivery, and strengthening the electrostatic coupling as shielding by salt counterions is reduced, thus strengthening the PE hydrogel.

[0177] In another embodiment, a small amount of PE hydrogel is delivered together with a hydrophobic liquid, such as ethodized oil (lipiodol), silicone, plant-derived oil (e.g., sesame oil), or other suitable biocompatible hydrophobic liquid.

[0178] In one embodiment, PE hydrogel can be used to reduce or inhibit blood flow in a target vascular. In one embodiment, the vascular is a blood vessel or tube (e.g., a lymphatic vessel). In one embodiment, PE hydrogel can be used to reduce or inhibit flow from a lymphatic vessel. In one embodiment, PE hydrogel can be used to reduce or inhibit lymphatic flow from the right lymphatic vessel, the thoracic duct, or both. In these embodiments, the hydrogel forms an artificial embolism within the vascular vessel or tube. Therefore, the PE hydrogel described herein can be used as a synthetic embolizer. In this embodiment, the hydrogel is injected intravascularly to partially or completely occlude the blood vessel. This method has many applications, including the formation of artificial embolizations to obstruct blood flow in tumors, aneurysms, endoleaks, varicose veins, spermatic cord aneurysms, gonadal veins, portal veins, vascular malformations, geniculate arteries, uterine fibroids, ovarian veins, pelvic veins, gastrointestinal arteries, rectal arteries, mesenteric arteries, gastroduodenal arteries, hepatic arteries, splenic arteries, iliac arteries, prostatic arteries, hemorrhoids, middle meningeal arteries, hemorrhagic wounds, or other vascular trauma or defects. In another embodiment, the injectable composition can be administered to other areas of target, including lymphatic vessels, airways, and other channels where occlusion is desired in medical applications. In yet another embodiment, the hydrogel described herein can be used to treat pain in musculoskeletal areas, such as joints. In one embodiment, the hydrogel can temporarily reduce or prevent blood flow within a joint, such as the elbow, knee, or shoulder, where pain is occurring.

[0179] As described above, PE hydrogels can be used as synthetic embolizers. However, in other embodiments, the hydrogels described herein may include or be used in combination with one or more additional embolizers. In one embodiment, the additional embolizers include coils, plugs, liquid embolizers, or gelatin foams. Commercially available embolizers are microparticles used in vascular embolization. The size and shape of the microparticles may vary. In one embodiment, the microparticles may be composed of polymer materials. An example of microparticles is Bearin® nsPVA particles manufactured by Merit Medical Systems, Inc., which are composed of polyvinyl alcohol with a size of 45 μm to 1180 μm. In another embodiment, the embolizer may be microspheres composed of polymer materials. Examples of such embolizing agents include Embosphere® microspheres manufactured from trisacrylic crosslinked gelatin with a size of 40 μm to 1200 μm, HepaSphere® microspheres (spherical hydrophilic microspheres manufactured from vinyl acetate and methyl acrylate) with a size of 30 μm to 200 μm, and QuadraSphere® microspheres (spherical hydrophilic microspheres manufactured from vinyl acetate and methyl acrylate) with a size of 30 μm to 200 μm, all of which are manufactured by Merit Medical Systems, Inc. In another embodiment, the microspheres can be impregnated with one or more metals that can be used as contrast agents. An example of this is EmboGold® microspheres manufactured by Merit Medical Systems, Inc., manufactured from crosslinked trisacrylic gelatin impregnated with 2% elemental gold with a size of 40 μm to 1200 μm.

[0180] In another embodiment, the hydrogels described herein can be used to treat bleeding. In one embodiment, the bleeding is a result of trauma. In one embodiment, the bleeding is treated intravascularly. In one embodiment, the hydrogel is administered at the site of bleeding. Furthermore, the effect of bleeding treatment can be adjusted by changing the charge ratio of the polyelectrolyte, the concentrations of monovalent and / or divalent ions, the selection of the polyelectrolyte, and the inclusion of additional components.

[0181] In another embodiment, the hydrogels described herein can be used in combination with one or more mechanical vascular devices, such as embolic coils or fibers. In one embodiment, first, a mechanical embolic agent is administered to the target vascular using techniques well known in the art, and then the hydrogel is administered to the vascular in or near the mechanical device.

[0182] In one embodiment, a hydrogel can be used to reinforce the inner wall of a target blood vessel. The hydrogel can be introduced into the blood vessel in an amount sufficient to cover the inner wall of the vessel so that the vessel is not completely blocked. For example, a hydrogel can be injected into a blood vessel containing an aneurysm. Here, the hydrogel can reduce or prevent the rupture of the aneurysm.

[0183] In one embodiment, the hydrogel can be used to close or seal the puncture site of a target blood vessel. In one embodiment, the hydrogel can be injected into the blood vessel in an amount sufficient to close or seal the puncture site from within the vessel, so as not to occlude the vessel. In another embodiment, the hydrogel can be applied to the puncture site on the outer surface of the vessel to seal the puncture site.

[0184] In another embodiment, the hydrogels described herein can be used to fill cavities in a subject. In certain circumstances, it is desirable to fill cavities in a subject to prevent or avoid significant health risks. Cavities may be closed or open spaces in a subject formed by the bone, muscle, skin, cartilage, tissue, or a combination thereof. In one embodiment, the hydrogel can be delivered into the cavity using a catheter or needle. In one embodiment, the cavity may be completely filled with the hydrogel. In another embodiment, the cavity may be partially (i.e., less than 100%) filled with the hydrogel.

[0185] In one embodiment, the cavity is located in the left atrial appendage (LAA). The left atrial appendage (LAA) is a small sac located in the upper left (left atrium) of the heart. The LAA may promote blood clot formation and increase the risk of stroke in patients with atrial fibrillation (approximately 6 million people). These patients can be treated with medication, surgery, or surgical intervention.

[0186] Two common LAA closure devices are the Watchman (Boston Scientific) and the Amplatzer Amulet (Abbott). Both use a transseptal approach that allows the passage of a large 12Fr-14Fr catheter to deliver a closure device that punctures the septum between the right and left atria and fixes to the LAA opening to seal the opening.

[0187] The hydrogel described herein can be delivered via catheter or needle without the need to puncture the atrial septum. The hydrogel is delivered from the left ventricle to the left atrium by catheter (Figure 16) and can fill and close the left atrial appendage. The hydrogel fills the available space within the LAA and is strengthened over several minutes. As it strengthens, the material is held three-dimensionally in place by the ridges of the LAA topography.

[0188] In another embodiment, the hydrogel described herein can fill cavities within lymph nodes in addition to reducing or inhibiting lymphatic flow from the right lymphatic vessel, the thoracic duct, or both. Here, the hydrogel can be delivered into the lymph to reduce or prevent lymphatic flow into the lymphatic vessel.

[0189] In other embodiments, the hydrogels described herein can encapsulate, support, seal, or retain one or more bioactive agents. Thus, the hydrogels can be used as delivery devices or implantable drug depots.

[0190] kit This specification describes a kit for the manufacture and use of hydrogels. In one embodiment, the kit includes (a) a first syringe containing the polymer electrolyte hydrogel described herein, and (b) instructions for administering the hydrogel to a target.

[0191] In one embodiment, the hydrogel may be prepared using the technique described above and then introduced into the first syringe. In one embodiment, the hydrogel may contain optional components such as the contrast agent, PE hydrogel modifier, and bioactive agent described herein. In another embodiment, the kit may contain a second syringe containing optional components such as the contrast agent, PE hydrogel modifier, and bioactive agent. In this embodiment, the optional components may be prepared as water or saline before being introduced into the second syringe. In one embodiment, the second syringe is attached to the first syringe by a female-to-female Luer adapter. The contents of the second syringe are then introduced into the first syringe along with the hydrogel. After the contents of the second syringe have been introduced into the first syringe, the hydrogel is administered to the subject via the first syringe.

[0192] The kit also includes instructions for administering the hydrogel. As used herein, “Instructions” means documents describing the materials or methods related to the kit. These materials may include any combination of background information, a list of ingredients and their availability information (such as purchasing information), a concise or detailed protocol for using the kit, troubleshooting, reference materials, technical support, and other relevant documents. The Instructions may be provided with the kit or as a separate component, either in paper form, electronically (provided from a computer-readable storage device or downloaded from a website on the Internet), or as a recorded presentation. The Instructions may include one or more documents, including future updates.

[0193] The kit may also include additional components as described herein, including optional mechanical components such as additional syringes, microcatheters, injector tips, and other devices for delivering the hydrogel described herein to the target.

[0194] In one configuration, the kit is A delivery system containing a polymer electrolyte hydrogel as described herein, Polymer electrolyte hydrogels, Includes instructions for administering polymer electrolyte hydrogels.

[0195] In this embodiment, the polymer electrolyte hydrogel is stored within the delivery system. As shown in Figure 27F, the delivery system 1 may have caps 10, 11 at each end of the delivery system. When ready for use, each cap can be removed in sequence to attach a catheter or needle and syringe to the delivery device.

[0196] In another manner, the kit is A delivery system for delivering the polymer electrolyte hydrogel described herein, Polymer electrolyte hydrogels, Includes instructions for administering polymer electrolyte hydrogels.

[0197] In this embodiment, the polymer electrolyte hydrogel is stored outside the delivery system. For example, the polymer electrolyte hydrogel can be stored in a vial in a dry or aqueous form. When ready for use, the polymer electrolyte hydrogel can be introduced into the delivery system.

[0198] In one embodiment, the kit may include a syringe containing a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof. Alternatively, the kit may include an empty syringe and a vial containing a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof. In one embodiment, if a low-viscosity liquid is used, the liquid may include additional components such as lidocaine, nitroglycerin, or verapamil.

[0199] Having described the aspects of this disclosure in general terms, the following embodiments illustrate some additional aspects of this disclosure. While the aspects of this disclosure are described in relation to the following embodiments, corresponding texts, and figures, the embodiments of this disclosure are not intended to be limited to this description. Conversely, all alternative examples, modifications, and equivalents that fall within the spirit and scope of this disclosure are intended to be covered. manner Appearance 1 A method for reducing or inhibiting flow within a target blood vessel, comprising the step of introducing a viscoelastic polymer electrolyte hydrogel containing a polycationic polymer electrolyte, a polyanionic polymer electrolyte, and monovalent and / or divalent ions into the blood vessel, Before administering the polymer electrolyte hydrogel to the subject, the polymer electrolyte hydrogel has an initial elastic modulus greater than its viscosity. The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear when administered to the subject. A method wherein the recovery modulus of the polymer electrolyte hydrogel under physiological conditions is at least 80% of the initial modulus of the polymer electrolyte hydrogel. Appearance 2 The polyanionic polymer electrolyte has 10 mol% to 90 mol% ionized side chains when the pH exceeds 4.5, according to the method of embodiment 1. Appearance 3 The method according to embodiment 1, wherein the polyanionic polymer electrolyte comprises only anionic charged groups. Pattern 4 The method according to embodiment 1, wherein the polycationic polymer electrolyte has 10 mol% to 90 mol% of ionized side chains when the pH exceeds 4.5. Appearance 5 The method according to embodiment 1, wherein the polycationic polymer electrolyte comprises only cationic charged groups. Appearance 6 The method according to embodiment 1, wherein when the pH is approximately 6 to approximately 8, the charge ratio of the polycationic polymer electrolyte to the polyanionic polymer electrolyte is 6:1 to 1:6. Appearance 7 The method according to embodiment 1, wherein the initial modulus of elasticity is 200 Pa or more. Appearance 8 The method according to embodiment 1, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel are reduced under shear so that the injection force through the catheter is less than 20 lbf. Appearance 9 The method according to embodiment 1, wherein the molecular weight of the polyanionic polymer electrolyte is approximately 20 kDa to approximately 10,000 kDa. Appearance 10 The method according to embodiment 1, wherein the polyanionic polymer electrolyte comprises a plurality of molecular weight polymers to form a multimodal molecular weight distribution. Appearance 11 The method according to embodiment 1, wherein the polyanionic polymer electrolyte is linear or branched. Appearance 12 The method according to embodiment 1, wherein the monovalent ions are sodium ions and chloride ions having concentrations of about 0.10 M to about 2.5 M. Appearance 13 The method according to any one of embodiments 1 to 12, wherein the polymer electrolyte hydrogel forms a right-handed or left-handed coil during delivery by a catheter, needle, or other delivery device. Appearance 14 The method according to any one of embodiments 1 to 13, for reducing or inhibiting blood flow to a tumor, aneurysm, lower extremity varicose veins, vascular malformation, geniculate artery, uterine fibroid, prostatic artery, hemorrhoid, middle meningeal artery, or hemorrhagic wound. Appearance 15 The method according to any one of embodiments 1 to 13, for strengthening the inner wall of the target blood vessel. Appearance 16 The method according to any one of embodiments 1 to 15, wherein the polymer electrolyte hydrogel further comprises a bioactive agent released from the polymer electrolyte hydrogel after the polymer electrolyte hydrogel has been administered to the subject. Appearance 17 The polyanionic polymer electrolyte is the method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises a polyanionic polysaccharide. Appearance 18 The method according to embodiment 17, wherein the polyanionic polysaccharide comprises xanthan gum, hyaluronic acid, gellan gum, alginic acid, carrageenan, or any combination thereof. Appearance 19 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises two or more carboxylic acid groups, sulfate groups, sulfonic acid groups, boric acid groups, boronic acid groups, phosphonic acid groups, or phosphate groups. Appearance 20 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises a negatively charged glycosaminoglycan or an acidic protein. Appearance 21 The method according to embodiment 20, wherein the negatively charged glycosaminoglycan comprises chondroitin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid. Appearance 22 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte contains a negatively charged protein having a net negative charge at pH 6 or higher. Appearance 23 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises a negatively charged polymer including anionic groups pendanted from the polymer skeleton, anionic groups incorporated into the polymer skeleton, or a combination thereof. Pattern 24 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises a negatively charged homopolymer or copolymer containing two or more anionic groups. Appearance 25 The polyanionic polymer electrolyte is a copolymer comprising two or more fragments having formula XI, [ka] In the formula, R 4 is hydrogen or alkyl group, n is between 1 and 10. Y is oxygen, sulfur, or NR 30 And here, R 30 is hydrogen, alkyl group, or aryl group, The method according to any one of embodiments 1 to 16, wherein Z' is a pharmaceutically acceptable salt of an anionic group. Appearance 26 The method according to embodiment 25, wherein Z' is a carboxylate, sulfate, sulfonate, borate, boronate, substituted or unsubstituted phosphate, or phosphonate. Appearance 27 The method according to embodiment 26, wherein n is 2. Appearance 28 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte comprises xanthan gum. Appearance 29 The method according to embodiment 28, wherein the xanthan gum, which is a polyanion, has a molecular weight of about 100 kDa to about 10,000 kDa. Appearance 30 The method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte includes hyaluronic acid. Appearance 31 The method according to embodiment 30, wherein the hyaluronic acid has a molecular weight of approximately 100 kDa to approximately 5000 kDa. Appearance 32 The polyanionic polymer electrolyte is the method according to any one of embodiments 1 to 16, wherein the polyanionic polymer electrolyte contains polyacrylic acid. Appearance 33 The method according to embodiment 32, wherein the polyacrylic acid has a molecular weight of about 100 kDa to about 5000 kDa. Appearance 34 The method according to any one of embodiments 1 to 33, wherein the polyanionic polymer electrolyte is about 1% to about 12% by weight of the hydrogel. Appearance 35 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte comprises protamine. Appearance 36 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte is salmine or clepein. Appearance 37 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte is a natural polymer or synthetic polymer containing two or more guanidinyl side chains. Appearance 38 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte comprises a polyacrylate containing two or more pendanted guanidinyl groups. Appearance 39 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte comprises a homopolymer containing a pendanted guanidinyl group. Pattern 40 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte comprises a copolymer containing two or more pendanted guanidinyl groups. Appearance 41 The method according to any one of embodiments 1 to 34, wherein the polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer comprising an acrylate skeleton, a methacrylate skeleton, an acrylamide skeleton, or a methacrylamide skeleton and two or more guanidinyl groups pendanted from the skeleton. Pattern 42 The polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer containing a polymerization product of a monomer selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, or any combination thereof, and a pharmaceutically acceptable salt of a compound of formula I. [ka] In the formula, R 1 is hydrogen or alkyl group, and X is oxygen or NR 5 And here, R 5 The method according to any one of embodiments 1 to 34, wherein is hydrogen or an alkyl group, and m is 1 to 10. Appearance 43 The method according to embodiment 42, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and acrylate, methacrylate, acrylamide, or methacrylamide. 44 The method according to embodiment 42, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-[3-(N'-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3-aminopropyl)methacrylamide, N-(1,3-dihydroxypropan-2-yl)methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof. Appearance 45 R 1 The method according to embodiment 42, wherein is methyl, X is NH, and m is 3. Appearance 46 The method according to aspect 42, wherein the molar ratio of the guanidinyl monomer of formula I to the comonomer is 1:20 to 20:1. Aspect 47 The method according to aspect 42, wherein the polyguanidinyl copolymer has an average molar mass of 1 kDa to 1000 kDa. Aspect 48 The method according to any one of aspects 1 to 47, wherein the polycationic polyelectrolyte is from about 1.0 weight percent to about 25.0 weight percent of the PE hydrogel. Aspect 49 The method according to aspect 1, wherein the polyanionic polyelectrolyte is xanthan gum, and the polycationic polyelectrolyte is protamine. Aspect 50 The method according to aspect 49, wherein the protamine is salmine. Aspect 51 The method according to aspect 1, wherein the polyanionic polyelectrolyte is xanthan gum, and the polycationic polyelectrolyte is polyguanidinium methacrylamide (pGPMA). Aspect 52 The method according to aspect 1, wherein the PE hydrogel comprises two different anionic polysaccharides. Aspect 53 The method according to aspect 52, wherein the anionic polysaccharides comprise xanthan gum and hyaluronic acid. Aspect 54 The method according to any one of aspects 1 to 53, wherein the monovalent ions are sodium ions and potassium ions, and the divalent ions are magnesium ions and calcium ions. Aspect 55 The method according to any one of aspects 1 to 53, wherein the monovalent anion is a chloride ion. Aspect 56 The method according to any one of aspects 1 to 53, wherein the total concentration of the monovalent cations and anions in the PE hydrogel is from about 0.1 M to about 2.5 M. Aspect 57 The method according to any one of aspects 1 to 56, wherein the PE hydrogel further comprises a contrast agent. Appearance 58 The method according to embodiment 57, wherein the contrast agent is an X-ray contrast agent. Appearance 59 The method according to embodiment 57, wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles. Appearance 60 The method according to embodiment 57, wherein the contrast agent is a transient contrast agent. Appearance 61 The method according to embodiment 60, wherein the transient contrast agent comprises an iodized organic compound. Appearance 62 The method according to embodiment 61, wherein the iodized organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobitridol, iomeprole, iopentol, iopamilon, ioxiran, iotorol, ioversol, iopanoate, diatrizoic acid, iotalamic acid, ioxagrate, or any combination thereof. Appearance 63 The method according to embodiment 61, wherein the iodized organic compound includes iodized oil. Appearance 64 The method according to any one of embodiments 60 to 63, wherein the concentration of the transient contrast agent in the PE hydrogel is 50 mgI / mL to 450 mgI / mL. Appearance 65 The method according to any one of embodiments 60 to 64, wherein the transient contrast agent diffuses from the polymer electrolyte hydrogel and becomes undetectable within 5 minutes to 30 days. Appearance 66 The method according to any one of embodiments 1 to 65, wherein the polymer electrolyte hydrogel further comprises natural fibers or synthetic fibers, water-insoluble filler particles, nanoparticles, or fine particles. Appearance 67 The method according to embodiment 66, wherein the fibers include pulverized and sieved cross-linked gelatin foam fibers. Appearance 68 The method according to any one of embodiments 1 to 67, wherein the polymer electrolyte hydrogel further comprises one or more bioactive agents, the bioactive agents comprising antibiotics, analgesics, immunomodulators, growth factors, enzyme inhibitors, hormones, messenger molecules, cell signaling molecules, receptor agonists, oncolytic viruses, chemotherapeutic agents, receptor antagonists, nucleic acids, chemically modified nucleic acids, or any combination thereof. Appearance 69 The method according to any one of embodiments 1 to 68, wherein the polymer electrolyte hydrogel further comprises a nonionic polysaccharide. Appearance 70 The method according to embodiment 69, wherein the nonionic polysaccharide includes guar gum, locust bean gum, modified starch, or a combination thereof. Appearance 71 The method according to any one of embodiments 1 to 70, wherein the polymer electrolyte hydrogel further comprises silicate nanoparticles. Appearance 72 A polymer electrolyte hydrogel containing polycations, polyanions, and monovalent ions, having an initial modulus greater than its viscosity, The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear. A polymer electrolyte hydrogel in which the recovery modulus of the polymer electrolyte hydrogel under physiological conditions is at least 80% of the initial modulus of the polymer electrolyte hydrogel. Appearance 73 The polyanionic polymer electrolyte hydrogel according to embodiment 72, wherein the polyanionic polymer electrolyte has 10 mol% to 90 mol% of ionized side chains when the pH is greater than 6. Appearance 74 The polyanionic polymer electrolyte hydrogel according to embodiment 72, wherein the polyanionic polymer electrolyte comprises only anionic charged groups. Appearance 75 The polycationic polymer electrolyte has 10 mol% to 90 mol% of ionized side chains when the pH is greater than 6, as described in embodiment 72 of the polymer electrolyte hydrogel. Appearance 76 The polycationic polymer electrolyte according to aspect 72, wherein the polycationic polymer electrolyte contains only cationic charged groups. Aspect 77 The polymer electrolyte hydrogel according to aspect 72, wherein when the pH is from about 6 to about 8, the charge ratio of the polycationic polymer electrolyte to the polyanionic polymer electrolyte is 6:1 to 1:6. Aspect 78 The polymer electrolyte hydrogel according to aspect 72, wherein the initial elastic modulus is 200 Pa or more. Aspect 79 The polymer electrolyte hydrogel according to aspect 72, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel decrease under shear such that the injection force through a catheter is less than 14 lbf. Aspect 80 The polymer electrolyte hydrogel according to aspect 72, wherein the molecular weight of the polyanionic polymer electrolyte is from about 20 kDa to about 10000 kDa. Aspect 81 The polymer electrolyte hydrogel according to aspect 72, wherein the polyanionic polymer electrolyte comprises a plurality of polymers with different molecular weights to form a multimodal molecular weight distribution. Aspect 82 The polymer electrolyte hydrogel according to aspect 72, wherein the polyanionic polymer electrolyte is linear or branched. Aspect 83 The polymer electrolyte hydrogel according to aspect 72, wherein the monovalent ions are sodium ions and chloride ions having a concentration of from about 0.10 M to about 2.5 M. Aspect 84 The polymer electrolyte hydrogel according to any one of aspects 72 to 83, which forms a right-handed or left-handed coil during delivery by a catheter, needle, or other delivery device. Aspect 85 The polymer electrolyte hydrogel according to any one of aspects 72 to 84, wherein the method reduces or inhibits blood flow to a tumor, aneurysm, lower extremity varicose vein, vascular malformation, knee artery, uterine fibroid, prostatic artery, hemorrhoid, middle dura artery, or hemorrhagic wound. Aspect 86 The method described above involves strengthening the inner wall of the target blood vessel using a polymer electrolyte hydrogel according to any one of embodiments 72 to 84. Appearance 87 The polymer electrolyte hydrogel according to any one of embodiments 72 to 84, further comprising a bioactive agent released from the polymer electrolyte hydrogel after the polymer electrolyte hydrogel has been administered to the subject. Feature 88 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises a polyanionic polysaccharide. Appearance 89 The polyanionic polysaccharide comprises xanthan gum, hyaluronic acid, gellan gum, alginic acid, carrageenan, or any combination thereof, as described in embodiment 86 of the polymer electrolyte hydrogel. Appearance 90 The polyanionic polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises two or more carboxylic acid groups, sulfate groups, sulfonic acid groups, boric acid groups, boronic acid groups, phosphonic acid groups, or phosphate groups. Appearance 91 The polyanionic polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises a negatively charged glycosaminoglycan or an acidic protein. Appearance 92 The negatively charged glycosaminoglycan comprises chondroitin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid, as described in embodiment 89, for the polymer electrolyte hydrogel. Appearance 93 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 85, comprising a negatively charged protein having a net negative charge at pH 6 or higher. Appearance 94 The polyanionic polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises a negatively charged polymer including anionic groups pendanted from the polymer skeleton, anionic groups incorporated into the polymer skeleton, or a combination thereof. Appearance 95 The polyanionic polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises a negatively charged homopolymer or copolymer containing two or more anionic groups. Appearance 96 The polyanionic polymer electrolyte is a copolymer comprising two or more fragments having formula XI, [ka] In the formula, R 4 is hydrogen or alkyl group, n is between 1 and 10. Y is oxygen, sulfur, or NR 30 And here, R 30 is hydrogen, alkyl group, or aryl group, A polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein Z' is a pharmaceutically acceptable salt of an anionic group. Appearance 97 The polymer electrolyte hydrogel according to embodiment 96, wherein Z' is a carboxylate, sulfate, sulfonate, borate, boronate, substituted or unsubstituted phosphate, or phosphonate. Appearance 98 The polymer electrolyte hydrogel according to embodiment 97, wherein n is 2. Appearance 99 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises xanthan gum. Appearance 100 The polyelectrolyte hydrogel according to embodiment 99, wherein the xanthan gum, which is a polyanion, has a molecular weight of about 100 kDa to about 10,000 kDa. Appearance 101 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises hyaluronic acid. Appearance 102 The hyaluronic acid has a molecular weight of approximately 100 kDa to approximately 5000 kDa, as described in embodiment 101 of the polymer electrolyte hydrogel. Appearance 103 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 85, wherein the polyanionic polymer electrolyte comprises polyacrylic acid. Appearance 104 The polyacrylic acid has a molecular weight of approximately 100 kDa to approximately 5000 kDa, as described in embodiment 103 of the polymer electrolyte hydrogel. Appearance 105 The polyanionic polymer electrolyte hydrogel according to any one of embodiments 72 to 104, wherein the polyanionic polymer electrolyte is about 1% to about 12% by weight of the hydrogel. Appearance 106 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 105, wherein the polycationic polymer electrolyte contains protamine. Appearance 107 The polycationic polymer electrolyte is salmine or crupein, according to any one of embodiments 72 to 105, wherein the polycationic polymer electrolyte is salmine or crupein. Appearance 108 The polycationic polymer electrolyte is a natural polymer or synthetic polymer containing two or more guanidinyl side chains, according to any one of embodiments 72 to 105, the polymer electrolyte hydrogel. Appearance 109 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 105, comprising a polyacrylate containing two or more pendanted guanidinyl groups. Appearance 110 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 72 to 105, comprising a homopolymer containing a pendanted guanidinyl group. Appearance 111 The polycationic polymer electrolyte comprises a copolymer containing two or more pendanted guanidinyl groups, according to any one of embodiments 72 to 105, wherein the polymer electrolyte hydrogel is according to embodiment 72 to 105. Appearance 112 The polycationic polymer electrolyte hydrogel according to any one of embodiments 72 to 105, comprising a synthetic polyguanidinyl copolymer containing an acrylate skeleton, a methacrylate skeleton, an acrylamide skeleton, or a methacrylamide skeleton and two or more guanidinyl groups pendanted from the skeleton. Appearance 113 The polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer containing a polymerization product of a monomer selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, or any combination thereof, and a pharmaceutically acceptable salt of a compound of formula I. [ka] In the formula, R 1 is hydrogen or alkyl group, and X is oxygen or NR 5 And here, R 5 A polymer electrolyte hydrogel according to any one of embodiments 72 to 105, wherein is hydrogen or an alkyl group, and m is 1 to 10. Appearance 114 The polycationic polymer electrolyte hydrogel according to embodiment 113, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and acrylate, methacrylate, acrylamide, or methacrylamide. Appearance 115 The polycationic polymer electrolyte hydrogel according to embodiment 113, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-[3-(N'-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3-aminopropyl)methacrylamide, N-(1,3-dihydroxypropan-2-yl)methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof. Appearance 116 R 1 A polymer electrolyte hydrogel according to embodiment 113, wherein is methyl, X is NH, and m is 3. Appearance 117 The polymer electrolyte hydrogel according to embodiment 113, wherein the molar ratio of the guanidinyl monomer to the comonomer in formula I is 1:20 to 20:1. Appearance 118 The polyguanidinyl copolymer has an average molar mass of 1 kDa to 1000 kDa, as described in embodiment 113, and is a polymer electrolyte hydrogel. Appearance 119 The polycationic polymer electrolyte is in an amount of about 1.0 weight percent to about 25.0 weight percent of the PE hydrogel, according to any one of embodiments 72 to 118. Appearance 120 The polymer electrolyte hydrogel according to embodiment 72, wherein the polyanionic polymer electrolyte is xanthan gum and the polycationic polymer electrolyte is protamine. Appearance 121 The polymer electrolyte hydrogel according to embodiment 120, wherein the protamine is salmin. Appearance 122 The polymer electrolyte hydrogel according to embodiment 72, wherein the polyanionic polymer electrolyte is xanthan gum, and the polycationic polymer electrolyte is polyguanidinium methacrylamide (pGPMA). Appearance 123 A polymer electrolyte hydrogel according to embodiment 72, comprising two different anionic polysaccharides. Appearance 124 The polymer electrolyte hydrogel according to embodiment 123, wherein the anionic polysaccharide comprises xanthan gum and hyaluronic acid. Appearance 125 The polymer electrolyte hydrogel according to any one of embodiments 72 to 124, wherein the monovalent cation is a sodium ion or a potassium ion, and the divalent cation is a magnesium ion or a calcium ion. Appearance 126 The polymer electrolyte hydrogel according to any one of embodiments 72 to 124, wherein the monovalent anion is a chloride ion. Appearance 127 The polymer electrolyte hydrogel according to any one of embodiments 72 to 124, wherein the total concentration of monovalent and / or divalent ions in the PE hydrogel is about 0.1 M to about 2.5 M. Appearance 128 A polymer electrolyte hydrogel according to any one of embodiments 72 to 127, further comprising a contrast agent. Appearance 129 The polymer electrolyte hydrogel according to embodiment 128, wherein the contrast agent is an X-ray contrast agent. Appearance 130 The polymer electrolyte hydrogel according to embodiment 128, wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles. Appearance 131 The contrast agent is a transient contrast agent, as described in embodiment 128 of the polymer electrolyte hydrogel. Appearance 132 The transient contrast agent is a polymer electrolyte hydrogel according to embodiment 131, comprising an iodized organic compound. Appearance 133 The polyelectrolyte hydrogel according to embodiment 132, wherein the iodized organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobitridol, iomeprole, iopentol, iopamilon, ioxiran, iotorol, ioversol, iopanoate, diatrizoic acid, iotalamic acid, ioxagrate, or any combination thereof. Appearance 134 The iodized organic compound is a polymer electrolyte hydrogel according to embodiment 132, wherein the iodized organic compound contains iodized oil. Appearance 135 The polymer electrolyte hydrogel according to any one of embodiments 131 to 134, wherein the concentration of the transient contrast agent in the PE hydrogel is 50 mgI / mL to 450 mgI / mL. Appearance 136 The transient contrast agent diffuses from the PE hydrogel and becomes undetectable within 5 minutes to 30 days, according to any one of embodiments 131 to 135 of the polymer electrolyte hydrogel. Appearance 137 A polymer electrolyte hydrogel according to any one of embodiments 72 to 136, further comprising natural fibers or synthetic fibers, water-insoluble filler particles, nanoparticles, or fine particles. Appearance 138 The polymer electrolyte hydrogel according to embodiment 66, wherein the fibers include pulverized and sieved cross-linked gelatin foam fibers. Appearance 139 A polymer electrolyte hydrogel according to any one of embodiments 72 to 138, further comprising one or more bioactive agents, wherein the bioactive agents include antibiotics, analgesics, immunomodulators, growth factors, enzyme inhibitors, hormones, messenger molecules, cell signaling molecules, receptor agonists, oncolytic viruses, chemotherapeutic agents, receptor antagonists, nucleic acids, chemically modified nucleic acids, or any combination thereof. Appearance 140 A polymer electrolyte hydrogel according to any one of embodiments 72 to 139, further comprising a nonionic polysaccharide. Appearance 141 The polymer electrolyte hydrogel according to embodiment 140, wherein the nonionic polysaccharide comprises guar gum, locust bean gum, modified starch, or a combination thereof. Appearance 142 A polymer electrolyte hydrogel according to any one of embodiments 72 to 139, further comprising silicate nanoparticles. Appearance 143 (a) A first syringe comprising a polymer electrolyte hydrogel as described in any one of embodiments 72 to 142, (b) A kit comprising instructions for administering the polymer electrolyte hydrogel to a target. Appearance 144 The kit according to embodiment 143, further comprising a second syringe containing a contrast agent and water or saline solution. Appearance 145 The kit according to embodiment 143 or 144, further comprising a second syringe attached to the first syringe by a female-to-female Luer adapter for mixing the PE hydrogel before use. Appearance 146 The kit according to embodiment 143 or 144, further comprising a second syringe filled with dehydrated fibers, hydrated fibers, or a gel modifier. Appearance 147 The kit according to embodiment 143 or 144, further comprising an adapter for loading the PE hydrogel into the catheter or the lumen of the delivery device while minimizing contact with the hub of the delivery device. Appearance 148 A polymer electrolyte hydrogel comprising (a) xanthan gum, (b) one or more polycationic polymer electrolytes, and (c) ions including monovalent ions, divalent ions, or combinations thereof. Appearance 149 The aforementioned polymer electrolyte hydrogel has an initial elastic modulus greater than its viscosity. The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear when delivered through the conduit. The polymer electrolyte hydrogel according to embodiment 148, wherein the elastic modulus of the polymer electrolyte hydrogel recovers to a level sufficient to occlude or fill a desired position under physiological conditions. Appearance 150 The polymer electrolyte hydrogel according to embodiment 148 or 149, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel decrease under shear such that the injection force through the catheter is less than 20 lbf. Appearance 151 The polymer electrolyte hydrogel according to any one of embodiments 148 to 150, wherein the xanthan gum is present in an amount of about 1.0 weight percent to about 12 weight percent of the hydrogel. Appearance 152 The xanthan gum has a molecular weight of about 100 kDa to about 10,000 kDa, as described in any one of embodiments 148 to 151. Appearance 153 The polycationic polymer electrolyte has 10 mol% to 90 mol% of ionized side chains when the pH exceeds 6.3, as described in any one of embodiments 148 to 152. Appearance 154 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 148 to 153, wherein the polycationic polymer electrolyte comprises only cationic charged groups. Appearance 155 A polymer electrolyte hydrogel according to any one of embodiments 148 to 154, wherein when the pH is approximately 4.5 to approximately 8, the charge ratio of the polycationic polymer electrolyte and the xanthan gum is 6:1 to 1:6. Appearance 156 The polymer electrolyte hydrogel according to any one of embodiments 148 to 155, wherein the initial modulus of elasticity is 200 Pa or more and less than 6000 Pa. Appearance 157 The polycationic polymer electrolyte hydrogel according to any one of embodiments 148 to 156, wherein the polycationic polymer electrolyte is about 0.70% to about 15% by weight of the hydrogel. Appearance 158 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 148 to 157, wherein the polycationic polymer electrolyte comprises a pharmaceutically acceptable salt of chitosan. Appearance 159 The pharmaceutically acceptable salt of the chitosan is a hydrochloride, glutamate, or acetate, as described in Embodiment 158, for the polymer electrolyte hydrogel. Appearance 160 The polyelectrolyte hydrogel according to embodiment 158 ​​or 159, wherein the chitosan has an average molecular weight of about 10 kDa to about 130 kDa. Appearance 161 The chitosan has a degree of deacetylation (DDA) greater than 85%, as described in any one of embodiments 148 to 160. Appearance 162 The polymer electrolyte hydrogel according to any one of embodiments 148 to 161, wherein the pharmaceutically acceptable salt of the chitosan is about 0.70% to about 8% by weight of the hydrogel. Appearance 163 The polycationic polymer electrolyte has 85 mol% to 100 mol% ionized side chains when the pH is about 4.5 to 6.3, as described in any one of embodiments 148 to 162. Appearance 164 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 148 to 157, wherein the polycationic polymer electrolyte contains protamine. Appearance 165 The polycationic polymer electrolyte is salmine or crupein, according to any one of embodiments 147 to 157, wherein the polycationic polymer electrolyte is salmine or crupein. Appearance 166 The polycationic polymer electrolyte hydrogel according to embodiment 165, wherein the polycationic polymer electrolyte is in an amount of about 0.70% to about 12% by weight of the hydrogel. Appearance 167 The polycationic polymer electrolyte is a natural polymer or synthetic polymer containing two or more guanidinyl side chains, according to any one of embodiments 148 to 157, wherein the polymer electrolyte hydrogel is a natural polymer or synthetic polymer. Appearance 168 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 148 to 157, comprising a polyacrylate containing two or more pendanted guanidinyl groups. Appearance 169 The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 148 to 157, comprising a homopolymer containing a pendanted guanidinyl group. Appearance 170 The polycationic polymer electrolyte comprises a copolymer containing two or more pendanted guanidinyl groups, as described in any one of embodiments 148 to 157. Appearance 171 The polycationic polymer electrolyte hydrogel according to any one of embodiments 148 to 157, comprising a synthetic polyguanidinyl copolymer containing an acrylate skeleton, a methacrylate skeleton, an acrylamide skeleton, or a methacrylamide skeleton and two or more guanidinyl groups pendanted from the skeleton. Appearance 172 The polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer containing a polymerization product of a monomer selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, or any combination thereof, and a pharmaceutically acceptable salt of a compound of formula I. [ka] In the formula, R 1 is hydrogen or alkyl group, and X is oxygen or NR 5 And here, R 5 A polymer electrolyte hydrogel according to any one of embodiments 148 to 157, wherein is hydrogen or an alkyl group, and m is 1 to 10. Appearance 173 The polycationic polymer electrolyte hydrogel according to embodiment 172, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and acrylate, methacrylate, acrylamide, or methacrylamide. Appearance 174 The polycationic polymer electrolyte hydrogel according to embodiment 172, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-[3-(N'-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3-aminopropyl)methacrylamide, N-(1,3-dihydroxypropan-2-yl)methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof. Appearance 175 R 1 A polymer electrolyte hydrogel according to embodiment 172, wherein is methyl, X is NH, and m is 3. Appearance 176 The polymer electrolyte hydrogel according to embodiment 172, wherein the molar ratio of the guanidinyl monomer to the comonomer in formula I is 1:20 to 20:1. Appearance 177 The polyguanidinyl copolymer has an average molar mass of 1 kDa to 1000 kDa, as described in embodiment 172, and is a polymer electrolyte hydrogel. Appearance 178 The polycationic polymer electrolyte hydrogel according to any one of embodiments 167 to 177, wherein the polycationic polymer electrolyte is about 0.70% to about 12.0% by weight of the hydrogel. Appearance 179 The polymer electrolyte hydrogel according to any one of embodiments 148 to 178, wherein the ions include sodium ions, potassium ions, calcium ions, magnesium ions, or any combination thereof, and chloride ions. Appearance 180 The polymer electrolyte hydrogel according to any one of embodiments 148 to 179, wherein the total concentration of the ions in the polymer electrolyte hydrogel is about 0.1 M to about 2.5 M. Appearance 181 The polymer electrolyte hydrogel according to any one of embodiments 148 to 180, wherein the ions include calcium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M. Appearance 182 The polymer electrolyte hydrogel according to any one of embodiments 148 to 181, wherein the ions include sodium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M. Appearance 183 The polymer electrolyte hydrogel according to any one of embodiments 148 to 180, wherein the ions include potassium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M. Appearance 184 The polymer electrolyte hydrogel according to any one of embodiments 148 to 180, wherein the ions include magnesium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M. Appearance 185 A polymer electrolyte hydrogel according to any one of embodiments 148 to 184, further comprising a contrast agent. Appearance 186 The polymer electrolyte hydrogel according to embodiment 185, wherein the contrast agent is an X-ray contrast agent. Appearance 187 The polymer electrolyte hydrogel according to embodiment 185, wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles. Appearance 188 The contrast agent is a transient contrast agent, as described in embodiment 185 of the polymer electrolyte hydrogel. Appearance 189 The transient contrast agent is a polymer electrolyte hydrogel according to embodiment 188, comprising an iodized organic compound. Appearance 190 The polyelectrolyte hydrogel according to embodiment 189, wherein the iodized organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobitridol, iomeprole, iopentol, iopamilon, ioxiran, iotorol, ioversol, iopanoate, diatrizoic acid, iotalamic acid, ioxagrate, or any combination thereof. Appearance 191 The iodized organic compound is a polymer electrolyte hydrogel according to embodiment 189, wherein the iodized organic compound contains an iodized oil. Appearance 192 The polymer electrolyte hydrogel according to any one of embodiments 185 to 191, wherein the contrast agent is up to 40 weight percent of the polymer electrolyte hydrogel. Appearance 193 A polymer electrolyte hydrogel according to any one of embodiments 148 to 192, further comprising natural fibers or synthetic fibers, water-insoluble filler particles, nanoparticles, or fine particles. Appearance 194 The polymer electrolyte hydrogel according to embodiment 193, wherein the fiber includes cross-linked gelatin foam fiber. Appearance 195 The polymer electrolyte hydrogel according to embodiment 193, wherein the fiber comprises type A cross-linked gelatin foam fiber or type A cross-linked gelatin foam fiber. Appearance 196 The polymer electrolyte hydrogel according to embodiment 194 or 195, wherein the fibers constitute 0.1 to 5 weight percent of the polymer electrolyte hydrogel. Appearance 197 A polymer electrolyte hydrogel according to any one of embodiments 148 to 196, further comprising a bioactive agent. Appearance 198 The polymer electrolyte hydrogel according to embodiment 197, wherein the bioactive agent comprises an antibiotic, analgesic, immunomodulator, growth factor, enzyme inhibitor, hormone, messenger molecule, cell signaling molecule, receptor agonist, oncolytic virus, chemotherapeutic agent, receptor antagonist, nucleic acid, chemically modified nucleic acid, or any combination thereof. Appearance 199 A polymer electrolyte hydrogel according to any one of embodiments 148 to 198, further comprising a nonionic polysaccharide. Appearance 200 The polymer electrolyte hydrogel according to embodiment 199, wherein the nonionic polysaccharide comprises guar gum, locust bean gum, modified starch, or a combination thereof. Appearance 201 A polymer electrolyte hydrogel according to any one of embodiments 148 to 200, further comprising silicate nanoparticles. Appearance 202 A polymer electrolyte hydrogel comprising (a) a pharmaceutically acceptable salt of chitosan, a polyguanidinyl copolymer, protamine, or any combination thereof; (b) a polyanionic polymer electrolyte; and (c) ions comprising monovalent ions, divalent ions, or combinations thereof. Appearance 203 The aforementioned polymer electrolyte hydrogel has an initial elastic modulus greater than its viscosity. The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear when delivered through the conduit. The polymer electrolyte hydrogel according to embodiment 202, wherein the elastic modulus of the polymer electrolyte hydrogel recovers to a level sufficient to occlude or fill a desired position under physiological conditions. Feature 204 The polymer electrolyte hydrogel according to embodiment 202 or 203, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel decrease under shear such that the injection force through the catheter is less than 20 lbf. Appearance 205 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 202 to 204, wherein the polyanionic polymer electrolyte comprises a polyanionic polysaccharide. Appearance 206 The polyelectrolyte hydrogel according to embodiment 205, wherein the polyanionic polysaccharide comprises xanthan gum, hyaluronic acid, gellan gum, alginic acid, carrageenan, or any combination thereof. Appearance 207 The polyanionic polymer electrolyte hydrogel according to embodiment 205, wherein the polyanionic polymer electrolyte comprises a negatively charged glycosaminoglycan or an acidic protein. Appearance 208 The polymer electrolyte hydrogel according to embodiment 207, wherein the negatively charged glycosaminoglycan comprises chondroitin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid. Appearance 209 The polyanionic polymer electrolyte is a polymer electrolyte hydrogel according to any one of embodiments 202 to 204, comprising xanthan gum. Appearance 210 The polymer electrolyte hydrogel according to embodiment 209, wherein the xanthan gum is present in an amount of about 1.0 weight percent to about 12 weight percent of the hydrogel. Appearance 211 The xanthan gum has a molecular weight of about 100 kDa to about 10,000 kDa, as described in the polymer electrolyte hydrogel according to embodiment 209 or 210. Appearance 212 The polymer electrolyte hydrogel according to embodiments 148-211, wherein, after being delivered to a physiological medium, the elastic modulus and viscosity of the polymer electrolyte hydrogel continue to increase. Appearance 213 The polymer electrolyte hydrogel according to embodiment 212, wherein after 30 minutes in the physiological medium, the elastic modulus of the polymer electrolyte hydrogel is 600 Pa to 25000 Pa. Appearance 214 The polymer electrolyte hydrogel according to embodiment 212 or 213, wherein the elastic modulus of the polymer electrolyte hydrogel remains greater than the viscosity. Appearance 215 The polymer electrolyte hydrogel according to any one of embodiments 148 to 214, wherein, in order to increase the elastic modulus before delivery, the polymer electrolyte hydrogel is exposed to a liquid having a lower ion content than the polymer electrolyte hydrogel. Appearance 216 The polymer electrolyte hydrogel according to embodiment 215, wherein the elastic modulus continues to increase after being delivered to a physiological medium. Appearance 217 The polymer electrolyte hydrogel according to embodiment 215, wherein, after being delivered to a physiological medium, the elastic modulus is within ±10% of the initial elastic modulus before delivery. Appearance 218 A method for reducing or inhibiting flow within a target blood vessel, comprising the step of introducing a polymer electrolyte hydrogel according to any one of embodiments 148 to 217 into the blood vessel. Appearance 219 The method according to embodiment 218, for reducing or inhibiting blood flow to tumors, aneurysms, endoleaks, varicose veins of the lower extremities, spermatic cord vein aneurysms, gonadal veins, ovarian veins, pelvic veins, gastrointestinal arteries, rectal arteries, mesenteric arteries, gastroduodenal arteries, hepatic arteries, splenic arteries, iliac arteries, portal veins, vascular malformations, geniculate arteries, uterine fibroids, prostatic arteries, hemorrhoids, middle meningeal arteries, or hemorrhagic wounds. Appearance 220 The method according to embodiment 219, for strengthening the inner wall of the target blood vessel. Appearance 221 The method according to embodiment 219, which temporarily reduces blood flow. Appearance 222 The method according to embodiment 221, which temporarily reduces blood flow in the musculoskeletal region. Appearance 223 A method for filling a target cavity, comprising the step of introducing a polymer electrolyte hydrogel according to any one of embodiments 148 to 217 into the cavity. Appearance 224 The method according to embodiment 223, wherein the cavity is located within the bone, muscle, skin, cartilage, tissue, or organ of the subject, or the cavity is a sac or pouch attached to the bone, muscle, skin, cartilage, tissue, or organ of the subject. Appearance 225 The cavity is located in the left atrial appendage, according to the method of embodiment 223. Appearance 226 The method according to embodiment 223, wherein the cavity is located within a lymph node. Appearance 227 The method according to any one of embodiments 223 to 226, wherein the composition is introduced into the cavity by a catheter or needle. Appearance 228 The method according to any one of embodiments 223 to 227, wherein first the polymer electrolyte hydrogel is introduced into the object by a delivery system, and subsequently a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof is introduced into the object by a syringe connected to the delivery system. Appearance 229 The delivery system includes a housing having a first end and a second end, an internal chamber containing the polymer electrolyte hydrogel within the housing, a first Luer connector at the first end of the housing, and a second Luer connector at the second end of the housing. The method according to embodiment 228, wherein the needle or catheter is attached to the first Luer connector or the second Luer connector, and the one of the first Luer connector and the second Luer connector that is not attached to the needle or catheter is capable of receiving the syringe containing the low viscosity liquid, hydrophobic liquid, aqueous contrast agent, or any combination thereof. Appearance 230 The method according to embodiment 228 or 229, wherein the low-viscosity liquid is physiological saline, a nonionic iodized contrast agent, glucose, or distilled water for injection. Appearance 231 The method according to embodiment 228 or 229, wherein the low viscosity liquid also comprises lidocaine, nitroglycerin, or verapamil. Appearance 232 The method according to embodiment 228 or 229, wherein the hydrophobic liquid comprises ethodized oil (lipiodol), plant-derived oil, or silicone. Appearance 233 The method according to embodiment 228 or 229, wherein the polymer electrolyte hydrogel is used in combination with one or more coils, plugs, liquid embolizers, or gelatin foam. Appearance 234 A delivery system for delivering a polymer electrolyte hydrogel according to any one of embodiments 148 to 217, The polymer electrolyte hydrogel and, A kit including instructions for administering the aforementioned polymer electrolyte hydrogel to a target. Appearance 235 A delivery system containing a polymer electrolyte hydrogel according to any one of embodiments 148 to 217 inside, A kit including instructions for administering the aforementioned polymer electrolyte hydrogel to a target. Appearance 236 The kit according to embodiment 234 or 235, further comprising a syringe containing a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof. Appearance 237 The kit according to embodiment 234 or 235, further comprising a syringe filled with dehydrated fibers, hydrated fibers, or a gel modifier. [Examples]

[0200] The following examples are provided to give a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods described herein are manufactured and evaluated, and are intended to be illustrative of the disclosure and not to limit the scope that the inventors consider to be the disclosure. Although efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., quantity, temperature, etc.), some errors and deviations should be taken into account. Unless otherwise specified, parts are parts by weight, temperatures are °C or ambient temperature, and pressures are ambient pressures.

[0201] Materials and methods

[0202] material

[0203] This specification describes several shear-thickening PE hydrogel formulations produced from polycations such as protamine sulfate, polyguanidinium methacrylamide (pGPMA), and chitosan hydrochloride and anionic polysaccharides, as well as methods for producing them. Protamine sulfate (Salmin) was purchased from MP Biomedical. Xanthan gum (product number G1253) derived from xanthomonas campestris, i-carrageenan (Type II commercial grade), sulfated kappa-carrageenan, guar gum, and sodium alginate salt (medium viscosity) were purchased from Sigma Aldrich. USP grade sodium chloride was purchased from Sigma Aldrich. Type A porcine gelatin was purchased from Sigma-Aldrich, and cross-linked gelatin foam fibers of the brand SURGIFOAM® from Ethicon were purchased from eSutures. Low-acylgellan gum and high-acylgellan gum were purchased from Modernist Pantry. Calcium chloride, magnesium chloride, and potassium chloride were purchased from Sigma Aldrich. Chitosan hydrochloride was purchased from Glentham Life Science Ltd.

[0204] Method 1

[0205] Before mixing, stock solutions of the main polycations (protamine sulfate, pGPMA, chitosan) and polyanions (xanthan gum, sodium hyaluronate) were prepared. Endotoxin-free deionized water (Fisher-Scientific) was used for all stock solutions. A 10% protamine sulfate solution was prepared by heating the deionized water (pH 5.5-7) to 60°C and then gradually adding the protamine powder while vortexing for 1-5 minutes. Next, the mixture was placed in a heated bath at 50-60°C until the protamine was completely dissolved. The heated 10% protamine solution was clear, but became cloudy at lower temperatures. An 8-12% xanthan gum stock solution was prepared by adding the xanthan gum to the deionized water while vortexing. After vortexing, the stock solutions were mixed using an IKA paddle mixer with a Teflon paddle (Teflon is a registered trademark). A stock solution of 5M physiological saline was prepared by adding sodium chloride to deionized water in a glass container and shaking to dissolve the salt. Sodium hydroxide was added to the physiological saline to adjust the pH as needed (target 7.0-7.4). Then, the pH of endotoxin-free water was adjusted to 7.0-7.4 with NaOH, and a 20% stock solution of pGPMA was prepared by dissolving lyophilized pGPMA powder, prepared according to the procedure provided in U.S. Patent No. 9,913,927B2 (which is incorporated by reference for the preparation of pGPMA), in deionized water at room temperature and vortexing for 1-2 minutes. The stock solution of chitosan should be adjusted to an acidic pH of less than 2 with hydrochloric acid.

[0206] Compositions with PE solid weights ranging from 3% to 12% were prepared by combining the ratios of the components. Generally, the desired salt content of the composition was selected, and an appropriate amount of 5M saline solution was added to deionized water in a 50 mL centrifuge tube to obtain the appropriate salt content. Next, calculations were performed to determine the ratio of positive to negative charges, and an appropriate amount of polycation stock solution was added to the saline solution. The solution was gently shaken to completely disperse the polycation.

[0207] Next, the polyanion stock solution was gradually added to the saline-polycation solution while vortexing. Initially, the vortex setting was set to 5 to prevent the low-viscosity polycation solution from overflowing, and the vortex intensity was increased to 9 as the polyanion was added and the mixture began to gel. After vortexing the mixture for 5 minutes, homogeneity was checked. If further mixing was necessary, rotary paddle mixing was performed at 1000 rpm to 1400 rpm until the mixture appeared to form a homogeneous gel. The higher the salt concentration, the faster a homogeneous PE hydrogel formed and the clearer it appeared, but at salt concentrations less than 0.75 M, mixing took longer and the mixture appeared white (in the case of alginate, it appeared yellow). After all mixing operations were completed, the mixture was centrifuged at 3000 rpm for 15 minutes to remove any air bubbles introduced during the mixing process.

[0208] Exemplary formulations are provided in the table below.

[0209] [Table 2] *While the salt concentrations of protamine and pGPMA include counterionic salts derived from the polymer, the salt concentrations listed for chitosan preparations only refer to the amount of added salt.

[0210] The scope of action of each major component is summarized in the table below.

[0211] [Table 3]

[0212] Method for producing a formulation containing two or more polycations, one polyanion, and a chloride salt.

[0213] Guar gum and calcium chloride

[0214] Before adding xanthan gum, the desired weight of guar gum powder and calcium chloride were added to the protamine saline solution and completely hydrated. Mixing and centrifugation were carried out according to Method 1.

[0215] Gellan gum, I-carrageenan, K-carrageenan

[0216] When used as a secondary additive, these were added in powder form to a polycationic saline solution and heated at over 90°C for 5 minutes. As the mixture cooled, the main anionic polysaccharide (e.g., xanthan gum) was added from the stock solution while vigorously vortexing. After mixing at 1000 rpm to 1400 rpm using an IKA overhead paddle mixer and a PTFE mixing paddle, the mixture was centrifuged to remove air bubbles. The addition of gellan gum, I-carrageenan, and K-carrageenan increased the elastic modulus of the xanthan gum-based gel. Before in vivo administration, endotoxins should be removed from the anionic polysaccharides using a method such as that described in U.S. Patent No. 6,451,772B1. The stock solution can then be prepared from the purified material as described above.

[0217] fiber

[0218] The mixing was carried out according to Method 1 before centrifugation, with fibers such as cross-linked gelatin fibers being gradually added while vortexing. Then, aggregates were removed by paddle mixing, with the speed varied between 400 rpm and 1400 rpm as needed to remove aggregates and minimize bubble formation. Next, the mixture was centrifuged at 4000 rpm at 4°C for 5 minutes to remove all bubbles.

[0219] Alternatively, the fibers can be added to the cationic saline mixture before being combined with xanthan gum. This method eliminates the tendency for the fibers to aggregate, but increases the time it takes for the PE hydrogel to become homogenized.

[0220] Tantalum or iodized contrast agent

[0221] After the PE hydrogel was fully formed and all additives were thoroughly mixed, the tantalum or iodized contrast agent was added. While it is possible to add the contrast agent to the protamine saline solution, it is preferable to add it last and mix it using a vortexer, paddle mixer, or IKA Ultra-Turrax tube drive, as this may mask the lack of homogeneity in the PE hydrogel.

[0222] Chitosan

[0223] The powders of chitosan hydrochloride, desired salt, xanthan gum, gelatin fiber (if desired), and contrast agent (if desired) were combined and vigorously mixed at the maximum vortex setting. Next, the powders were added to an appropriate amount of endotoxin-free water and vortexed vigorously for 3-5 minutes until no lumps were visible and the resulting gel appeared homogeneous. The PE hydrogel was allowed to stand for 10-20 minutes to continue hydrating, and then vortexed for 1-2 minutes. The PE hydrogel was loaded back into a 10 mL syringe using a stainless steel spatula, and then transferred to a 1 mL syringe for autoclaving.

[0224] In the case of unmodified chitosan, the procedure was the same as above, except that the unmodified chitosan was first dissolved in 1% HCl, the pH was adjusted to approximately 5.5 with sodium hydroxide or potassium hydroxide, and then the other powders were added and mixed as described above.

[0225] Gel property evaluation

[0226] The gel was loaded into a syringe and dispensed into equilibrium salt solution (BSS), 0.9% physiological saline, water, and blood solutions using a Luer-lock dispensing tip to evaluate the cohesive force of the mixtures under physiological conditions. PE hydrogels that remained stable and did not swell for more than one week in BSS at room temperature and 37°C were considered promising candidates for PE hydrogel embolization agents. At a charge ratio of 1:1, the minimum concentration of stable PE solids was 3%.

[0227] Note entry

[0228] To measure the injection force, a polymer electrolyte PE hydrogel was first added to a 1 mL syringe (Merit Medallion PC 1 mL syringe). Infusion was performed at a rate of 1 mL per minute using a Harvard Apparatus PHD Ultra syringe pump equipped with a Load Star iLoad mini load cell, connected to a computer via a serial USB port, through a catheter with an inner diameter of 0.0235 inches and a length of 120 cm. Data was recorded using LoadVue LV-1000 software.

[0229] Rheometry

[0230] All rheometry experiments were performed using a TA Instruments AR-2000EX rheometer equipped with a Peltier plate temperature control system and TA Instruments RHEOLOGY ADVANTAGE software. A 20 mm diameter plate was used, with a gap of 500 μm to 1000 μm, and a moisture-proof cap and deionized water droplets were used in combination to prevent drying.

[0231] Temperature stability and temperature sweep

[0232] Before starting the test, a 30-second adjustment step was performed to equalize the temperature and ensure equilibrium. The temperature gradient was increased in 1°C increments from 20°C to 45°C with a 1% strain and a frequency of 1 Hz. A delay time of 10 seconds was set between each measurement.

[0233] Distortion sweep

[0234] Before starting the test, the temperature was set to 37°C, and a 60-second adjustment step was performed before the test to ensure equilibrium. Strain sweeps were performed at a frequency of 1 Hz and strains from 0.01% to 1000%, on a logarithmic scale with 5 points per decade. A delay time of 6 seconds was set between each measurement.

[0235] Frequency sweep

[0236] Before starting the test, the temperature was set to 37°C, and a 60-second adjustment step was performed before the test to ensure equilibrium. A frequency sweep was performed with 1% distortion and a frequency range of 0.1 Hz to 100 Hz, using a logarithmic scale with 5 points per decade. A delay time of 6 seconds was set between each measurement.

[0237] Yield stress

[0238] Before starting the test, the temperature was set to 37°C, and to ensure equilibrium, a preliminary shear stress of 6.4 Pa (10.0 Nm torque) was applied, followed by a 2-minute adjustment step. The yield stress was determined using a stepwise flow routine of 10 points per decade at shear rates of 1.00E-3 to 1.00E3. The constant time parameter was set to 00:05 seconds, and each data point was taken as the average value over the last 2 seconds. Next, the yield stress point was determined by plotting the shear stress (Pa) against the shear rate (1 / s) and calculating the point that deviated approximately 5% from the initial linearity.

[0239] viscosity

[0240] A 20 mm diameter plate was used with a 500 μm gap. Before starting the test, the temperature was set to 37°C, and to ensure equilibrium, a pre-shear stress of 6.4 Pa (10.0 Nm torque) was applied, followed by a 2-minute adjustment step. Viscosity at various shear rates was determined using a stepwise flow routine of 10 points per decade at shear rates from 1.00E-3 to 1.00E3. A constant time parameter was set to 00:05 seconds, and each data point was taken as the average value over the last 2 seconds. Viscosity was then plotted against shear rate (1 / s), and the peak viscosity and viscosity at a shear rate of 100 / s were calculated.

[0241] Distortion recovery

[0242] Before starting the test, the temperature was set to 37°C, and a 2-minute adjustment step was performed before the test to ensure equilibrium. The modulus G' was sampled 10 times over 1 minute at high strain (100%) and a frequency of 1 Hz, followed by up to 3 more samples over 1 minute at low strain (1%) and a frequency of 1 Hz. Rapid strain recovery is crucial in procedures where, after significant deformation occurs during delivery, the properties of the PE hydrogel need to be restored to their pre-delivery state as quickly as possible after it exits the catheter tip.

[0243] pH

[0244] pH can affect the charge intensity of the components of PE hydrogels and their stability over time. Protamine and pGPMA have a pka of approximately 13 and are completely positively charged across almost the entire pH range. Xanthan has a pka of approximately 4.5 and is negatively charged only above pH 4.5. Chitosan and its derivatives are positively charged and soluble below approximately 6.3 pH, but some degree of charge and partial solubility are observed up to pH 6.4. pH was measured using an InLab pH electrode from Mettler Toledo.

[0245] Gel strength after delivery

[0246] To evaluate the strength of a preparation after delivery in a equilibrium salt solution representative of the ion content of blood, or in the blood itself, the following procedure was followed: Approximately 0.30 mL of material was placed in a plastic mold with a diameter of 20 mm and a depth of 1.0 mm. The material was spread throughout the mold to form a uniform gel layer. The mold and material were then immersed in a BSS solution or blood for 30 minutes. After the incubation period, the sample was removed from the mold and placed on a rheometer measuring stand, and G' was measured according to the frequency sweep, temperature sweep, viscosity and strain sweep procedures described herein. The gap was adjusted to 0.80 mm to 1.0 mm so that the material was in contact with the base plate and the rheometer spindle and the normal force did not exceed 1 N.

[0247] Simulated use in extracorporeal occlusion models

[0248] Static pressure model

[0249] A 10-inch long, 0.071-inch (1.8 mm) inner diameter male-to-male Luer connector (Qosina 33019) was connected to a hemostatic valve. The hemostatic valve was then connected to a two-way stopcock and tubing at the bottom of a 2-foot to 5-foot water column corresponding to 44.8 mmHg to 112.1 mmHg. A dispensing tip (Jensen Global) with an inner diameter of 0.012 inches (304 μm) to 0.026 inches (660 μm) was attached to the distal end of the male-to-male tubing. Using a microcatheter with an inner diameter of 0.0235 inches or 0.027 inches, 0.1 mL to 0.3 mL of material was placed into the blood vessel along with water flowing at a pressure of approximately 90 mmHg. The ability to occlude distal 304 μm–660 μm tubing and proximal 1.8 mm tubing was evaluated by observing the material for up to 24 hours, removing the dispensing tip, and confirming whether the embolic material packed more proximal could occlude the flow. The point at which occlusion failed was recorded. During the test, the tubing was placed in a heated 37°C bath. All compositions containing 9% solids and PX5M1.5 were able to occlude a 550 μm tapered section at 89 mmHg for at least 10 minutes. PX5M1_2+, PX5M1, and PX5M.5 occluded 304 μm simulated blood vessels for more than 24 hours. In the tested pressure range (40 mmHg to 112 mmHg), smooth delivery and complete flow occlusion in a 550 μm simulated blood vessel were superior to 500 μm to 700 μm PVA particles (Cook Medical) and 2.5 mm gelatin foam (Embocube, Merit Medical).

[0250] Pump flow model

[0251] An extracorporeal vascular model for occlusion efficiency was created using a Cole Parmer Masterflex peristaltic pump. The pump tubing was attached to an inline pressure gauge and then to various models simulating vascular anatomy. In the simplest example, a Tuohy-borst hemostatic valve (Qosina) was connected to a Y-branch Luer lock valve distal to the pressure gauge, and two Luer connector tubes were connected to it. Dispensing tips (Jensen Global) of various inner diameters and tapered shapes were attached to the ends of the Luer connector tubes to quantitatively evaluate the size of blood vessels that could be occluded under various pressure and flow conditions. The model catheter was supplied to the desired branch through the port of the hemostatic valve and used to inject the embolic agent. In the most common procedure, less than 0.45 mL of embolic agent was injected, taking into account the dead volume in the catheter.

[0252] The second pump flow model was created by 3D printing a transparent model of a human kidney (see Figure 25B). This model was tested at higher flow rates than the other models to better simulate the more complex blood flow patterns that occur in the body during embolization and to simulate the effects of higher flow rates in intravascular delivery. As previously mentioned, a hemostatic valve was connected inline to the tube carrying the flow from the pump, and a catheter was inserted to the desired delivery site. After placement within the model by the catheter, the qualitative behavior of the gel was evaluated, and the maximum flow rate and pressure achieved were measured.

[0253] result

[0254] Example 1: Effect of charge ratio on protamine-xanthan PE hydrogel embolizer

[0255] The charge ratio of the polyelectrolyte in the PE hydrogel embolizer can be adjusted to change the desired properties. When the charge ratio of protamine to xanthan gum was 1:1, the PE hydrogel exhibited the highest durability in an equilibrium salt solution maintained at 37°C. PE hydrogel embolizers with a net negative charge of 1:4 dissolved more quickly in an equilibrium salt solution maintained at 37°C compared to the 1:1 and 2:1 examples, resulting in faster in vivo absorption, which is desirable in some applications.

[0256] 1 + :4 - At a charge ratio of 0:1, viscosity and injection force increased (Figures 1A and 1B), but at a charge ratio of 2:1, the injection force decreased. Viscosity measurements at various shear rates showed that the ideal PE hydrogel embolizer has high viscosity at shear rates less than 0.01, but becomes very low at higher shear rates of 100 / s to 500 / s. This suggests that PE hydrogels can provide a mechanical barrier to flow while being easily delivered to the target site. The decrease in injection force with a 2:1 charge ratio is reasonable considering the higher proportion of small protamine molecules compared to large xanthan gum molecules.

[0257] All concepts demonstrated temperature stability, and it was found that the elastic modulus (G') of the PE hydrogel increased because the net negative charge was greater due to the greater number of large-branched xanthanum molecules compared to small polycations (Figures 1C and 1D). The recovery of the PE hydrogel after being strained to 100% was consistent across charge ratios, with the degree of decrease and recovery being highest in the gel with a net negative charge ratio of 1:4.

[0258] Because vascular endothelium is negatively charged overall due to the presence of negatively charged molecules such as glycosaminoglycans, a high positive-negative charge ratio is desirable for some embolization applications. Due to the net positive charge of the embolizing agent, the PE hydrogel embolizer can be fixed to the negatively charged vascular wall, preventing distal migration.

[0259] Example 2: Effect of sodium chloride molar concentration on protamine-xanthan PE hydrogel embolizer

[0260] The effect of changes in the molar concentration of added monovalent ions was studied by preparing PE hydrogels with fixed PE solid weights of 5% and 9% containing protamine sulfate and xanthan gum in a 1:1 charge ratio. As a result, formulations containing approximately 1.5% protamine sulfate and 3.5% xanthan gum were obtained. Sodium chloride was added to achieve molar concentrations of 0.50 mol, 1.0 mol, and 1.5 mol. As a result, the total molar concentrations of monovalent ions were 0.57, 1.07, and 1.57, respectively, due to the monovalent ion content in xanthan gum. The addition of salt increased the overall viscosity, resulting in PE hydrogels with increased injection force through a catheter with an inner diameter of 0.0235 inches and a length of 130 cm (Figures 2A and 2B). Furthermore, increased salt molar concentration resulted in an elevated modulus of elasticity, stable at 20°C and 37°C (Figure 2C). Higher salt concentrations resulted in a greater degree of G' recovery after 100% strain, but all compositions consistently recovered to more than 90% of the measured peak G' within 10 seconds of reducing the strain to 1% (Figure 2D).

[0261] Stable, self-supporting PE hydrogels were formed at all three sodium chloride concentrations. At the lowest sodium chloride concentration (0.50 mol), the appearance was white (Figure 3A), and it required the most time and mixing to fully form the gel. Increasing the salt content improved the transparency of the PE hydrogel and reduced the time required to form a homogeneous PE hydrogel (Figures 3B, 3C).

[0262] Example 3: Effect of PE solid content on protamine-xanthan PE hydrogel embolizer

[0263] Gel embolic preparations with 1.0 mol of sodium chloride added, a charge ratio of xanthanum to protamine of 1:1, and solid content of 5%, 7.5%, and 9% were prepared. Viscosity was significantly higher in the 9% group than in the 5% group, and the injection force through a catheter with an inner diameter of 0.0235 inches and a length of 130 cm using a 1 mL Merit Medallion syringe was observed to increase almost linearly with increasing polyelectrolyte concentration. Generally, injection force values ​​of less than 14 lbf are considered ergonomically acceptable, so the high-concentration polyelectrolyte version with 1.0 mol of sodium chloride added is suitable for larger catheters. Based on the results of Example 2, a combination of reduced salt and increased polyelectrolyte concentration can be used to create PE hydrogels with a good balance of strength and injectability.

[0264] The modulus of elasticity G' was stable at 20°C and 37°C for all weight percent of the PE solids, and G' increased as expected with increasing polyelectrolyte concentration (Figure 4C). Higher polyelectrolyte concentrations resulted in a greater degree of G' recovery after 100% strain, but all compositions consistently recovered to more than 90% of the measured peak G' within 10 seconds of reducing strain to 1%.

[0265] Example 4: Effect of sodium chloride molar concentration on pGPMA-xanthan PE hydrogel embolic material

[0266] Compositions of 5% PE hydrogel were prepared using poly(guanidinyl-propyl-methacrylamide) (pGPMA) and xanthanum in a charge ratio of 1:1, with the addition of 0.5 mol, 1.0 mol, and 1.5 mol of sodium chloride. The 0.5 mol version was excluded from testing because it did not form a homogeneous PE hydrogel. To form a gel, at least 0.75 mol of sodium chloride was required when the PE solids were 5 wt%. However, when the concentration of the polymer electrolyte was increased to 12%, the addition of 0.5 mol of sodium chloride formed a homogeneous white PE hydrogel. This is because the contribution of the salt increases with higher concentrations of pGPMA and xanthanum, which helps to shield the oppositely charged polymer and produce a homogeneous gel. Similar to the polyelectrolyte PE hydrogel composed of protamine and xanthanum, increasing the concentration of sodium chloride increased viscosity (Figure 5A), injection force via a 130 cm long, 0.027 inch inner diameter catheter (Figure 5B), G' at 20°C and 37°C (Figure 5C), and the degree of recovery after repeated 100% strain (Figure 5D). Reducing the salt content from 1.0 mol to 0.5 mol in the 12% solids version reduced the injection force at a rate of 1 mL / min from an average of 18.8 lbf to 10.4 lbf, which is within acceptable limits and demonstrates the adjustability of the composition.

[0267] pGPMA is a synthetic polycation that can be manufactured to adjust its molecular weight and other properties, offering the advantage of obtaining desired properties such as low injection force and high strength of PE hydrogels.

[0268] Example 5: Effect of polymer electrolyte concentration on pGPMA-xanthan PE hydrogel material

[0269] Polymer electrolyte hydrogel embolic preparations were prepared with 1.0 mol of sodium chloride added, a xanthanum to pGPMA charge ratio of 1:1, and solid content of 5%, 7.0%, and 12%. Viscosity was significantly higher in the 12% group than in the 5% and 7% groups, and the injection force through a 1 mL Merit Medallion syringe with a 0.027-inch inner diameter, 130 cm length catheter increased almost linearly with increasing polymer electrolyte concentration (Figures 6A and 6B). For solid concentrations of 5% and 7%, the injection force through this catheter was at an acceptable level. The modulus of elasticity at 20°C and 37°C was stable and increased with increasing polymer electrolyte concentration (Figure 6C). Higher polymer electrolyte concentrations resulted in a greater degree of G' recovery after 100% strain, but all compositions consistently recovered to greater than 90% of the measured peak G' within 10 seconds after reducing strain to 1%.

[0270] Based on the results of Example 2, a combination of reducing salt content and increasing the concentration of polymer electrolytes can be used to create PE hydrogels with an appropriate balance of strength and injectability.

[0271] Example 6: Effect of adding fibers to polymer electrolyte hydrogel embolizer

[0272] As described in other examples, at the molecular level, the decrease in viscosity during catheter delivery of polyelectrolyte PE hydrogels is due to the alignment of polymer chains of anionic polysaccharides and the mutual dissociation of charged components under shear. On a larger scale, this chain alignment can be achieved by adding fibers that give structure to the gel, thereby increasing the modulus of elasticity, alignment during catheter delivery, and increasing the rate of viscosity reduction under shear. This concept was demonstrated by fibers produced from cross-linked gelatin foam that was crushed and sieved to produce branched fibers (Figure 8). By adding 1 wt% of fibers, the viscosity at low shear increased, and the injection force through a catheter with a diameter of 0.0235 inches and a length of 130 cm decreased at a rate of 1 mL per minute (Figures 7A, 7B). By increasing the concentration to 2%, the average injection force decreased further, but the viscosity (Figure 7A) or modulus of elasticity G' (Figure 7C) did not increase. This indicates that a balance exists between the fiber concentration and the polyelectrolyte concentration. In this example, if the PE solid content is 7% by weight, a concentration of 1% is considered ideal.

[0273] Both concentrations of fibers showed recovery of the elastic modulus of the PE hydrogel after 100% strain (Figure 7D). Just as the linear and branched morphologies of anionic polysaccharides influence their behavior, the morphology of the fibers also plays a role in the behavior of the gel. The cross-linked gelatin fibers used in this example are considered desirable branched fibers for maximizing the elastic modulus at low shear and increasing the viscosity reduction rate at high shear.

[0274] Example 7: Effect of polymer electrolyte hydrogel containing radiopaque contrast agent

[0275] A composition containing protamine sulfate and xanthan gum, with 0.5 mol of sodium chloride added, and containing 7 wt% PE solids, was combined with 25 wt% tantalum particles (1 μm to 5 μm) and 200 mg I / mL iohexol powder. When these PE hydrogels were injected, they exhibited a coiling behavior corresponding to the inner diameter of the placement catheter. The tantalum version formed a black coiled mass (Figure 9A), while the iohexol version formed a white, coilable PE hydrogel (Figure 9B). These radiopaque PE hydrogels were characterized according to the procedure of the previously described examples. The tantalum-containing device showed high viscosity at low shear, but decreased rapidly with increasing shear, exhibiting an injection force comparable to that of the tantalum-free PE hydrogel (Figure 10B). This decrease in force is presumed to be due to the inhibition of ionic interactions by the inert tantalum particles. Iohexol is soluble, and its viscosity increases due to competitive interactions between iohexol molecules and water. Iohexol may also hydrogen bond with xanthan gum, which can explain the increase in elastic modulus at low strain (Figures 10C and 10D). Similar to the fiber examples, tantalum exhibits lower recovery after strain compared to iohexol or PE hydrogels without added fibers or contrast agents. This is because ionic interactions between the components of the polyelectrolyte are blocked by the tantalum particles. Iohexol recovers more slowly than PE hydrogels without additives, but faster than PE hydrogels containing tantalum or fibers (Figure 10D).

[0276] The ability of PE hydrogels to occlude blood vessels of various sizes under various pressures and flow rates was studied using an extracorporeal flow model. At a flow rate of 20 mL / min, both tantalum PE hydrogel and iohexol PE hydrogel were able to occlude a simulated tapered blood vessel with an inner diameter of 0.012 inches (304 μm) for more than 5 minutes at a peak pressure of 157 mmHg (Figure 11). As the vessel diameter increased, the maximum occluding pressure decreased. The maximum pressure held also decreased with increasing flow rate.

[0277] A tantalum-containing polymer electrolyte (PE) hydrogel containing protamine sulfate and xanthan gum, to which 1.0 mol of sodium chloride was added, was evaluated in a pig animal model. Angiography showed that the PE hydrogel was visible upon placement and formed an occlusion (Figure 12). The material was delivered using a microcatheter with an inner diameter of 0.022 inches to 0.027 inches and a length of 110 cm to 150 cm.

[0278] Example 8: Temporary visibility of iodized contrast agent containing PE hydrogel

[0279] The elimination rate of iohexol from a PE hydrogel containing protamine and xanthanum in a 1:1 charge ratio and 7% by weight of PE solids, to which 0.75 mol of sodium chloride was added, was characterized using UV-Vis spectroscopy. Iohexol exhibited high absorbance at 240 nm–260 nm, and the peak at 245 nm was selected for characterization. 0.15 mL of iohexol PE hydrogel was injected into a gelatin vascular mold. The gelatin vascular mold simulates the expected diffusion through the vascular wall. The vascular mold containing the iohexol PE hydrogel was placed in a 50 mL centrifuge tube containing 35 mL of equilibrium salt solution (Figure 13A). This ratio of polymer electrolyte hydrogel to BSS was optimal for measuring the iohexol concentration over time using UV-Vis spectroscopy. A Nanodrop One C UV-Vis spectrometer (Thermo-Scientific) was used for the experiment. A 40-microliter sample was taken from the BSS, and measurements were performed every 5 minutes after introducing iohexol PE hydrogel into the gelatin vessels in the BSS. The elimination rate was calculated based on the absorption intensity, and the average result was plotted against time (Figure 13B).

[0280] After 5 minutes, in this example, only 10%–23% of iohexol was released from the PE hydrogel, and it took more than an hour for the iohexol to be completely released from the gel. Due to this property of the PE hydrogel structure, the embolic agent is visible for at least 5 minutes after delivery but gradually disappears, so no artifacts occur during subsequent CT scans.

[0281] Iodinated contrast agents are typically mixed with embolic materials such as PVA particles, gelatin, or other microspheres to provide visibility and visual feedback to the physician as the particles exit the catheter. The visibility is faint and fleeting, usually disappearing within 5 seconds. This carries a risk of extratarget embolism.

[0282] Example 9: Hyaluronic acid-protamine gel

[0283] Hyaluronic acid is available in a wide range of molecular weights, from very low molecular weights of less than 10 kDa to molecular weights exceeding 2 million kDa. Low molecular weight versions of HA form a viscous liquid rather than a semi-solid PE hydrogel. The molar concentration of sodium chloride added required to form a homogeneous PE hydrogel using hyaluronic acid polyanions ranges from 0 to 1 mole. High molecular weight (>500 kDa) versions of hyaluronic acid formed very strong PE hydrogels with shear-thinning properties and the ability to recover after shearing (Figure 14A). The ideal concentration, molecular weight, and sodium chloride concentration of the hyaluronic acid PE hydrogel depend on the desired size of the delivery catheter and the vascular structure to be occluded.

[0284] Example 10: Wrapping of polymer electrolyte hydrogel and shape memory of catheter

[0285] The PE hydrogel embolizer described in the above-mentioned examples demonstrated the ability to maintain the shape of the delivery catheter under simulated physiological conditions. As a result, several desirable behaviors were obtained. During simulated extracorporeal vascular occlusion, as the flow slowed downstream and the PE hydrogel embolizing material continued to be delivered from the catheter, the embolizing material spontaneously coiled and began to fill larger blood vessels (Figure 15). The significance of this behavior is that the catheter can be selected to form a desired gel-coil diameter. It also means that blood vessels of a wide range of sizes can be occluded depending on the size of the catheter, the flow conditions, the tapering of the blood vessel, and the amount of material delivered. The greater the amount of material delivered, the denser the coiled mass formed, and the larger the blood vessel that can be occluded.

[0286] Another implication of this behavior is that the shape of the catheter tip can be designed to deliver or influence the behavior of materials of a specific shape or size. For example, an angled catheter tip increases the cross-sectional area of ​​delivery, introducing the material into the vascular wall and initiating the wrapping process. A catheter tip design that splits the lumen divides the embolic agent into two coil streams, which are delivered simultaneously. Thus, a wide range of custom behaviors can be achieved through the combination of PE hydrogel properties and catheter design.

[0287] Example 11: Role of salts in chitosan-xanthan gum (CS-XG) PE hydrogel

[0288] At low ion concentrations, PE hydrogels prepared from polycationic chitosan or its cationic derivatives and polyanionic xanthan gum ionically bond to small particles, forming a viscous colloidal liquid (Figure 17A). In this example, potassium chloride was gradually added to a solution of 4.0% chitosan hydrochloride (Glentham Lifesciences) and 4.5% xanthan gum (Sigma-Aldrich), and the pH was adjusted to 5.5 using sodium hydroxide. At approximately 0.48 M KCl, the viscous liquid begins to gel. Additional salts are added to obtain the desired level of shielding. In backlight, it is more apparent when the hydrogel is sufficiently shielded. The gel may not be completely transparent due to remaining air bubbles, but there should be no shadows indicating precipitated polymer electrolytes (Figure 17, top). Subsequently, centrifugation and autoclaving yield a clear amber-colored polymer electrolyte hydrogel.

[0289] The properties of CS-XG PE hydrogels may vary depending on the type and concentration of salt used. In Figure 18A, the CS-XG hydrogel containing sodium chloride in a dry Petri dish (left) appears opaque, while the CS-XG hydrogel containing calcium chloride (center) and xanthan gum alone (right) appear transparent. Key properties of PE hydrogels are shown in Figures 18B and 18C. After adding the equilibrium salt solution to the PE hydrogels, the hydrogel containing only xanthan gum (Figure 18C, right) almost dissolved after 2 minutes, but the PE hydrogels containing chitosan and xanthan gum remained opaque and insoluble in water.

[0290] There are lower and upper limits to the optimal salt concentration for CS-XG gels. The lower limit is determined by the minimum ionic concentration required to ionically shield polyanions and polycations and form a hydrogel. The upper limit is determined by the solubility of chitosan in the presence of a specific salt or multiple salts. At high salt concentrations, chitosan salts out and becomes water-insoluble. In Figure 18A, the leftmost PE hydrogel is white, indicating that chitosan has begun to salt out due to the concentration of sodium chloride. However, sufficient charge remains to maintain a cohesive, water-insoluble gel without dissolving or fragmenting in BSS. This indicates that the salting-out phenomenon is continuous, and that even at higher salt concentrations where chitosan begins to salt out, a cohesive hydrogel with all the desirable properties for embolization can be obtained.

[0291] The lower and upper limits of salt concentration vary depending on the type of salt. To determine the upper limit, 4.0% chitosan hydrochloride solutions containing chloride salts (NaCl, MgCl2, KCl, and CaCl2) at concentrations of 0 mg / mL, 25 mg / mL, 35 mg / mL, 45 mg / mL, or 55 mg / mL were prepared. After completely hydrating the solutions for 1 hour, 0.25 mL portions were pipetted into 96-well polystyrene plates. Figure 19A shows the results of solubility evaluation at room temperature, allowing for easy confirmation of the solubility of the backlit samples. Next, solubility was quantified using UV-VIS absorbance at a wavelength of 600 nm, which is within the visible light spectrum and has low noise for these samples (Figure 19D). After placing the well plates in a -20°C freezer, the same experiment was repeated (Figures 19B and 19E). The results of both experiments indicate that the solubility of chitosan in salts is temperature-dependent, and that larger cations of CaCl2 are more soluble. 2+ and K + However, Na + and Mg 2+ This shows that monovalent metal cations have a wider solubility range in terms of mass compared to divalent metal cations, and that their solubility is improved compared to divalent metal cations. To compare the salts based on total charge molar concentration, the two experiments described above were repeated with the charge molar concentration (chloride ion molar concentration) fixed at 0.85 M. This experiment supported the previous conclusion that larger monovalent cation salts, such as KCl, have higher upper limits in terms of both mass and molar concentration compared to divalent salts or salts of smaller period 3 metal ions. The steric hindrance of larger cations is more important than the monovalent or divalent nature of the cation, resulting in a significantly higher upper limit of chitosan solubility for CaCl2 compared to NaCl or MgCl2. Figure 19F also shows the gradual salting out of chitosan and the continuity of solubility that can be quantified by absorbance.

[0292] To study the continuity of positive charge loss with increasing salt concentration, zeta potential measurements were performed on chitosan hydrochloride samples using an Anton Paar Litesizer instrument. While the zeta potential naturally decreases with increasing salt concentration, when chitosan is completely salted out and residual solubility is lost, this should be reflected by a zeta potential close to 0 mV. Figure 20A shows that although solubility appears to be lost by visual and absorbance measurements, the zeta potential decreases stepwise with increasing salt concentrations of 0.45 M and 0.85 M, where G0 represents pure chitosan hydrochloride without added salt. Figure 20A also shows that chemically modified carboxymethyl chitosan has a zeta potential of approximately -30 mV, illustrating why modified chitosan with negatively charged functional groups is unsuitable for this application.

[0293] Figure 21 shows the lower limit determined by the phase transition from a viscous liquid to a semi-solid PE hydrogel, and the upper limit determined by partial solubility loss and complete solubility loss when the PE hydrogel loses the cohesive force necessary for use as an embolizer or space filler. Figure 21A shows the data with respect to total charge molar concentration (chloride ion molar concentration), and Figure 21B shows the data with respect to total salt mass. Divalent cations form hydrogels more efficiently than monovalent cations, as can be seen from the lower limits of MgCl2 and CaCl2 starting at low chloride ion molar concentrations and low masses. Bigger cations have a much wider range than smaller cations, and overall calcium chloride is the most efficient salt, showing the lowest lower limit and a relatively wide solubility range, while potassium chloride shows the widest functional range and the highest upper limit. The results of these experiments vary slightly depending on the pH, concentration, molecular weight, and type of chitosan, so these experiments should be performed before determining the exact salt concentration for a given chitosan or chitosan derivative.

[0294] Example 12: Effect of polymer electrolyte concentration on chitosan-xanthan PE hydrogel

[0295] The effect of polyelectrolyte concentrations when the charge ratio exceeds 1:1 was investigated by preparing PE hydrogels with a fixed CaCl2 concentration of 0.27 M, high and low xanthan gum concentrations of 50 mg / mL and 40 mg / mL, and high and low chitosan concentrations of 37 mg / mL and 28 mg / mL. Before testing, all samples were autoclaved at 121°C for 30 minutes using a ventilated liquid cycle. Figure 22A shows that the peak viscosity is highest in the "high-high" formulation. When the XG concentration is low, the effect of chitosan concentration on viscosity is small. Figure 22B shows the effect of concentration on the degree of shear viscosity reduction. Xanthan gum concentration has the greatest effect on viscosity at high shear, but chitosan concentration also clearly has an effect. This indicates that reducing chitosan is beneficial to optimize the injection force and has a smaller effect on peak viscosity (Figure 22A) or recovered modulus (Figure 22C) compared to adjusting the xanthan gum concentration. As shown in Figure 22D, the recovered G' and 100s -1 By calculating the ratio of shear reduction viscosity to viscosity, the design trade-off between the initial strength of the embolic agent when it exits the delivery conduit and the force injected through the delivery conduit, such as a catheter, can be quantified. A higher value in this ratio is desirable and can indicate the point at which the effect of adjusting the polycation or polyanion begins to diminish.

[0296] Furthermore, the lower limit of chitosan concentration in CS-XG PE hydrogel was investigated. Three charge ratios (CR), i.e., 1 + :2 - , 2 + :3 - , and 1 + :1 -Preparations containing 40 mg / mL XG and 0.30 M CaCl2, with different charge ratios, were qualitatively observed over 24 hours. In Figure 23E, after 24 hours, the sample with a charge ratio of 1:2 swelled significantly and tended to break down. The sample with a charge ratio of 1:1 was clearly opaque and highly aggregated. With a charge ratio of 2:3, opacity decreased, and with a charge ratio of 1:2, dissolution began. Compared to xanthan gum or other anionic polysaccharides alone, a charge ratio of 1:2 provides long-lasting insolubility that eventually degrades over 24 hours. By adjusting the aggregation time and duration of insolubility with the charge ratio, polymer electrolyte hydrogels can be adapted to different embolic applications. Short-term embolic agents indicated with charge ratios of 1:2 or 2:3 are beneficial for sites requiring temporary occlusion, such as musculoskeletal embolization including epicondylitis, knee artery embolization, and embolization for periarthritis of the shoulder. Permanent embolizers can be manufactured with a selectable charge ratio of 1:1 or greater and are useful for embolization of most hemorrhagic conditions, prostate tumors, uterine fibroids, and hypervascular tumors.

[0297] Example 13: Enhancement of chitosan-xanthan PE hydrogel in a physiological medium

[0298] CS-XG PE hydrogels, with varying ranges of polymer electrolyte concentrations and different types of salts, can be continuously strengthened in a tunable form within a physiological medium. PE hydrogels begin as semi-solids with an elastic modulus at least twice their viscosity and do not undergo phase changes like current commercially available liquid embolizers that transform from liquid to solid through various mechanisms. Rather, as salt counterions diffuse and electrostatic interactions between chitosan and xanthan gum strengthen, the PE hydrogel gradually becomes a strong elastic semi-solid. This improves the safety of PE hydrogels in permanent embolization applications, preventing continued shear reduction in viscosity even with changes in blood flow patterns due to hypertension, vasoconstriction, or adjunctive procedures.

[0299] To demonstrate the strengthening characteristics of CS-XG PE hydrogels, four formulations were tested at various concentrations of XG and CS using either 0.75 M NaCl, 0.66 M KCl, or 0.27 M CaCl2. All had a pH of 5.7–5.95. The results are shown in Figure 24. In Figures 24A–24B, monovalent KCl is shown. + and Na + PE hydrogels manufactured using Ca 2+ The strength appears to be improved compared to formulations using Ca. 2+ This can be explained by the divalent nature of xanthan gum, which causes slow diffusion or no diffusion at all because it bridges the negatively charged branches of xanthan gum. 2+ The formulation appears to have higher ductility, undergoing significant deformation without breaking, which can be confirmed from the shape of the yield stress curve. The behavior of both monovalent and divalent PE hydrogels is useful and can be adapted to meet the needs of specific embolization procedures. In Figures 24A-24B, Na + The variation in the formulation was greater than that of the other two salts. This is due to the larger ion K, as shown in Example 11. + and Ca 2+ This is thought to be due to the higher likelihood of chitosan "salting out" in NaCl compared to chloride salts composed of the same components. The strengthening characteristics of PE hydrogels can be optimized by adjusting the concentrations of chitosan and xanthan gum, selecting the salts, or using salt combinations. One useful and possible salt combination is potassium chloride and calcium chloride, which has the best solubility compatibility with CS. When calcium chloride and potassium chloride are combined, a smaller total salt mass can be used, and the PE hydrogel is strengthened faster than with calcium chloride alone.

[0300] Example 14: Combinations of polycations in PE hydrogel

[0301] By combining polycations, PE hydrogels can be modified to specific functions. pGPMA has higher solubility than both salmin and chitosan (CS) and, when used in combination, can improve shelf life by reducing the possibility of salting out, while also increasing the positive charge density beyond the level achievable with CS alone. At high concentrations, the viscosity of pGPMA is much lower than that of CS, and when combined with CS, it can be used to modify the PE hydrogel to a desired injection force while maintaining the desired charge ratio or total polymer electrolyte content.

[0302] CS-XG hydrogels exhibit higher elongation viscosity and cohesiveness than PE hydrogels made solely from pGPMA and xanthan gum. While this is often desirable, excessive cohesiveness can lead to additional time required for separation from the catheter tip in blood vessels with low fluid flow. By combining cations, the enhanced cohesiveness and improved CS-XG PE hydrogel properties, combined with the improved solubility, injection force, and easy separation from the catheter of pGPMA PE hydrogels, result in a PE hydrogel with an improved user experience. The ideal formulation for this type of PE hydrogel is a CS to pGPMA ratio of 1:3, maintaining a total polymer electrolyte solids content of approximately 7.5%–10%. When CS is used alone at a charge ratio of less than 1:1 relative to xanthan gum, the PE hydrogel does not become permanently water-insoluble (Figure 23). However, when combined with pGPMA, low chitosan concentrations of 0.5% to 1.5% can be combined with pGPMA concentrations of approximately 1.5% to 3.5% to form a PE hydrogel with enhanced properties that can be cleanly separated from the catheter tip during delivery. When a formulation of 3.0% pGPMA, 1% CS, 4.8% XG, and 30% fine-particle tantalum powder was tested on a 3D-printed kidney flow model, this formulation easily separated from the tip, could occlude blood vessels of 100 μm to 300 μm in size at pressures greater than 150 mmHg, and could occlude blood vessels of 500 μm in size at pressures less than 70 mmHg. In all experiments, the flow rate was set to 160 mL / min (Figure 25A).

[0303] Example 15: Formation of gel coils and gel pre-jets from hydrogels

[0304] The use of CS-XG PE hydrogel gel coils and gel prejet was demonstrated using a formulation consisting of 4.2% chitosan hydrochloride, 4.5% xanthan gum, 32.5% tantalum, and 0.27M CaCl2 (pH 5.70), and the results are shown in Figures 26A-26C. The versatility of the low-viscosity extrusion medium is shown in Figure 26A, where 0.9% saline and Ultravist contrast agent extruded 0.10 mL of CS-XG through a 0.020 inch inner diameter, 150 cm long microcatheter without leaving any residue in the hub. No further material was extruded even after repeated flow through the lumen. Ten repeated injections of 0.10 mL prejet were performed, and no material was observed in the catheter hub or flowed out of the catheter lumen. The force required to inject the prejet was velocity-dependent and within the comfortable limit. The injection rate peaked when the final volume of material was pushed out of the hub into the lumen, and then tended to gradually decrease. When the injection rate was faster, reaching 1 mL / min, the proximal end of the pre-jet became significantly thinner and elongated. However, even after exiting the catheter, it self-compressed and formed aggregates.

[0305] Furthermore, gel coils and gel prejets with reduced or no salt diffusion can be manufactured by various methods. One method is to dialysis the PE hydrogel until the desired level of salt diffusion occurs. The PE hydrogel is loaded into a suitable delivery system and sterilized. A second method is to prepare the PE hydrogel by suspending it in an aqueous delivery medium immediately before use, similar to hydrating gel foam cubes and prejets before use. This method was tested with a 3 mL syringe, where 0.10 mL of PE hydrogel was pressed into a 3 mL syringe with 0.9% physiological saline and suspended in the 3 mL syringe for 1 minute. The material was then pressed into a 65 cm 4 Fr glidecath for delivery. As mentioned above, the prejet coils and conforms to itself. Gel coils and pre-jet can also be delivered with a hydrophobic medium such as oil, ethidized oil, silicone, or other suitable hydrophobic liquid. This method maintains a cleaner interface at the proximal interface of the PE hydrogel but does not exchange ions.

[0306] Example 16: Delivery system for gel coils and gel pre-jet

[0307] This specification describes a mechanical delivery system for gel coils / gel prejet. The delivery system contains a quantified amount of embolic material in a single sterile package. The user can connect the delivery system to a syringe and catheter to deliver this quantified amount of gel coil / gel prejet embolic material to the desired vascular site.

[0308] The delivery system shown in Figure 27 consists of a conduit containing a metering chamber, a female Luer connector, and a male Luer connector. A metered amount of gel coil / gel prejet embolic material (e.g., 0.1 mL, 0.2 mL, etc.) is introduced into the delivery system and contained within the metering chamber. An appropriate Luer cap is attached to the Luer connector of the conduit (i.e., the male cap is attached to the female connector and the female cap is attached to the male connector) to properly contain the embolic material within the metering chamber. The filled delivery system is packaged and sterilized. When needed, the user removes the filled delivery system from the package and removes the Luer cap. A syringe filled with an appropriate delivery medium (e.g., saline, oil, contrast agent, ethidized oil, D5W, DMSO, etc.) is attached to the female connector of the delivery system. This assembly is then attached to a properly prepared delivery catheter via the male Luer connector. The gel coil / gel prejet is delivered to the conduit by inserting a syringe plunger, thereby allowing the delivery medium in the syringe to deliver a fixed amount of gel coil / gel prejet embolic material through the delivery catheter to the desired site.

[0309] It should be emphasized that the embodiments described herein are merely feasible examples described for the sake of a clear understanding of the principles of this disclosure. Many changes and modifications may be made to the embodiments without substantially departing from the spirit and principles of this disclosure. All such changes and modifications are intended to be included within the scope of this disclosure and protected by the following claims.

Claims

1. A polymer electrolyte hydrogel comprising (a) xanthan gum, (b) one or more polycationic polymer electrolytes, and (c) ions including monovalent ions, divalent ions, or combinations thereof.

2. The aforementioned polymer electrolyte hydrogel has an initial elastic modulus greater than its viscosity. The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear when delivered through the conduit. The polymer electrolyte hydrogel according to claim 1, wherein the elastic modulus of the polymer electrolyte hydrogel recovers to a level sufficient to occlude or fill a desired location under physiological conditions.

3. The polymer electrolyte hydrogel according to claim 1, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel decrease under shear such that the injection force through the catheter is less than 20 lbf.

4. The polymer electrolyte hydrogel according to claim 1, wherein xanthan gum is present in an amount of about 1.0% to about 12% by weight of the hydrogel.

5. The polyelectrolyte hydrogel according to claim 1, wherein xanthan gum has a molecular weight of about 100 kDa to about 10,000 kDa.

6. The polycationic polymer electrolyte has 10 mol% to 90 mol% of ionized side chains when the pH exceeds 6.3, as described in claim 1.

7. The polycationic polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte comprises only cationic charged groups.

8. The polymer electrolyte hydrogel according to claim 1, wherein when the pH is approximately 4.5 to approximately 8, the charge ratio of the polycationic polymer electrolyte to the xanthan gum is 6:1 to 1:

6.

9. The polymer electrolyte hydrogel according to claim 1, wherein the initial modulus of elasticity is 200 Pa or more and less than 6000 Pa.

10. The polycationic polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte is in an amount of about 0.70% to about 15% by weight of the hydrogel.

11. The polycationic polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte comprises a pharmaceutically acceptable salt of chitosan.

12. The pharmaceutically acceptable salt of the chitosan is a hydrochloride, glutamate, or acetate, according to claim 11.

13. The polyelectrolyte hydrogel according to claim 11, wherein the chitosan has an average molecular weight of about 10 kDa to about 130 kDa.

14. The polymer electrolyte hydrogel according to claim 11, wherein the chitosan has a degree of deacetylation (DDA) greater than 85%.

15. The polymer electrolyte hydrogel according to claim 11, wherein the pharmaceutically acceptable salt of the chitosan is about 0.70% to about 8% by weight of the hydrogel.

16. The polycationic polymer electrolyte has 85 mol% to 100 mol% ionized side chains when the pH is about 4.5 to 6.3, as described in claim 1.

17. The polycationic polymer electrolyte is a polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte comprises protamine.

18. The polycationic polymer electrolyte is salmine or crupein, according to claim 1, in the polymer electrolyte hydrogel.

19. The polycationic polymer electrolyte hydrogel according to claim 17, wherein the polycationic polymer electrolyte is in an amount of about 0.70% to about 12% by weight of the hydrogel.

20. The polycationic polymer electrolyte is a natural polymer or synthetic polymer containing two or more guanidinyl side chains, as described in claim 1, for the polymer electrolyte hydrogel.

21. The polycationic polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte comprises a polyacrylate containing two or more pendanted guanidinyl groups.

22. The polycationic polymer electrolyte comprises a homopolymer containing a pendanted guanidinyl group, as described in claim 1, for the polymer electrolyte hydrogel.

23. The polycationic polymer electrolyte comprises a copolymer containing two or more pendanted guanidinyl groups, as described in claim 1, for the polymer electrolyte hydrogel.

24. The polycationic polymer electrolyte hydrogel according to claim 1, wherein the polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer comprising an acrylate skeleton, a methacrylate skeleton, an acrylamide skeleton, or a methacrylamide skeleton and two or more guanidinyl groups pendanted from the skeleton.

25. The polycationic polymer electrolyte comprises a synthetic polyguanidinyl copolymer containing a polymerization product of a monomer selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, or any combination thereof, and a pharmaceutically acceptable salt of a compound of formula I. 【Chemistry 1】 In the formula, R １ is hydrogen or alkyl group, and X is oxygen or NR ５ And here, R ５ The polymer electrolyte hydrogel according to claim 1, wherein is hydrogen or alkyl group, and m is 1 to 10.

26. The polycationic polymer electrolyte hydrogel according to claim 25, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and acrylate, methacrylate, acrylamide, or methacrylamide.

27. The polycationic polymer electrolyte hydrogel according to claim 25, wherein the polycationic polymer electrolyte comprises a copolymer product of the compound of formula I and methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-[3-(N'-dicarboxymethyl)aminopropyl]methacrylamide (DAMA), N-(3-aminopropyl)methacrylamide, N-(1,3-dihydroxypropan-2-yl)methacrylamide, N-isopropylmethacrylamide, N-hydroxyethylacrylamide (HEMA), or any combination thereof.

28. R １ The polymer electrolyte hydrogel according to claim 25, wherein is methyl, X is NH, and m is 3.

29. The polymer electrolyte hydrogel according to claim 25, wherein the molar ratio of the guanidinyl monomer to the comonomer of formula I is 1:20 to 20:

1.

30. The polyguanidinyl copolymer has an average molar mass of 1 kDa to 1000 kDa, as described in claim 25.

31. The polycationic polymer electrolyte hydrogel according to claim 20, wherein the polycationic polymer electrolyte is in an amount of about 0.70% to about 12.0% by weight of the hydrogel.

32. The polymer electrolyte hydrogel according to claim 1, wherein the ions include sodium ions, potassium ions, calcium ions, magnesium ions, or any combination thereof, and chloride ions.

33. The polymer electrolyte hydrogel according to claim 1, wherein the total concentration of the ions in the polymer electrolyte hydrogel is about 0.1 M to about 2.5 M.

34. The polymer electrolyte hydrogel according to claim 1, wherein the ions include calcium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M.

35. The polymer electrolyte hydrogel according to claim 1, wherein the ions include sodium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M.

36. The polymer electrolyte hydrogel according to claim 1, wherein the ions include potassium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M.

37. The polymer electrolyte hydrogel according to claim 1, wherein the ions include magnesium ions and chloride ions, and the total concentration of the ions in the polymer electrolyte hydrogel is about 0.10 M to about 2.50 M.

38. The polymer electrolyte hydrogel according to claim 1, further comprising a contrast agent.

39. The polymer electrolyte hydrogel according to claim 38, wherein the contrast agent is an X-ray contrast agent.

40. The polymer electrolyte hydrogel according to claim 38, wherein the contrast agent is tantalum metal particles, gold particles, or tantalum oxide particles.

41. The polymer electrolyte hydrogel according to claim 38, wherein the contrast agent is a transient contrast agent.

42. The transient contrast agent comprises an iodized organic compound, as described in claim 41, for the polymer electrolyte hydrogel.

43. The polyelectrolyte hydrogel according to claim 42, wherein the iodized organic compound comprises iopamidol, iodixanol, iohexol, iopromide, iobitridol, iomeprole, iopentol, iopamilon, ioxiran, iotorol, ioversol, iopanoate, diatrizoic acid, iotalamic acid, ioxagrate, or any combination thereof.

44. The polymer electrolyte hydrogel according to claim 42, wherein the iodized organic compound comprises iodized oil.

45. The polymer electrolyte hydrogel according to claim 38, wherein the contrast agent is up to 40 weight percent of the polymer electrolyte hydrogel.

46. The polymer electrolyte hydrogel according to claim 1, further comprising natural fibers or synthetic fibers, water-insoluble filler particles, nanoparticles, or fine particles.

47. The polymer electrolyte hydrogel according to claim 46, wherein the fiber comprises cross-linked gelatin foam fiber.

48. The polymer electrolyte hydrogel according to claim 46, wherein the fiber comprises type A cross-linked gelatin foam fiber or type A cross-linked gelatin foam fiber.

49. The polymer electrolyte hydrogel according to claim 47, wherein the fibers constitute 0.1% to 5% by weight of the polymer electrolyte hydrogel.

50. The polymer electrolyte hydrogel according to claim 1, further comprising a bioactive agent.

51. The polymer electrolyte hydrogel according to claim 50, wherein the bioactive agent comprises an antibiotic, an analgesic, an immunomodulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapeutic agent, a receptor antagonist, a nucleic acid, a chemically modified nucleic acid, or any combination thereof.

52. The polymer electrolyte hydrogel according to claim 1, further comprising a nonionic polysaccharide.

53. The polymer electrolyte hydrogel according to claim 52, wherein the nonionic polysaccharide comprises guar gum, locust bean gum, modified starch, or a combination thereof.

54. The polymer electrolyte hydrogel according to claim 1, further comprising silicate nanoparticles.

55. A polymer electrolyte hydrogel comprising (a) a pharmaceutically acceptable salt of chitosan, a polyguanidinyl copolymer, protamine, or any combination thereof; (b) a polyanionic polymer electrolyte; and (c) ions comprising monovalent ions, divalent ions, or combinations thereof.

56. The aforementioned polymer electrolyte hydrogel has an initial elastic modulus greater than its viscosity. The initial elastic modulus of the polymer electrolyte hydrogel decreases under shear when delivered through the conduit. The polymer electrolyte hydrogel according to claim 55, wherein the elastic modulus of the polymer electrolyte hydrogel recovers to a level sufficient to occlude or fill a desired location under physiological conditions.

57. The polymer electrolyte hydrogel according to claim 55, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel decrease under shear such that the injection force through the catheter is less than 20 lbf.

58. The polyanionic polymer electrolyte hydrogel according to claim 55, wherein the polyanionic polymer electrolyte comprises a polyanionic polysaccharide.

59. The polyelectrolyte hydrogel according to claim 58, wherein the polyanionic polysaccharide comprises xanthan gum, hyaluronic acid, gellan gum, alginic acid, carrageenan, or any combination thereof.

60. The polyanionic polymer electrolyte hydrogel according to claim 58, wherein the polyanionic polymer electrolyte comprises a negatively charged glycosaminoglycan or an acidic protein.

61. The polymer electrolyte hydrogel according to claim 60, wherein the negatively charged glycosaminoglycan comprises chondroitin sulfate, dermatan sulfate, keratin sulfate, or hyaluronic acid.

62. The polyanionic polymer electrolyte hydrogel according to claim 55, wherein the polyanionic polymer electrolyte comprises xanthan gum.

63. The polymer electrolyte hydrogel according to claim 62, wherein the xanthan gum is in an amount of about 1.0% to about 12% by weight of the hydrogel.

64. The polymer electrolyte hydrogel according to claim 62, wherein the xanthan gum has a molecular weight of about 100 kDa to about 10,000 kDa.

65. The polymer electrolyte hydrogel according to claim 1, wherein the elastic modulus and viscosity of the polymer electrolyte hydrogel continue to increase after being delivered to a physiological medium.

66. The polymer electrolyte hydrogel according to claim 65, wherein after 30 minutes have elapsed in the physiological medium, the elastic modulus of the polymer electrolyte hydrogel is 600 Pa to 25000 Pa.

67. The polymer electrolyte hydrogel according to claim 65, wherein the elastic modulus of the polymer electrolyte hydrogel remains greater than the viscosity.

68. The polymer electrolyte hydrogel according to claim 1, wherein, in order to increase the elastic modulus before delivery, the polymer electrolyte hydrogel is exposed to a liquid with a lower ion content than the polymer electrolyte hydrogel.

69. The polymer electrolyte hydrogel according to claim 68, wherein the modulus of elasticity continues to increase after being delivered to a physiological medium.

70. The polymer electrolyte hydrogel according to claim 68, wherein, after being delivered to a physiological medium, the elastic modulus is within ±10% of the initial elastic modulus before delivery.

71. A method for reducing or inhibiting flow within a target blood vessel, comprising the step of introducing a polymer electrolyte hydrogel according to any one of claims 1 to 70 into the blood vessel.

72. The method according to claim 71, for reducing or inhibiting blood flow to tumors, aneurysms, endoleaks, varicose veins of the lower extremities, spermatic cord vein aneurysms, gonadal veins, ovarian veins, pelvic veins, gastrointestinal arteries, rectal arteries, mesenteric arteries, gastroduodenal arteries, hepatic arteries, splenic arteries, iliac arteries, portal veins, vascular malformations, geniculate arteries, uterine fibroids, prostatic arteries, hemorrhoids, middle meningeal arteries, or hemorrhagic wounds.

73. The method according to claim 71, which strengthens the inner wall of the target blood vessel.

74. The method according to claim 71, which temporarily reduces blood flow.

75. The method according to claim 74, which temporarily reduces blood flow in the musculoskeletal region.

76. A method for filling a target cavity, comprising the step of introducing a polymer electrolyte hydrogel according to any one of claims 1 to 70 into the cavity.

77. The method according to claim 76, wherein the void is located within the bone, muscle, skin, cartilage, tissue, or organ of the subject, or the cavity is a sac or pouch attached to the bone, muscle, skin, cartilage, tissue, or organ of the subject.

78. The method according to claim 76, wherein the cavity is located in the left atrial appendage.

79. The method according to claim 76, wherein the cavity is located within a lymph node.

80. The method according to claim 76, wherein the composition is introduced into the cavity by a catheter or needle.

81. The method according to claim 76, wherein first the polymer electrolyte hydrogel is introduced into the object by a delivery system, and subsequently a low viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof is introduced into the object by a syringe connected to the delivery system.

82. The delivery system includes a housing having a first end and a second end, an internal chamber containing the polymer electrolyte hydrogel within the housing, a first Luer connector at the first end of the housing, and a second Luer connector at the second end of the housing. The method according to claim 81, wherein the needle or catheter is attached to the first Luer connector or the second Luer connector, and the one of the first Luer connector and the second Luer connector that is not attached to the needle or catheter is capable of receiving the syringe containing the low viscosity liquid, hydrophobic liquid, aqueous contrast agent, or any combination thereof.

83. The method according to claim 81, wherein the low-viscosity liquid is physiological saline, a nonionic iodized contrast agent, glucose, or distilled water for injection.

84. The method according to claim 81, wherein the low-viscosity liquid also comprises lidocaine, nitroglycerin, or verapamil.

85. The method according to claim 81, wherein the hydrophobic liquid comprises ethodized oil (lipiodol), plant-derived oil, or silicone.

86. The method according to claim 81, wherein the polymer electrolyte hydrogel is used in combination with one or more coils, plugs, liquid embolizers, or gelatin foam.

87. A delivery system for delivering a polymer electrolyte hydrogel according to any one of claims 1 to 70, The polymer electrolyte hydrogel and, A kit including instructions for administering the aforementioned polymer electrolyte hydrogel to a target.

88. A delivery system comprising a polymer electrolyte hydrogel according to any one of claims 1 to 70 inside, A kit including instructions for administering the aforementioned polymer electrolyte hydrogel to a target.

89. The kit according to claim 87, further comprising a syringe containing a low-viscosity liquid, a hydrophobic liquid, an aqueous contrast agent, or any combination thereof.

90. The kit according to claim 87, further comprising a syringe filled with dehydrated fibers, hydrated fibers, or a gel modifier.

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