WO2024027143A1

WO2024027143A1 - Absorbable autoradiographic-contrast-enhancing hydrogel, preparation method therefor and application thereof

Info

Publication number: WO2024027143A1
Application number: PCT/CN2023/078515
Authority: WO
Inventors: Zhuo Xiong; Yongsen ZHOU; Jingqi HU; Dingjun Zhang; Ting Zhang; Binhan Li; Chao Zhao; Hao ZUO
Original assignee: Tsinghua University; Tisshue Biomedical Technology (Beijing) Co., Ltd.
Priority date: 2022-08-05
Filing date: 2023-02-27
Publication date: 2024-02-08
Also published as: CN116077744A

Abstract

An absorbable autoradiographic-contrast-enhancing hydrogel, preparation method therefor and application thereof, wherein the hydrogel is formed from a precursor component and a buffer component through polymerization and has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions, wherein the precursor component includes a first component containinga star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and a second component containing a multi-amino compound, wherein the first and the second component are dissolved in the buffer component to form a first and a second hydrogel precursor component respectively, which will be mixed and delivered to a target site to form the hydrogel through an in-situ cross-linking reaction, or be mixed and after a first reaction stage undergo a second reaction stage at the target site to through an in-situ cross-linking.

Description

ABSORBABLE AUTORADIOGRAPHIC-CONTRAST-ENHANCING HYDROGEL, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to the technical field of hydrogel materials, and more particularly to an absorbable autoradiographic-contrast-enhancing hydrogel, a preparation method therefor and applications thereof.

2. Description of Related Art

Hydrogels are polymers having a three-dimensional net structure that contains hydrophilic groups. Due to physical and chemical cross-linking effects of polymers therein, a hydrogel swells in water but is insolvable to water, so is particularly useful in simulation of extracellular matrices and organismic tissues. In addition, controllable mobility, dimensions, elasticity, and hardness, as well as outstanding biocompatibility and biodegradability, make hydrogels the most used polymer material in the biomedical field.

CN114891242A discloses a radiographic-contrast-enhancing hydrogel that is formed by a first-phase solution and a second-phase solution through polymerization. Therein, the first-phase solution is formed by dissolving an iodine-containing polyethylene glycol in a first buffer solution, and the second-phase solution is formed by dissolving an amino compound in a second buffer solution. The iodine-containing polyethylene glycol is 4-arm iodine-containing polyethylene glycol or 8-arm iodine-containing polyethylene glycol, and the amino compound is trilysine, polyethylenimine or aminopolyethylene glycol, wherein the aminopolyethylene glycol is 4-arm aminopolyethylene glycol or 8-arm aminopolyethylene glycol.

Currently, X-ray-radiographic-contrast-enhancing hydrogel materials are prepared through physical or chemical methods. Therein, the existing physical methods usually involve introducing small molecules or polymers contributive to imaging into a system through blending to form a homogeneous and stable unity that has imaging ability. By comparison, the existing chemical methods usually involve introducing contrast-enhancing groups into a polymer through polymerization, grafting or terminal modification, so as to endow the polymer with imaging ability. However, since small-molecule contrast agents produced using these physical methods diffuse relatively fast in human bodies, the resulting effective windows for visibility are very short. For another, in the existing chemical methods, when contrast-enhancing groups are introduced into polymers through grafting or terminal modification, the polymers may be degraded in terms of temperature sensitivity. Thus, the existing physical and chemical methods for synthesizing hydrogel materials gave unsolved issues.

SUMMARY OF THE INVENTION

In view of the shortcomings of the prior art, the objective of the present invention is to provide an absorbable autoradiographic-contrast-enhancing hydrogel, a preparation method therefor and applications thereof, which address one or more technical issues unsolved in the prior art.

Preferably, to achieve the foregoing objective, the present invention provides an absorbable autoradiographic-contrast-enhancing hydrogel, wherein the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions.

Therein, the precursor component includes a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and a second component containing a multi-amino compound.

Therein, the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component form the hydrogel through mixing and the in-situ cross-linking reaction taking place at the target site. Particularly, the disclosed hydrogel is prepared by fully mixing the precursor component (e.g. the star-shaped multi-arm polyethylene glycol) terminated by two different functional groups with a buffer component at a target site in the body of a subject through in-situ gel formulation. After the hydrogel is implanted into the body of the subject, the buffer component (mainly anions) in the hydrogel can actively recruit salt ions surrounding it (for example, when the buffer is a phosphate buffer, the hydrogel actively recruits calcium ions in body fluids) , thereby generating inorganic nanoparticles having the desired contrast-enhancing function. The hydrogel is not only useful for in-situ isolation and protection during radiotherapy, but also has the in-situ autoradiographic-contrast-enhancing function endowed by the generated inorganic nanoparticles, thereby eliminating the need of preparing groups having the contrast-enhancing function out of the body of the subject through modification or synthesis in advance.

Preferably, the present invention provides another absorbable autoradiographic-contrast-enhancing hydrogel, the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions.

Therein, the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component mix together and undergo a first reaction stage, and then a mixture solution obtained through the first reaction stage is delivered to the target site to undergo a second reaction stage where an in-situ cross-linking reaction is performed so as to form the hydrogel. Particularly, the disclosed hydrogel is prepared by fully mixing the precursor component (e.g. the star-shaped multi-arm polyethylene glycols) terminated by two different functional groups with a buffer component at a target site in the body of a subject through in-situ gel formulation. Further, if the process where the precursor component and the buffer component fully react to form the desired hydrogel having the contrast-enhancing function would take more than five minutes, it is preferred that the precursor component and the buffer component are mixed and undergo a first reaction stage (for, for example, 2 minutes) outside the human body, and the mixture solution obtained in the first reaction stage (containing the precursor component and the buffer component) is delivered to the target site in the body of the subject to undergo a second reaction stage where in-situ gel formulation is performed, so as to form the hydrogel having the contrast-enhancing function. Therein, in the second reaction stage, the buffer component (mainly anions) in the hydrogel can actively recruit salt ions surrounding it (for example, when the buffer is a phosphate buffer, the hydrogel actively recruits calcium ions in body fluids) , thereby generating inorganic nanoparticles having the desired contrast-enhancing function. The hydrogel is not only useful for in-situ isolation and protection during radiotherapy, but also has the in-situ autoradiographic-contrast-enhancing function endowed by the generated inorganic nanoparticles, thereby eliminating the need of preparing groups having the contrast-enhancing function outside the body of the subject through modification or synthesis in advance.

Preferably, the present invention further provides an absorbable autoradiographic-contrast-enhancing hydrogel, wherein the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions.

Therein, the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component mix together, and undergo cross-linking polymerization with a solution containing the salt ions so as to form the hydrogel.

Preferably, the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester may be but not limited to one or several of a multi-arm polyethylene glycol succinimidyl glutarate, a multi-arm polyethylene glycol succinimidyl succinate, and a multi-arm polyethylene glycol succinimidyl carbonate.

Preferably, the star-shaped multi-arm polyethylene glycol terminated by the aldehyde may be but not limited to one or several of a multi-arm aromatic aldehyde-polyethylene glycol and an alkyl aldehyde-polyethylene glycol.

Preferably, the multi-amino compound includes but is not limited to one or more of amine-terminated star-shaped multi-arm polyethylene glycol, triglycine, poly-lysine and any inorganic salt derivative thereof and a branched polyethylenimine.

Preferably, the buffer component may be one or more a phosphate buffer, a borax buffer, a citrate buffer, and an acetate buffer.

Preferably, in the present invention, the first component containing a star-shaped multi- arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and the second component containing a multi-amino compound have a functional-group molar ratio of 0.2: 1 to 1: 0.2.

Preferably, in the present invention, the first hydrogel precursor component and the second hydrogel precursor component have a mass fraction ranging between 5%and 15%.

Preferably, in the present invention, the buffer component has a molar concentration ranging between 0.01 and 0.5.

Preferably, in the present invention, where the buffer component is at least one phosphate buffer, its corresponding pH is 5.5 to 7.8.

Preferably, the present invention provides a method for preparing an absorbable autoradiographic-contrast-enhancing hydrogel, comprising:

providing at least one buffer component;

providing a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde;

providing the second component containing a multi-amino compound;

dissolving the first component in the buffer component so as to obtain a first hydrogel precursor component;

dissolving the second component in the buffer component so as to obtain a second hydrogel precursor component; and

mixing and delivering the first hydrogel precursor component and the second hydrogel precursor component to a target site to undergo an in-situ cross-linking reaction so as to form the hydrogel.

Preferably, the present invention provides another method for preparing an absorbable autoradiographic-contrast-enhancing hydrogel, comprising:

providing at least one buffer component;

providing the second component containing a multi-amino compound;

mixing and subjecting the first hydrogel precursor component and the second hydrogel precursor component to a first reaction stage, and delivering a mixture solution obtained through the first reaction stage to a target site to undergo a second reaction stage where an in-situ cross-linking reaction is performed so as to form the hydrogel.

Preferably, the present invention further provides a method for preparing an absorbable autoradiographic-contrast-enhancing hydrogel, comprising:

providing at least one buffer component;

providing the second component containing a multi-amino compound;

mixing the first hydrogel precursor component and the second hydrogel precursor component to a target site to undergo a cross-linking polymerization with a solution containing the salt ions so as to form the hydrogel.

Preferably, the absorbable autoradiographic-contrast-enhancing hydrogel of the present invention is applicable to various scenes such as radiotherapy isolation, laser ablation, cryoablation, radiation isolation, spacing, and position marking. The present invention provides applications of the foregoing hydrogel in radiotherapy isolation, laser ablation, cryoablation, radiation isolation, spacing, and position marking.

Preferably, the hydrogel contains a precursor component and a buffer component that are mixed and implanted at a target site inside a subject, so that the hydrogel is formed at the target site through in-situ cross-linking reaction polymerization, and the hydrogel can spontaneously recruit its surrounding inorganic salt ions (e.g., calcium ions) to form an X-ray-autoradiographic hydrogel outline.

Preferably, the X-ray-autoradiographic hydrogel outline can decompose with degradation of major structure of the hydrogel, and be excreted from the subject through a circulatory system of the subject.

The present invention has the following beneficial effects. The disclosed medical hydrogel is formed by having fully mixed star-shaped multi-arm polyethylene glycol components terminated by two different functional groups undergo an in-situ gel formulation process, so the hydrogel advantageously has short formulation time, a low swelling rate, excellent mechanical properties, good biocompatibility, and degradability. Particularly, the disclosed hydrogel enables presentation of high quality X-ray-radiographic images without using any contrast agent. The disclosed method for preparing an injectable medical hydrogel is simple and allows the hydrogel to be customed according to practical needs in terms of mechanical performance, swelling/degradation performance, and autoradiographic-contrast-enhancing function. The resulting hydrogel is versatilely suitable for various clinical scenes such as radiotherapy isolation, laser ablation, cryoablation, radiation isolation, spacing, and position marking.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows rat subcutaneous CT images obtained on Day 0 with and without the disclosed hydrogel, respectively, wherein the left is of an experimental group using the disclosed hydrogel, and the right is of a control group not using the disclosed hydrogel;

FIG. 2 shows rat subcutaneous CT images obtained on Day 4 with and without the disclosed hydrogel, respectively, wherein the left is of the experimental group using the disclosed hydrogel, and the right is of the control group not using the disclosed hydrogel;

FIG. 3 shows rat subcutaneous CT images obtained on Day 9 with and without the disclosed hydrogel, respectively, wherein the left is of the experimental group using the disclosed hydrogel, and the right is of the control group not using the disclosed hydrogel;

FIG. 4 shows rat subcutaneous CT images obtained on Day 18 with and without the disclosed hydrogel, respectively, wherein the left is of the experimental group using the disclosed hydrogel, and the right is of the control group not using the disclosed hydrogel;

FIG. 5 shows rat subcutaneous CT images obtained on Day 26 with and without the disclosed hydrogel, respectively, wherein the left is of the experimental group using the disclosed hydrogel, and the right is of the control group not using the disclosed hydrogel;

FIG. 6 graphically shows variation in hydrogel volume over time of the experimental group using the disclosed hydrogel;

FIG. 7 graphically shows variation in hydrogel volume over time of the control group not using the disclosed hydrogel;

FIG. 8 shows images of the disclosed hydrogel obtained using a scanning electron microscope (SEM) and an energy-dispersive X-ray spectroscope (EDX) , as well as the composition of the hydrogel;

FIG. 9 shows comparison of in vivo and in vitro contrast-enhancing effects provided by the disclosed hydrogel;

FIG. 10 is a schematic structural drawing of a device for preparing the disclosed hydrogel according to a preferred implementation of the present invention;

FIG. 11 shows subcutaneous CT images of a New Zealand rabbit at different time points after subcutaneous implantation of the disclosed hydrogel, wherein FIG. 11a shows that a “white circle” indicating the existence of the hydrogel was invisible on Day 0 of the implantation, and FIG. 11b shows that such a “white circle” turned to be visible on Day 14 (in the dotted-line box) ; and

FIG. 12 shows subcutaneous CT images of an SD rat at different time points after subcutaneous implantation of a sodium hyaluronate hydrogel, wherein FIG. 12a shows that a “white circle” indicating the existence of the hydrogel was invisible on Day 7, and FIG. 12b shows that such a “white circle” turned to be visible but not complete on Day 10 (in the dotted-line box) .

List of reference numbers

1: First Injection Tube 4: Injection Head

2: Second Injection Tube 5: Fixing Clamp

3: Dual-chamber Connecting Tube

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be detailed below with reference to the accompanying drawings.

Embodiment 1

The present invention provides an absorbable autoradiographic-contrast-enhancing hydrogel, which may comprise a precursor component and a buffer component. Specifically, the precursor component and the buffer component are mixed and then implanted at a target site inside a subject, so as to form the target product, i.e., the hydrogel, at the target site through in-situ cross-linking reaction polymerization. The hydrogel can spontaneously recruit surrounding calcium ions and make them enter the hydrogel through diffusion, thereby forming an absorbable, X-ray-autoradiographic hydrogel that have desired mechanical strength through in-situ covalent cross-linking reaction. Particularly, the target site inside the subject includes but is not limited to any one of subcutaneous tissues, the chest cavity, the abdominal cavity, articular cavities, arteries, lymph nodes, marrow cavities, and soft tissues.

According to one preferred implementation, the hydrogel can acquire its X-ray-autoradiographic-contrast-enhancing function in several days after its implantation into a subject. Specifically, during CT imaging, calcium phosphate molecules generated at the target site inside the subject through the in-situ cross-linking reaction are distributed along the inner edge of the outline of the hydrogel, and exhibit as a visually obvious “white circle” . Particularly, the “white circle” significantly facilitates precise in-vivo positioning and long-term tracking and observation of the implanted hydrogel, thereby providing a reliable image basis for related therapy. Preferably, the hydrogel can be injected to a target site inside a subject and presented in an arbitrary 3D geometric shape, preferably a cylinder, or alternatively a cuboid, a cube, or a sphere. After the hydrogel is positioned in shape at the target site, it can spontaneously recruit inorganic salt ions, such as calcium ions, surrounding it inside the subject so that the calcium ions diffuse into the hydrogel, and becomes autoradiographic calcium phosphate after an in-situ covalent cross-linking reaction. The hydrogel can be accurately located when exposed to X-ray and become visible as the outline of the hydrogel, i.e., the “white circle” referred herein. It is thus clear that the term “white circle” is not limited to a circular ring but a general designation of the outline of the developed image, and the shape of the white circle is associated with the sectional shape selected for X-ray irradiation. The depth for calcium phosphate to enter the hydrogel is time-dependent. First, calcium phosphate is formed at the surface of the hydrogel and then permeates into the hydrogel over time. Under X-ray irradiation, according to the sectional shape selected, the outline of the image with the contrast enhanced by calcium phosphate can be seen as an accurate indication for radiotherapy isolation, laser ablation, cryoablation, radiation isolation, spacing, and position marking.

Specifically, accurately positioning the hydrogel during prostate radiotherapy is contributive to a solid radiotherapy plan, so as to ensure the optimal isolation. As another example, for treatment of aneurysm, accurate tracing of the embolic material allows real-time monitoring of the position of embolism and the therapeutical effects, thereby facilitating theranostics.

Particularly, in the present invention, the calcium-phosphate contrast agent generated at the target site inside the subject through the in-situ cross-linking reaction is in the form of equal-sized porous microbead clusters evenly distributed across the hydrogel network, which can be degraded with the degradation of the main structure of the hydrogel, sent to the kidneys by the circulatory system, and excreted from the body. Thus, it has good biocompatibility. Additionally, the calcium-phosphate particles generated through the in-situ cross-linking reaction may act as fillers and physically enhance the hydrogel in terms of mechanical strength and stability.

According to one preferred implementation, in the present embodiment, the precursor component may include a first component containing a first functional group and a second component containing a second functional group.

Specifically, the first component may be a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or an aldehyde. For example, the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester may include one or several of a multi-arm polyethylene glycol succinimidyl glutarate, a multi-arm polyethylene glycol succinimidyl succinate, and a multi-arm polyethylene glycol succinimidyl carbonate.

Particularly, the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester has 2 to 8 arms. Further, the star-shaped multi-arm polyethylene glycol usually has 4 or 8 arms.

According to one preferred implementation, in the present embodiment, the multi-arm polyethylene glycol succinimidyl glutarate may be an 8-arm-polyethylene glycol-succinimidyl glutarate having the structural formula below:

According to one preferred implementation, in the present embodiment, the multi-arm polyethylene glycol succinimidyl succinate may be an 8-arm-polyethylene glycol-succinimidyl succinate having the structural formula below:

According to one preferred implementation, the aldehyde group in the star-shaped multi-arm polyethylene glycol terminated by the aldehyde may be one or several of aromatic aldehyde and alkyl aldehyde.

According to one preferred implementation, the star-shaped multi-arm polyethylene glycol terminated by the aldehyde may be an 8-arm-polyethylene glycol-aldehyde group having the structural formula below:

Specifically, in the present embodiment, the second component may be a multi-amino compound, such as but not limited to amine-terminated star-shaped multi-arm polyethylene glycol, trilysine, poly-lysine and its inorganic salt derivatives or branched polyethylenimine. Particularly, the amine-terminated multi-arm polyethylene glycol has usually 2 to 8 arms.

According to one preferred implementation, amine-terminated star-shaped multi-arm polyethylene glycol may be 4-arm-polyethylene glycol-amino or 8-arm-polyethylene glycol-amino. The 8-arm-polyethylene glycol-amino has the structural formula below:

According to one preferred implementation, the trilysine and branched polyethylenimine have structural formulas below:

trilysine:

and

branched polyethylenimine:

According to one preferred implementation, the inorganic salt derivatives of the multi-amino compound may include but are not limited to hydrochloride and acetate.

According to one preferred implementation, in the present embodiment, for preparing the precursor component, i.e., the first component containing the first functional group and the second component containing the second functional group contained, the volume ratio between the first component and the second component is 1: 1. Further, the first component and the second component have a functional-group molar ratio that may be from 0.2: 1 to 1: 0.2, preferably from 0.5: 1 to 1: 0.5, and more preferably from 0.9: 1 to 1: 0.9.

According to one preferred implementation, in the present embodiment, the buffer component may include at least one phosphate buffer. Particularly, in addition to the phosphate buffer, the buffer components in the present invention may further include one or more of a borax buffer, a citrate buffer, and an acetate buffer.

According to one preferred implementation, in the present embodiment, for preparing the phosphate buffer component, the pH value of the phosphate buffer has to be controlled in a preferred range. Specifically, the preferred range for the phosphate buffer may be from 2.0 to 11.0, preferably from 2.0 to 8.0, and more preferably from 5.5 to 7.8.

According to one preferred implementation, the phosphate buffer may be prepared from sodium dihydrogen phosphate, phosphoric-acid solution and purified water.

According to one preferred implementation, where the buffer component is a borax buffer, the pH range of the borax buffer may be from 7.4 to 10.1, preferably from 7.8 to 10.0, and more preferably from 8.0 to 9.5.

According to one preferred implementation, where the buffer component is a citrate buffer, the pH range of the citrate buffer may be from 3.0 to 6.6, preferably from 4.0 to 6.6, and more preferably from 5.5 to 6.0.

According to one preferred implementation, where the buffer component is an acetate buffer, the pH range of the acetate buffer may be from 3.6 to 5.8, preferably from 4.0 to 5.8, and more preferably from 5.0 to 5.5.

According to one preferred implementation, in the present embodiment, in addition to the pH values of various buffer components, the different molar concentrations of the various buffer components in the composition of the hydrogel have to be controlled. Specifically, the molar concentration ranges of individual buffers used as the buffer components may be 0.01 to 0.5 mol/L, preferably from 0.02 to 0.25 mol/L, and more preferably from 0.05 to 0.1 mol/L.

According to one preferred implementation, in the present embodiment, the mass fraction of the precursor component in the composition of the hydrogel is dependent on the mass fraction (or the molar concentration) of the buffer component. Specifically, after the mass fractions (or the molar concentrations) of different buffer components in the composition of the hydrogel are determined according to the formula, the mass fraction (or the molar concentration) of the precursor component is controlled correspondingly in a proper range.

Specifically, in the present embodiment, the mass fraction of the precursor component may be in the range from be 2 to 50%, preferably from 2 to 20%, and more preferably from 5 to 15%.

According to one preferred implementation, the different precursor components when mixed with the buffer components form corresponding precursor components, respectively, and the mixture of the precursor components is delivered to the target site inside the subject, so as to form the target hydrogel at the target site through polymerization caused by the in-situ cross-linking reaction. Then the hydrogel can spontaneously recruit or absorb surrounding calcium ions, so that calcium ions can diffuse into the hydrogel and thereby form contrast-enhancing calcium phosphate molecules on the spot.

According to one preferred implementation, the principle for the hydrogel to be transformed into the contrast-enhancing calcium phosphate contrast agent through the in-situ reaction in vivo is as below. When the hydrogel with a certain volume is transformed in the human body, it takes up a certain amount of space in the body. The buffer component in the hydrogel is a phosphate solution containing a certain concentration of phosphate ions. The phosphate ions can bind with the calcium ions in the tissues (mainly the blood circulatory system) in the subject (in a manner that the calcium ions diffuse into the hydrogel from the surroundings of the hydrogel) , and react in the physiological environment to generated calcium phosphate molecules.

Further, as calcium phosphate generated on the spot accumulate over time, microbead clusters are formed. These microbead clusters are highly absorptive to X-ray irradiation, and shown as white highlighted parts in a CT image (similar to bones in a CT image) , and distribute right along the inner edge of the hydrogel, i.e., the “white circle” .

Particularly, many aspects, such as appearing timing, obviousness, and lasting duration of the “white circle” , or the contrast-enhancing calcium phosphate molecules, may be adapted by changing various parameters of the precursor component and/or the buffer component.

According to one preferred implementation, generation of the “white circle” , or the contrast-enhancing calcium phosphate molecules, is highly dependent on the concentration of phosphate ions in the hydrogel. The concentration of phosphate ions determines the amount of calcium phosphate molecules eventually generated. The amount of the generated calcium phosphate molecules in turn determines the brightness, or how obvious the “white circle” is in a CT image (a larger number of calcium phosphate molecules related to a more obvious “white circle” ) .

Specifically, the appearing timing of the “white circle” depends on not only how fast calcium ions diffuse in the body of the subject but also the concentration of phosphate ions. The diffusion velocity of calcium ions may be adjusted by changing the network structure and the size of pore channels inside the hydrogel (mainly determined by the cross-linking degree and the water content of the hydrogel) . The lasting duration of the “white circle” mainly depends on the degradation cycle of the hydrogel. Preferably, at the late stage of degradation, the hydrogel begins to decompose and disperse across the hydrogel network structure. As calcium phosphate molecules gradually decompose and eventually dissipate, the “white circle” disappears from the CT view. Particularly, the “white circle” may appear at about the 4th or 5th day after the hydrogel is implanted into the subject.

According to one preferred implementation, FIG. 1 to FIG. 5 show rat subcutaneous CT images obtained on Day 0, Day 4, Day 9, Day 18, and Day 26, with (the left) and without (the right) the disclosed hydrogel, respectively.

Additionally, FIG. 6 and FIG. 7 graphically show variations in hydrogel volume over time of the experimental group using the disclosed hydrogel and the control group not using the disclosed hydrogel, respectively. Specifically, as can be seen from FIG. 1 to FIG. 7, with the experimental group using the hydrogel, an obvious “white circle” gradually appeared at the target site on Day 4, and the brightness of the “white circle” increased over time. By comparison, with the experimental group, the volume of the hydrogel increased gradually over time. This can be understood as that the hydrogel became enriched in calcium phosphate molecules over time, and the calcium phosphate molecules gradually formed microbead clusters, so that the brightness and the scope of the “white circle” increase with the increase of calcium phosphate molecules.

As to one preferred implementation, FIG. 8 shows SEM and EDX images for the micropore structure of the disclosed hydrogel of the present embodiment. Therein, the image a) shows that porous microspheres (having a diameter <1μm) densely distributed in the hydrogel as seen in the scanning electron microscope (SEM) ; the image b) shows the energy-dispersive X-ray spectrum of the hydrogel of the present embodiment, wherein the “white circle” was formed by key elements including C, N, O, P, and Ca; and the image c) shows the composition of the hydrogel of the present embodiment, with a Ca-P atomic ratio of about 1.6, close to the Ga-P atomic ratio (1.5) in calcium phosphate (Ca₃ (PO₄) ₂) .

According to one preferred implementation, FIG. 9 shows comparison of in vivo and in vitro contrast-enhancing effects provided by the hydrogel of the present embodiment. Therein the image a) indicates that after the hydrogel generated in vivo through the in-situ cross-linking reaction was removed from the body, the “white circle” remained obvious in the corresponding CT image; and the image b) indicates that given a specific formula, the hydrogel prepared in vitro was not seen as the “white circle” in a CT image. Particularly, the condition for in vitro reproduction was: preparing the hydrogel in a mold (using the same formula as that used for the in vivo in-situ cross-linking reaction) , and immersing it in a solution simulating a liquid environment (normal saline containing 1.7wt%of calcium chloride, isotonic to blood serum) . As shown, the “white circle” hydrogel generated in vivo through the in-situ cross-linking reaction exhibited significant contrast-enhancing effects and the “white circle” had good evenness.

According to one preferred implementation, the contrast-enhancing function of the hydrogel of the present embodiment comes from the inorganic calcium phosphate (Ca₃ (PO₄) ₂) nanoparticles generated by in-situ combination of phosphate anions in the buffer solution and calcium ions in the human body. It is understandable that with the changes in the buffer component and in the inorganic salt particles corresponding to the buffer component, other inorganic precipitation nanoparticles providing the contrast-enhancing effect than calcium phosphate (Ca₃ (PO₄) ₂) are possible. Specifically, if the buffer is a sulfuric-acid buffer, the contrast-enhancing inorganic nanoparticles generated in the body of the subject through the in-situ cross-linking reaction are calcium sulfate.

According to one preferred implementation, FIG. 11 and FIG. 12 show time-dependent contrast-enhancing effects obtained of the disclosed absorbable autoradiographic-contrast-enhancing hydrogel and a sodium hyaluronate hydrogel subcutaneously implanted into a New Zealand rabbit and an SD rat. Therein, the disclosed absorbable autoradiographic-contrast-enhancing hydrogel subcutaneously implanted into the New Zealand rabbit was seen as a visually obvious “white circle” in the CT image around 14 days after the implantation. The sodium hyaluronate hydrogel subcutaneously implanted into the SD rat was seen as an incomplete “white circle” around 10 days after the implantation. It is thus clear that the disclosed absorbable autoradiographic-contrast-enhancing hydrogel had its brightness increased over time, and provided more significant contrast-enhancing effects than a hydrogel synthesized in vitro through introducing contrast-enhancing groups in advance.

Embodiment 2

The present embodiment provides a method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel of Embodiment 1. Particularly, since the composition of the absorbable autoradiographic-contrast-enhancing hydrogel has been explained with reference to Embodiment 1 previously, repeated description is omitted herein for conciseness.

According to one preferred implementation, the method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel in the present embodiment providing may include:

providing a precursor component and a buffer component, wherein the precursor component includes a first component and a second component;

dissolving the first component in at least one buffer component so as to obtain a first hydrogel precursor component;

dissolving the second component in at least one buffer component so as to obtain a second hydrogel precursor component;

mixing and delivering the first hydrogel precursor component and the second hydrogel precursor component to a target site; and

letting the precursor component (containing the first hydrogel precursor component and the second hydrogel precursor component) have in-situ cross-linking reaction at the target site so as to form the target hydrogel.

Alternatively, the method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel of the present embodiment may comprise:

mixing and subjecting the first hydrogel precursor component and the second hydrogel precursor component to a first reaction stage; and

delivering the mixture solution obtained through the first reaction stage (containing the first hydrogel precursor component and the second hydrogel precursor component) to the target site to undergo a second reaction stage where an in-situ cross-linking reaction is performed so as to form the hydrogel.

Particularly, when the hydrogel enters the target site inside the subject, it spontaneously recruits surrounding calcium ions and makes them enter the hydrogel through diffusion, so that the hydrogel and the calcium ions perform an in-situ reaction to form calcium phosphate molecules that have the contrast-enhancing function.

According to one preferred implementation, the target site may be but is not limited to any of subcutaneous tissues, the chest cavity, the abdominal cavity, articular cavities, arteries, lymph nodes, marrow cavities, and soft tissues of the subject.

According to one preferred implementation, in the present invention, first component may be a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or an aldehyde. For example, the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester may include one or several of a multi-arm polyethylene glycol succinimidyl glutarate, a multi-arm polyethylene glycol succinimidyl succinate, and a multi-arm polyethylene glycol succinimidyl carbonate.

Particularly, the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester usually has 2 to 8 arms.

According to one preferred implementation, in the present embodiment, the multi-arm polyethylene glycol succinimidyl glutarate may be an 8-arm-polyethylene glycol-succinimidyl glutarate.

According to one preferred implementation, in the present embodiment, the multi-arm polyethylene glycol succinimidyl succinate may be an 8-arm-polyethylene glycol-succinimidyl succinate.

According to one preferred implementation, the aldehyde group of the star-shaped multi-arm polyethylene glycol terminated by the aldehyde may be one or several of aromatic aldehyde and alkyl aldehyde.

According to one preferred implementation, the star-shaped multi-arm polyethylene glycol terminated by the aldehyde may be an 8-arm-polyethylene glycol-aldehyde group.

Specifically, in the present embodiment, the second component may be a multi-amino compound, such as but not limited to amine-terminated star-shaped multi-arm polyethylene glycol, trilysine, poly-lysine and its inorganic salt derivatives or branched polyethylenimine. Particularly, the amine-terminated multi-arm polyethylene glycol usually has 2 to 8 arms.

According to one preferred implementation, amine-terminated star-shaped multi-arm polyethylene glycol may be an 8-arm-polyethylene glycol-amino.

According to one preferred implementation, the inorganic salt derivatives of the multi-amino compound include but are not limited to hydrochloride and acetate.

According to one preferred implementation, in the present invention, for preparing the precursor component, the first component containing the first functional group and the second component containing the second functional group, the volume ratio between the first component and the second component is controlled at 1: 1. Further, the first component and the second component have a functional-group molar ratio that is from 0.2: 1 to 1: 0.2, more preferably from 0.5: 1 to 1: 0.5, and most preferably from 0.9: 1 to 1: 0.9.

According to one preferred implementation, in the present invention, the buffer component includes at least one phosphate buffer. Further, in the present embodiment, for preparing the phosphate buffer component, the pH value of the phosphate buffer is controlled in a preferred range. Specifically, the pH range corresponding to the phosphate buffer may be from 2.0 to 11.0, preferably from 2.0 to 8.0, and more preferably from 5.5 to 7.8.

According to one preferred implementation, in the present invention, the buffer component may further include one or more of a borax buffer, a citrate buffer, and an acetate buffer.

According to one preferred implementation, where the buffer component is a borax buffer, the pH range corresponding to the borax buffer may be from 7.4 to 10.1, preferably from 7.8 to 10.0, and more preferably from 8.0 to 9.5.

According to one preferred implementation, where the buffer component is a citrate buffer, the pH range corresponding to the citrate buffer may be from 3.0 to 6.6, preferably from 4.0 to 6.6, and more preferably from 5.5 to 6.0.

According to one preferred implementation, where the buffer component is an acetate buffer, the pH range corresponding to the acetate buffer may be from 3.6 to 5.8, preferably from 4.0 to 5.8, and more preferably from 5.0 to 5.5.

According to one preferred implementation, in the present embodiment, in addition to pH values of various buffer components, different molar concentration ratios of various buffer components in the composition of the hydrogel are controlled. Specifically, the molar concentration range of a buffer used as the buffer component is preferably from 0.01 to 0.5 mol/L, more preferably from 0.02 to 0.25 mol/L, and most preferably from 0.05 to 0.1 mol/L.

According to one preferred implementation, in the present embodiment, the mass fraction of the precursor component in the composition of the hydrogel is dependent on the mass fraction (or molar concentration) of the buffer component. Specifically, the mass fractions (or molar concentrations) of various buffer components in the composition of the hydrogel are first determined according to the formula, and then the mass fraction (or molar concentration) of the precursor component is controlled accordingly in a proper range.

Specifically, in the present embodiment, the mass fraction of the precursor component may range from 2 to 50%, preferably from 2 to 20%, and more preferably from 5 to 15%.

According to one preferred implementation, the present embodiment relates to a method for preparing a hydrogel that has an X-ray autoradiographic-contrast-enhancing function, which eliminates the need of chemically modifying the polymer gel network for anchoring any contrast-enhancing group or substance (e.g., an iodine compound, barium sulfate, etc. ) in advance. Instead, it produces a contrast agent having the desired contrast-enhancing function through implantation and in-situ synthesis, thereby significantly simplifying the process for preparing the contrast-enhancing hydrogel, and the contrast-enhancing hydrogel formed through in vivo in-situ cross-linking provides better homogeneity and clarity than those synthetized in vitro.

Embodiment 3

The present embodiment provides a preparing device used to implement the method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel of Embodiment 2. Particularly, since the method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel has been explained with reference to Embodiment 2 previously, repeated description is omitted herein for conciseness.

According to one preferred implementation, as shown in FIG. 10, a preparing device (or referred to as a delivering device) of the present embodiment may comprise a first injection tube 1, a second injection tube 2, a dual-chamber connecting tube 3, an injection head 4, and a fixing clamp 5.

According to one preferred implementation, as shown in FIG. 10, the outlet ends of the first injection tube 1 and the second injection tube 2 are connected to outlets of the two liquid connecting pipes of the dual-chamber connecting tube 3 that is roughly Y-shaped, respectively. Further, the dual-chamber connecting tube 3 has its outlet far from the first injection tube 1 and the second injection tube 2 connected to the injection head 4. Preferably, the solutions contained in the first injection tube 1 and in the second injection tube 2 are sent to the dual-chamber connecting tube 3 and mixed fully in the dual-chamber connecting tube 3, and then the mixture solution is delivered to the target site inside the subject through the injection head 4 located at the end of the dual-chamber connecting tube 3, so as to form the hydrogel at the target site through an in-situ cross-linking reaction.

According to one preferred implementation, as shown in FIG. 10, the first injection tube 1 and the second injection tube 2 may be fixed using a fixing clamp 5 that has retaining recesses, so that the injection operation happens synchronously between the first injection tube 1 and the second injection tube 2. Specifically, as shown in FIG. 10, the fixing clamp 5 has a pair of engaging portions that are arranged symmetrically. The engaging portions each have a channel that is shaped to the first injection tube 1 and/or the second injection tube 2 and is such engaged with the first injection tube 1 and/or the second injection tube 2 from outside that it embraces at least a part of the periphery of the first injection tube 1 and/or the second injection tube 2. Particularly, the distance between the two channels of the fixing clamp 5 is dependent on the distance between the first injection tube 1 and the second injection tube 2, and is dependent on the types and dimensions of the roughly Y-shaped dual-chamber connecting tube 3.

According to one preferred implementation, as shown in FIG. 10, a connecting portion is provided at the middle of the fixing clamp 5. The connecting portion serves to hold and connect the engaging portions at its two sides for engaging the first injection tube 1 and the second injection tube 2. Particularly, the connecting portion and the engaging portions at its two sides may be fixedly connected. Alternatively, they may be detachably connected. Preferably, the detachable connection may be realized by means of, for example, rails and slides.

According to one preferred implementation, as shown in FIG. 10, the connecting portion has a pushing portion close to the side where the first injection tube 1 and the second injection tube 2 are located. Specifically, the pushing portion includes a link and a pressing portion located at the end of the link. Further, the pressing portion is a platform covering both the first injection tube 1 and the second injection tube 2. Preferably, after the fixing clamp 5 is connected to and engaged with the first injection tube 1 and the second injection tube 2, respectively, as planned, the pressing portion of the fixing clamp 5 can be pressed to make the advancing ends the first injection tube 1 and the second injection tube 2 move in the direction along which the liquids is supposed to flow out, thereby pushing the liquids contained in the first injection tube 1 and the second injection tube 2 to the dual-chamber connecting tube 3 where they are fully mixed before delivered to the target site inside the subject through the injection head 4 at the end of the dual-chamber connecting tube 3, so that they can form the hydrogel of the present invention the at the target site through an in-situ cross-linking reaction.

Particularly, first injection tube 1 may be used to contain any one of the first hydrogel precursor component and the second hydrogel precursor component, such as, for example, the first hydrogel precursor component. The second injection tube 2 may be used to contain the other one of first hydrogel precursor component and the second hydrogel precursor component, such as, for example, the second hydrogel precursor component. Specifically, the first hydrogel precursor component may be obtained by dissolving the first component containing the first functional group as described in Embodiment 1 to at least one buffer component. The second hydrogel precursor component may be prepared by dissolving the second component containing the second functional group as described in Embodiment 1 in at least one buffer component.

According to one preferred implementation, to use the preparing device of the present embodiment to perform the method of Embodiment 2 for preparing the absorbable autoradiographic-contrast-enhancing hydrogel of Embodiment 1, the first hydrogel precursor component and the second hydrogel precursor component are first mixed at a predetermined concentration ratio and added into the first injection tube 1 and the second injection tube 2, respectively. Afterward, the dual-chamber connecting tube 3 and the injection head 4 are connected to the first injection tube 1 and the second injection tube 2 successively according to the assembly plan, and the fixing clamp 5 is fixed to the first injection tube 1 and the second injection tube 2 at proper fixing sites.

To operate, the pressing portion of the fixing clamp 5 is pressed so as to send the first hydrogel precursor set and the second hydrogel precursor set contained in the first injection tube 1 and the second injection tube 2, respectively, to the dual-chamber connecting tube 3 at the same time. The two parts are fully mixed in the dual-chamber connecting tube 3 and the mixture is injected into the body of the subject at the target site through the injection head 4, thereby forming the hydrogel of the present invention at the target site through the in-situ cross-linking reaction.

According to one preferred implementation, the X-ray-autoradiographic-contrast-enhancing function of the hydrogel becomes effective in several days after its implantation. Specifically, after the hydrogel is implanted into the body of a subject, due to its porous structure and the presence of a large number of anions (phosphate ions) , the hydrogel spontaneously recruits surrounding calcium ions and let them diffuse into its interior, thereby gradually generating contrast-enhancing calcium phosphate molecules on the spot, which form the “white circle” as described in Embodiment 1 and Embodiment 2. Particularly, one or more aspects, such as appearing timing, obviousness, and lasting duration of the “white circle” may be adjusted by changing various parameters of the precursor solution.

Embodiment 4

The present embodiment provides a gel injection system that uses the absorbable autoradiographic-contrast-enhancing hydrogel of Embodiment 1 and/or the method for preparing the absorbable autoradiographic-contrast-enhancing hydrogel of Embodiment 2.

According to one preferred implementation, the disclosed gel injection system may include an injection device (e.g., Embodiment 3) , a collector, a processor, and an analyzing unit.

According to one preferred implementation, the collector may be used to collect at least one type of position data related to the injection device while the injection device performs injection operations. Specifically, the collector may be an ultrasonic component, whose probe is placed at a target implantation site in the body of a subject to act as a guiding component. Alternatively, the collector may be a computed tomographic scanner or work on other examination methods such as magnetic resonance imaging and positron emission tomography.

According to one preferred implementation, the processor may include a first processor and a second processor. Therein, the first processor can process the position data acquired by the collector and send the at least one type of position data to the second processor. The second processor then based on the processed position data of the injection device adjusts the injection device for the next injection step.

Further, the analyzing unit can comparatively analyze the sagittal planes and the transverse plane at the implantation depth of the injection device at the target site in the body of the subject according to the position data of the injection device, so as to at least provide hazard risk assessment for the next injection step of the injection device directed by the second processor. Specifically, for a patient standing upright, the site to be examined in the body of the patient can be split into left and right parts, and the left and right sections are the sagittal planes. The transverse plane refers to the plane passing through the centerline of site to be examined a in a patient standing upright and perpendicular to the sagittal planes. The sagittal planes and the transverse plane vary with the body posture of the patient.

According to one preferred implementation, the collector may be located at the target site for implantation and close to the skin of the patient so as to collect position data of the site for injection, and can transmit the position data to the first processor. Further, the first processor performs data processing to get the implantation depth and the implantation angle of the injection device and transmits the information to the second processor, which moves the injection device to the corresponding depth and angle. Particularly, with the first processor that processes the data and adjust the operation of the injection device accordingly, the injection device can be pushed into the human body at a constant speed and inject the precursor solutions at a constant speed based on the capacity ratio, thereby facilitating formulation of the gel preparation and reducing complications.

According to one preferred implementation, when the injection device reaches the target implantation depth, based on the position data acquired by the collector and the data process performed by the first processor, the injection device is stopped from further advancing and injecting the precursor solution contained in the injection device. Further, based on the position data acquired by the collector, if the first processor determines that the injection device has to be further pushed for a depth that may be a movement distance from the current position of the injection device to the designation of the implantation. Particularly, based on the distance, the injection device is pushed at a constant speed and based on the liquid capacity of the injection device and the distance, the precursor solution is injected at a constant speed. When the injection needle is located at the target position, the remaining liquid is injected, so that the total amount of the injected liquid is the first capacity.

According to one preferred implementation, the analyzing unit can determine the sagittal planes and the transverse plane of the injection device at the implantation depth on the target site in the body of the subject based on the position data acquired by the collector and/or ultrasonic examination and perform risk comparison against a predetermined scheme. Specifically, the risk comparison at least involves whether the injection device is accurately positioned and whether the implantation depth or angle is accurate.

It is to be noted that the specific embodiment described previously are only intended to explain the present invention, and any modification devised by a person skilled in the art in light of the disclosure of the present invention shall be protected by the rights of the present invention. Also, as shall be appreciated by people skilled in the art, the description and drawings of the present invention are illustrative and not limiting. The scope of the present invention shall be defined by the appended claims and equivalents thereof. The description of the present invention contains various inventive conceptions, and a paragraph herein led by any of “preferably” , “according to one preferred mode” and “optionally” represents a disclosure of an independent conception of the present invention. The applicant reserves the right to file a divisional application for any of these conceptions.

Claims

Application of a hydrogel in radiotherapy isolation, laser ablation, cryoablation, radiation isolation, spacing, and position marking, wherein the hydrogel is formed by mixing and delivering a first hydrogel precursor component and a second hydrogel precursor component to a target site and performing an in-situ cross-linking reaction at the target site.
The application of claim 1, wherein the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions, wherein

the precursor component includes a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and a second component containing a multi-amino compound, wherein

the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component form the hydrogel through mixing and the in-situ cross-linking reaction taking place at the target site.
The application of claim 1, wherein the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions, wherein

the precursor component includes a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and a second component containing a multi-amino compound, wherein

the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component mix together and undergo a first reaction stage, and then a mixture solution obtained through the first reaction stage is delivered to the target site to undergo a second reaction stage where an in-situ cross-linking reaction is performed so as to form the hydrogel.
The application of claim 1, wherein the hydrogel is formed from a precursor component and a buffer component by means of polymerization, and the hydrogel has a contrast-enhancing function stemming from inorganic nanoparticles generated by in-situ combination between anions in the buffer component and salt ions, wherein

the precursor component includes a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and a second component containing a multi-amino compound, wherein

the first component is dissolved in the buffer component to form the first hydrogel precursor component and the second component is dissolved in the buffer component to form the second hydrogel precursor component, so that the first hydrogel precursor component and the second hydrogel precursor component mix together, and undergo cross-linking polymerization with a solution containing the salt ions so as to form the hydrogel.
The application of any of claims 2 to 4, wherein the star-shaped multi-arm polyethylene glycol terminated by the N-hydroxysuccinimide-activated ester includes one or more of a multi-arm polyethylene glycol succinimidyl glutarate, a multi-arm polyethylene glycol succinimidyl succinate, and a multi-arm polyethylene glycol succinimidyl carbonate.
The application of any of claims 2 to 4, wherein the multi-amino compound includes one or more of an amine-terminated star-shaped multi-arm polyethylene glycol, a trilysine, a poly-lysine and any inorganic salt derivative thereof and a branched polyethylenimine.
The application of any of claims 2 to 4, wherein the star-shaped multi-arm polyethylene glycol terminated by the aldehyde includes one or more of a multi-arm aromatic aldehyde-polyethylene glycol and an alkyl aldehyde-polyethylene glycol.
The application of any of claims 2 to 4, wherein the buffer component comprises one or more of a phosphate buffer, a borax buffer, a citrate buffer, and an acetate buffer.
The application of any of claims 2 to 4, wherein the first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde and the second component containing a multi-amino compound have a functional-group molar ratio of 0.2: 1 to 1: 0.2.
The application of any of claims 2 to 4, wherein the first hydrogel precursor component and the second hydrogel precursor component have a mass fraction ranging between 5%and 15%.
The application of any of claims 2 to 4, wherein the buffer component has a molar concentration ranging between 0.01 and 0.5.
The application of claim 1, wherein the hydrogel is formed from a precursor component and a buffer component, wherein the precursor component and the buffer component are mixed and implanted to the target site inside a subject, so as to form the hydrogel at the target site through polymerization caused by the in-situ cross-linking reaction, and the hydrogel can spontaneously recruit inorganic salt ions surrounding it to form an X-ray-autoradiographic hydrogel outline.
The application of claim 12, wherein the X-ray-autoradiographic hydrogel outline can decompose with degradation of major structure of the hydrogel, and be excreted from the subject through a circulatory system of the subject.
A method for preparing an absorbable autoradiographic-contrast-enhancing hydrogel, comprising:

providing at least one buffer component;

providing a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde;

providing a second component containing a multi-amino compound;

dissolving the first component in the buffer component so as to obtain a first hydrogel precursor component;

dissolving the second component in the buffer component so as to obtain a second hydrogel precursor component; and

mixing and delivering the first hydrogel precursor component and the second hydrogel precursor component to a target site to undergo an in-situ cross-linking reaction so as to form the hydrogel.
A method for preparing an absorbable autoradiographic-contrast-enhancing hydrogel, comprising:

providing at least one buffer component;

providing a first component containing a star-shaped multi-arm polyethylene glycol terminated by an N-hydroxysuccinimide-activated ester or by an aldehyde;

providing a second component containing a multi-amino compound;

dissolving the first component in the buffer component so as to obtain a first hydrogel precursor component;

dissolving the second component in the buffer component so as to obtain a second hydrogel precursor component; and

mixing and subjecting the first hydrogel precursor component and the second hydrogel precursor component to a first reaction stage, and delivering a mixture solution obtained through the first reaction stage to a target site to undergo a second reaction stage where an in-situ cross-linking reaction is performed so as to form the hydrogel.