阅读说明：本技术 一种用于预防手术后组织粘连的多功能超分子水凝胶及制备方法 (Multifunctional supramolecular hydrogel for preventing postoperative tissue adhesion and preparation method thereof ) 是由 张建祥 王言 李兰兰 马永昌 郭嘉伟 窦寅 于 2020-06-05 设计创作，主要内容包括：本发明公开了一种用于预防手术后组织粘连的多功能超分子水凝胶及制备方法。所述水凝胶由可注射温敏成凝胶材料、活性氧清除性药物和多酚类化合物三种组分构成。制备时,将上述三种组分按一定顺序在水中均匀混合即可得到用于预防手术后组织粘连的多功能超分子水凝胶。其中,可注射温敏成凝胶材料0.1-30wt％,活性氧清除性药物0.01-10wt％,多酚类化合物0.1-50wt％。该凝胶材料可在椎板切除术中局部应用防治硬膜外纤维化粘连以及其他外科手术后组织粘连。给药方式包括皮下注射、腔内注射、涂抹,以及以上任意方式的组合。本发明制备的水凝胶具有合适的温敏性溶胶-凝胶相转变温度,具有合适的生物黏附能力,具有理想的粘弹性、柔软性。(The invention discloses a multifunctional supermolecule hydrogel for preventing postoperative tissue adhesion and a preparation method thereof. The hydrogel is composed of an injectable temperature-sensitive gel forming material, an active oxygen scavenging drug and a polyphenol compound. When in preparation, the three components are uniformly mixed in water according to a certain sequence to obtain the multifunctional supermolecule hydrogel for preventing postoperative tissue adhesion. Wherein, 0.1 to 30 weight percent of injectable temperature-sensitive gel forming material, 0.01 to 10 weight percent of active oxygen scavenging medicament and 0.1 to 50 weight percent of polyphenol compound. The gel material can be locally applied in laminectomy to prevent and treat epidural fibrosis adhesion and tissue adhesion after other surgical operations. Modes of administration include subcutaneous injection, intraluminal injection, painting, and combinations of any of the above. The hydrogel prepared by the invention has proper temperature-sensitive sol-gel phase transition temperature, proper biological adhesion capability and ideal viscoelasticity and flexibility.)

1. A multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion, characterized by: comprises an injectable temperature-sensitive gel-forming material, an active oxygen scavenging medicament and a polyphenol compound, which are prepared according to the following specific weight: 0.1-30 wt% of injectable temperature-sensitive gel-forming material, 0.01-10 wt% of active oxygen scavenging drug and 0.1-50 wt% of polyphenol compound.

2. The multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in claim 1, characterized in that: the injectable temperature-sensitive gel-forming material is selected from poloxamer 407, poloxamer 188 or poly (lactic-glycolic acid) -polyethylene glycol-poly (lactic-glycolic acid) terpolymer.

3. The multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in claim 1, characterized in that: the active oxygen scavenging drug is selected from N-acetylcysteine, vitamin C, glutathione, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxygen free radical, nanoparticles based on a phenylboronic acid pinacol ester bond cyclodextrin material, nanoparticles based on a Tempol/phenylboronic acid pinacol ester co-bonded cyclodextrin material, or nanoparticles based on a luminol bonded cyclodextrin material.

4. The multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in claim 1, characterized in that: the polyphenol compound has tissue adhesion property, and is selected from tannic acid, epigallocatechin gallate, catechin, gallic acid or dopamine.

5. The multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in any one of claims 1 to 4, prepared by the following method: firstly, adding a polyphenol compound into water, and stirring to fully dissolve the polyphenol compound; then adding the injectable temperature-sensitive gel-forming material into the solution, and stirring for fully dissolving; and finally, adding the active oxygen scavenging medicament into the solution, and shaking up the solution to obtain the supermolecule multifunctional hydrogel.

6. A preparation method of multifunctional supramolecular hydrogel for preventing postoperative tissue adhesion is characterized by comprising the following steps: firstly, adding a polyphenol compound into water, and stirring to fully dissolve the polyphenol compound; then adding the injectable temperature-sensitive gel-forming material into the solution, and stirring for fully dissolving; and finally, adding the active oxygen scavenging medicament into the solution, and shaking up the solution to obtain the supermolecule multifunctional hydrogel.

7. The method of preparing a multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in claim 6, wherein: the addition ratio of the polyphenol compound, the injectable temperature-sensitive gel forming material and the active oxygen scavenging medicament is 0.1-50 wt%: 0.1-30 wt%: 0.01-10 wt%.

8. The method of preparing a multifunctional supramolecular hydrogel for preventing post-surgical tissue adhesion as claimed in claim 6, wherein: the concentration of the active oxygen-scavenging drug is 0.01-10 wt%.

9. Use of the multifunctional supramolecular hydrogel according to any one of claims 1 to 5 for the preparation of a medicament for the prevention of tissue adhesion after surgery.

10. Use of a multifunctional supramolecular hydrogel according to claim 9 for the preparation of a medicament for the prevention of tissue adhesion after surgery, characterized in that: modes of administration include subcutaneous injection, intramuscular injection, intraluminal injection, painting, and combinations of any of the above.

Technical Field

The invention relates to a supermolecule hydrogel with multiple functions of temperature-responsive gelation, self-healing, tissue adhesion, antioxidation, inflammation resistance, fibrosis resistance and the like, in particular to a material for preventing and treating epidural fibrosis adhesion after laminectomy and other tissue adhesion after surgical operation by reducing local oxidative stress and inflammation level of a focus, and a composition and a preparation method thereof.

Background

Lumbar laminectomy is one of the most common spinal procedures and is effective in relieving the compression of the spinal cord or nerve roots by surrounding tissues. However, about 8-40% of patients after a lumbar discectomy suffer from failed lumbar surgery syndrome (FBSS). FBSS is caused by many and complicated causes, and extensive adhesion of dura mater and nerve roots to tissues such as peripheral muscles, ligaments, and fibrous rings, which is caused by epidural fibrosis, is considered to be an important cause of FBSS. In recent years, minimally invasive spinal surgery has been developed rapidly, and minimally invasive surgical methods, surgical equipment and tools have advanced greatly, which significantly reduce the operation scale of most operations and tissue trauma caused by the operations. However, the complication of postoperative epidural fibrotic adhesions remains unavoidable and the challenge of clinical treatment remains. It is difficult and troublesome to solve such complications through secondary operations because the probability of nerve root damage and dura mater tear during secondary operations is high and the risk of the operations is extremely high. Meanwhile, the secondary surgical treatment causes great pain and risk to patients and also increases great pressure on social medical resources.

Currently, many experimental studies for preventing epidural fibrosis and reducing dural adhesion are reported in succession, mainly including drug therapy, biomaterial barrier protection, and drug-biomaterial combination methods. However, the developed anti-fibrotic adhesion biomaterials have limited therapeutic effects and have some side effects, and only a few of them enter clinical trials, but there are few widely accepted clinical biomaterial products.

From the pathological mechanism of epidural fibrosis, epidural adhesion develops gradually from scar tissue, and fibroblasts play an important role in the formation of scar tissue. Local inflammation and hematoma resulting from surgical procedures can affect fibroblasts to promote the gradual formation of adhesions. After activation of inflammatory cytokines and growth factors in the laminectomy area, a number of fibroblasts proliferate extensively and produce a large amount of collagen fibers to repair tissue defects localized to the laminectomy area. Meanwhile, the oxidative stress reaction promotes the infiltration capacity of inflammatory cells, the molecular mediators are up-regulated, the proliferation of fibroblasts and the synthesis of extracellular matrix are further promoted, and compact scar tissues are finally formed. In addition, oxidative stress-mediated release of Reactive Oxygen Species (ROS) can induce cellular damage, promote the production of inflammatory mediators, and further exacerbate chronic inflammation. The use of 2,2,6, 6-tetramethylpiperidine nitroxide (Tpl), a small molecule compound, has been tried to prevent and treat the adhesion formation after peritoneal surgery by removing the hydrogen peroxide from the surgical site after peritoneal surgery. However, hydrogen peroxide is only one of many ROS, and it is far from sufficient to scavenge hydrogen peroxide in the surgical site. Thus, the combination of anti-fibrosis, anti-inflammatory and reactive oxygen species scavenging to reduce oxidative stress is an effective strategy for preventing post-operative epidural fibrotic adhesions and other post-surgical tissue adhesions.

Disclosure of Invention

In view of the above problems, it is an object of the present invention to solve some of the problems of the prior art, or at least to alleviate them. Therefore, the invention aims to provide the supermolecular multifunctional hydrogel and the preparation method thereof.

A multifunctional supermolecule hydrogel for preventing postoperative tissue adhesion comprises an injectable temperature-sensitive gel-forming material, an active oxygen scavenging drug and a polyphenol compound, which are prepared according to the following specific gravity: 0.1-30 wt% of injectable temperature-sensitive gel-forming material, 0.01-10 wt% of active oxygen scavenging drug and 0.1-50 wt% of polyphenol compound.

Further, the injectable temperature-sensitive gel-forming material is selected from poloxamer 407, poloxamer 188 or a poly (lactic-co-glycolic acid) -polyethylene glycol-poly (lactic-co-glycolic acid) terpolymer.

Further, the active oxygen scavenging drug is selected from the group consisting of N-acetylcysteine, vitamin C, glutathione, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl (Tempol), nanoparticles based on a pinacol ester bond cyclodextrin material of phenylboronic acid, nanoparticles based on a Tempol/pinacol ester co-bond cyclodextrin material of phenylboronic acid, or nanoparticles based on a luminal bond cyclodextrin material.

Further, the polyphenol compound has tissue adhesion property and is selected from tannic acid, epigallocatechin gallate, catechin, gallic acid or dopamine.

The invention also provides a preparation method of the supermolecule multifunctional hydrogel, which comprises the following steps: firstly, adding a polyphenol compound into water, and stirring to fully dissolve the polyphenol compound; then adding the injectable temperature-sensitive gel-forming material into the solution, and stirring for fully dissolving; and finally, adding the active oxygen scavenging medicament into the solution, and shaking up the solution to obtain the supermolecule multifunctional hydrogel.

The multifunctional supramolecular hydrogel disclosed by the invention is applied to preparation of a medicine for preventing tissue adhesion after a surgical operation. Including but not limited to the preparation of the medicine for preventing and treating epidural fibrosis adhesion after lumbar spine resection operation.

The administration mode of the invention comprises subcutaneous injection, intramuscular injection, intracavity injection, smearing and the combination of any mode.

The invention has the beneficial effects that:

(1) the hydrogel can be used by injection, and can perform minimally invasive surgery;

(2) the hydrogel has a proper temperature-sensitive sol-gel phase transition temperature, completely covers the tissue surface when in use, and then is gelatinized to form an effective physical barrier;

(3) the hydrogel has proper biological adhesion capacity, prevents the material from being stripped from spinal cord tissues, and can conveniently regulate and control the adhesion performance through the type and the dosage of the polyphenol compounds;

(4) the hydrogel has proper in vivo residual time on the premise of ensuring the clinical effect, and avoids serious foreign body reaction caused by long-time residual;

(5) the hydrogel has ideal viscoelasticity and flexibility, does not influence the natural activity of spinal cord and avoids possible nerve compression;

(6) the hydrogel prevents and treats epidural fibrosis and postoperative tissue adhesion through effective antioxidant stress, anti-inflammatory and anti-fibrosis effects;

(7) the hydrogel has good biocompatibility and nerve function safety;

(8) the hydrogel can also be used as a drug delivery carrier material with bioadhesion;

(9) the hydrogel preparation method is simple, the preparation process is stable and controllable, and the large-scale production is easy to realize;

(10) in the preparation method of the hydrogel, the polyphenol compound is added firstly, and the injectable temperature-sensitive gel forming material and the active oxygen scavenging medicament are added after the polyphenol compound is dissolved. If the order of addition is changed, the dissolution rate of the solution may be slowed or insufficient dissolution may occur.

Drawings

FIG. 1 is a photograph of the sol-gel phase transition of a supramolecular multifunctional hydrogel (abbreviated as PXNT) under temperature change.

Figure 2 is a photograph of the distribution of Cy 5-labeled nanoparticles (dots in the figure) based on Tempol/phenylboronic acid pinacol ester co-bonded beta cyclodextrin material dispersed in PXNT hydrogel containing FITC-labeled poloxamer 407 (background in the figure).

FIG. 3 is (a) a typical scanning electron microscope image of the surface topography of a PXNT hydrogel, showing the protrusion of nanoparticles; and (b, c and d) are scanning electron microscope images of the PXNT hydrogel fracture surface under different resolutions, and a graph d shows that spherical nanoparticles are embedded in the gel.

Figure 4 is an assessment of the adhesion performance of PXNT gels of varying tannin content on dura mater and muscle tissue.

Fig. 5 shows in vitro hydrolysis and release properties (a, b) and in vivo residence time statistics (c) of PXNT hydrogel, PXN being hydrogel without tannins.

Fig. 6 is an epidural gross appearance picture and epidural fibrosis gross appearance score statistics for rats 8 weeks after PXNT hydrogel treatment and model group surgery.

Fig. 7 is PXNT hydrogel rheology test results.

Figure 8 is an image of a typical post-operative 8-week MRI scan of rats treated with PXNT hydrogel.

Fig. 9 is a picture of HE staining of rats after PXNT hydrogel treatment and a typical 8-week model group, and statistics of epidural fibrosis score and fibroblast infiltration score.

Fig. 10 is a typical gross and nmr image of a rabbit treated with PXNT hydrogel and model set, and statistics of gross scores and nmr epidural fibrosis scores.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments. It is to be understood that the embodiments of the present invention are merely for illustrating the present invention and not for limiting the present invention, and that various substitutions and alterations made according to the common knowledge and conventional means in the art without departing from the technical idea of the present invention are included in the scope of the present invention. The invention is illustrated in detail below with reference to non-limiting examples.

Example 1

At room temperature, 0.2g of tannic acid is added into 6mL of ultrapure water, stirred and dissolved at room temperature, then 1.8g of poloxamer 407 is added, fully stirred and dissolved, finally 2mL of nanoparticle aqueous solution with the concentration of 5mg/mL and based on Tempol/pinacol phenylboronate co-bonded beta-cyclodextrin material is added, and the solution is uniformly shaken, so that the supermolecule multifunctional hydrogel is obtained.

Example 2

At room temperature, 0.2g of dopamine is added into 6mL of ultrapure water, stirred and dissolved at room temperature, then 1.8g of poloxamer 188 is added, stirred and dissolved fully, finally 2mL of N-acetylcysteine aqueous solution with the concentration of 5mg/mL is added, and the mixture is shaken uniformly, so that the supermolecule multifunctional hydrogel is obtained.

Example 3

At room temperature, firstly adding 0.3g of epigallocatechin gallate into 8mL of ultrapure water, stirring and dissolving at room temperature, then adding 1.8g of poloxamer 188, fully stirring and dissolving, finally adding 2.5mL of aqueous solution of nanoparticles based on phenylboronic acid pinacol ester co-bonded beta-cyclodextrin material with the concentration of 4mg/mL, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

Example 4

At room temperature, firstly adding 0.2g of catechin into 6mL of ultrapure water, stirring and dissolving at room temperature, then adding 1.8g of poloxamer 407, fully stirring and dissolving, finally adding 2mL of luminol bonding alpha-cyclodextrin material-based nanoparticle aqueous solution with the concentration of 5mg/mL, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

Example 5

At room temperature, firstly adding 0.8g of gallic acid into 50mL of ultrapure water, stirring and dissolving at room temperature, then adding 0.5g of poloxamer 407, fully stirring and dissolving, finally adding 5mL of aqueous solution of 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxygen free radical (Tempol) with the concentration of 1mg/mL, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

Example 6

At room temperature, firstly adding 5g of tannic acid into 100mL of ultrapure water, stirring and dissolving at room temperature, then adding 10g of poloxamer 407, fully stirring and dissolving, finally adding 1mL of nanoparticle aqueous solution with the concentration of 10mg/mL based on Tempol/pinacol phenylboronic acid ester co-bonded beta-cyclodextrin material, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

Example 7

At room temperature, firstly adding 20g of catechin into 60mL of ultrapure water, stirring and dissolving at room temperature, then adding 3g of poloxamer 188, fully stirring and dissolving, finally adding 20mL of glutathione aqueous solution with the concentration of 1mg/mL, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

Example 8

At room temperature, firstly adding 10g of epigallocatechin gallate into 20mL of ultrapure water, stirring and dissolving at room temperature, then adding 1g of poly (lactic acid-glycolic acid) -polyethylene glycol-poly (lactic acid-glycolic acid) terpolymer, fully stirring and dissolving, finally adding 0.6mL of vitamin C aqueous solution with the concentration of 100mg/mL, and uniformly shaking to obtain the supermolecule multifunctional hydrogel.

The performance test was performed using PXNT prepared in example 1, with the following specific results:

PXNT gels of different tannin contents were evaluated for adhesion to dura mater and muscle tissue, as shown in figure 4. (wherein TA0 represents no tannic acid added, TA0.5 represents 0.5 wt% tannic acid, TA1 represents 1 wt% tannic acid, TA2 represents 2 wt% tannic acid.) the adhesion performance of supramolecular multifunctional hydrogels increases with increasing tannic acid concentration.

In vitro hydrolysis and release performance and in vivo residence time statistics of PXNT hydrogels are shown in fig. 5. It can be concluded from the figure that the gel can remain in vivo for about 7 days, and sustainedly release the bioactive nanoparticles during this period. In view of the inflammatory reaction occurring in epidural fibrosis, 3-5 days after surgery is the second stage of the process, during which a large amount of inflammatory factors and mediators are released in the surgical area, which is a crucial ring for the final chronic inflammation, so that the gel remains in the body for 7 days, which can be covered, and is beneficial to the treatment effect.

Using the hydrogel of example 1, SD rats were first shaved and disinfected, and then were subjected to a posterior midline incision, and then rats were subjected to a lumbar 4 laminectomy procedure to stop bleeding and fully expose the dura mater of the segment, and then the material gel was sprayed on the dura mater, after which gelation was reversed, the incisions were closed layer by layer and tightly sutured. Epidural gross images of rats treated with PXNT hydrogel and model group typically post-surgery for 8 weeks, and epidural fibrosis gross score statistics, as shown in figure 6. Among them, the PXNT group showed less scar tissue formation and less tissue adhesion.

Typical rheological test results for PXNT hydrogels are shown in fig. 7. The gel is prompted to realize rapid sol-gel phase transition in the process of gradually increasing the room temperature to 37 ℃, has the modulus similar to that of normal spinal cord tissues after being formed into the gel, can bear 60% strain amount to the maximum, is thinned by shearing, and has self-repairing capacity. FIG. 7a shows that both the storage modulus (denoted G) and the loss modulus (denoted G and) increase with increasing temperature. With further temperature increase, G 'meets G' and the sol-gel transition temperature is 26.9 ℃, indicating that PXNT has gelated and phase-inverted. G' is 3000-3500Pa at 37 ℃, and is similar to the normal spinal cord modulus value (4000 Pa). FIG. 7b shows that the gel at 37 ℃ can complete the gel transformation within 15 seconds. Fig. 7c shows the angular frequency test in the viscoelastic region, where G and G' are linear responses, with tan ranging from 0.48 to 0.37, showing typical elastic change behavior. FIG. 7d shows that PXNT are in a stable gel state and can sustain the maximum strain in the human body (10%) when the strain rate varies between 1% and 60%. Fig. 7e shows that at a high strain rate of 200%, PXNTs exhibit fluid-like behavior, and when the strain rate is reduced to 2%, PXNTs rapidly recover the initial modulus, and this process can be repeated. The viscosity as a function of shear rate test shown in fig. 7f demonstrates the shear-thinning behavior of PXNT hydrogels. The stepped shear rate change test shown in fig. 7g indicates that PXNT can quickly self-heal to the original viscosity at high shear and low shear rates for switching.

Rats were treated with PXNT hydrogel and model group typical postoperative 8-week magnetic resonance scan images, and axial epidural fibrosis area and MRI epidural fibrosis adhesion score statistics, as shown in figure 8. The PXNT group showed a lower fibrosis score and epidural scar tissue area.

Images of HE staining of rats after PXNT hydrogel treatment and model group typically 8 weeks, and statistics of epidural fibrosis score and fibroblast infiltration score are shown in fig. 9. The PXNT group rats had less fibrosis in the epidural tissue and less fibroblast content.

Typical gross appearance and nuclear magnetic resonance images of rabbits treated with PXNT hydrogel and model groups, and statistics of gross appearance scores and nuclear magnetic resonance epidural fibrosis scores are shown in fig. 10. Compared with a model group, the epidural tissue of the rabbit after PXNT intervention is sparser and easy to peel, and the fibrosis adhesion degree in a nuclear magnetic resonance image is lower.

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