WO2024140931A1 - 多糖基高分子交联剂、多糖基生物材料及制备方法与应用 - Google Patents
多糖基高分子交联剂、多糖基生物材料及制备方法与应用 Download PDFInfo
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- C08J2477/02—Polyamides derived from omega-amino carboxylic acids or from lactams thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2489/00—Characterised by the use of proteins; Derivatives thereof
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- Chinese patent CN114907558A discloses a method for preparing polyethylene glycol-based low swelling hydrogel by reducing its hydrophilicity through hydrophobic modification of the polyethylene glycol polymer skeleton.
- the method is based on complex modification of the polyethylene glycol skeleton and involves multi-step chemical synthesis.
- P is selected from hyaluronic acid, cellulose derivatives, alginic acid, heparin, chondroitin sulfate, xanthan gum, gellan gum, starch or hydrolyzates or derivatives thereof.
- the starch derivative may be selected from oxidized starch, esterified starch, etherified starch or alkylated starch.
- the polysaccharide-based polymer crosslinking agent modified with o-phthalaldehyde groups is selected from one of the following structures:
- the second aspect of the present invention provides a method for preparing the polysaccharide-based polymer cross-linking agent.
- R includes, but is not limited to, carboxyl substituents, vinyl sulfone substituents, epoxy substituents, halogenated alkane substituents, isocyanate substituents, and amine substituents.
- the active groups of the polysaccharide polymer are selected from hydroxyl groups and carboxyl groups.
- the aldehyde pre-protected o-phthalaldehyde precursor derivative is covalently linked to the active group on the polysaccharide polymer in a manner selected from ether bond, amide bond, ester bond, carbamate bond or urea bond, preferably ether bond, amide bond, ester bond or carbamate bond.
- the covalent bond connection is based on an ether bond connection between a vinyl sulfone substituent, an epoxy substituent or a halogenated alkane substituent on the o-phthalaldehyde precursor derivative and the hydroxyl group on the polysaccharide polymer, based on a carboxyl substituent on the o-phthalaldehyde precursor derivative.
- ester bond between the substituent group on the precursor derivative of o-phthalaldehyde and the hydroxyl group on the polysaccharide polymer is connected based on the carbamate bond between the isocyanate substituent group on the precursor derivative of o-phthalaldehyde and the hydroxyl group on the polysaccharide polymer;
- the covalent bond connection is preferably selected from an ether bond connection based on a vinyl sulfone substituent on a phthalaldehyde precursor derivative and a hydroxyl group on a polysaccharide polymer, an ether bond connection based on a epoxy substituent on a phthalaldehyde precursor derivative and a hydroxyl group on a polysaccharide polymer, an ester bond connection based on a carboxyl substituent on a phthalaldehyde precursor derivative and a hydroxyl group on a polysaccharide polymer, and an amide bond connection based on a amino substituent on a phthalaldehyde precursor derivative and a carboxyl group on a polysaccharide polymer.
- Deprotecting the aldehyde group of the polysaccharide polymer modified with the o-phthalaldehyde precursor derivative means deprotecting the pre-protected o-phthalaldehyde functional group of the aldehyde group connected to the polysaccharide polymer under acidic conditions to obtain a polysaccharide polymer crosslinker modified with the o-phthalaldehyde group.
- the third aspect of the present invention provides a method for preparing a polysaccharide-based two-component hydrogel: dissolving component A and component B in a solvent to obtain a component A solution and a component B solution, respectively, wherein the component A solution and the component B solution are the two components of the polysaccharide-based two-component hydrogel; mixing the component A solution and the component B solution to obtain the polysaccharide-based two-component hydrogel;
- the fourth aspect of the present invention provides a polysaccharide-based two-component hydrogel prepared by the method according to the third aspect of the present invention.
- the component A is a polysaccharide-based polymer cross-linking agent modified with o-phthalaldehyde groups
- the component B is a water-soluble small molecule, a water-soluble artificial synthetic polymer, or a water-soluble natural polymer (such as protein, nucleic acid, and polysaccharide) containing one or more of primary amine, hydrazine, hydrazide, hydroxylamine, or thiol groups, and the number of primary amine, hydrazine, hydrazide, hydroxylamine, or thiol functional groups contained in a single molecule is not less than 2.
- the present invention provides an application of the polysaccharide-based two-component hydrogel according to the fourth aspect of the present invention, selected from one of the following applications:
- tissue repair includes skin repair, abdominal wall repair, etc.
- Tissue fluid leakage blocking includes pancreatic fluid leakage blocking, cerebrospinal fluid leakage blocking, intestinal leakage blocking, stomach leakage blocking, etc.
- Tissue air leakage blocking includes lung parenchyma air leakage blocking, etc.
- Hemostasis includes liver hemostasis, kidney hemostasis, spleen hemostasis, pancreas hemostasis, bone section hemostasis, artery hemostasis and heart hemostasis, etc.
- the application of the polysaccharide-based powder material is selected from one of the following applications:
- the polysaccharide-based sponge material When used to prepare a hemostatic product, it can be used for liver hemostasis, kidney hemostasis, spleen hemostasis, Hemostasis, pancreatic hemostasis, bone section hemostasis, arterial hemostasis, cardiac hemostasis and non-compression penetrating wound hemostasis, etc.
- FIG3 is a photo of the precursor solution of the polysaccharide-based two-component hydrogel (Formula 7) in Example 11 and the hydrogel after gelation.
- DMSO dimethyl sulfoxide
- the labeling of compound 12 on HA was identified by H NMR spectrum.
- the supernatant of the reaction system was collected and the amount of residual compound 12 in the supernatant was determined by HPLC.
- the labeling rate of compound 12 was calculated to be approximately 4.01% (w/w).
- Example 3 Synthesis of representative components A-2.1 to A-2.4 of carboxymethyl cellulose-based crosslinking agents modified with o-phthalaldehyde groups
- Example 4 Synthesis of Representative Components A-3.1 to A-3.3 of the Alginate-Based Crosslinking Agent Modified with O-Phthalaldehyde Groups
- Example 5 Synthesis of representative components A-4.1 and A-4.2 of carboxymethyl starch-based crosslinking agents modified with o-phthalaldehyde groups
- component A-4.2 CMS (type A, 5 g, pH 5.0-7.5) was dissolved in 40 mL of 0.25 M NaOH solution; compound 12 (0.3 g, 1.2 mmol) was added to the above system; and finally 10 The mixture was reprecipitated with 100 times the volume of anhydrous ethanol to precipitate a white powder. The rest of the synthesis process was referred to the synthesis of component A-1.4.
- the labeling of compound 12 on CMS was identified by H NMR spectrum. The supernatant of the reaction system was collected, and the amount of residual compound 12 in the supernatant was determined by HPLC. The labeling rate of compound 12 was calculated to be approximately 1.78% (w/w).
- Example 7 Synthesis of Representative Component A-6.1 of Heparin-Based Crosslinker Modified with O-Phthalaldehyde Group
- Heparin sodium (Hep, 5 g, 15 kDa) was dissolved in 150 mL of deionized water and stirred until completely dissolved.
- Example 9 Synthesis of Representative Component A-8.1 of Xanthan Gum-Based Crosslinking Agent Modified with O-Phthalaldehyde Groups
- the inventors prepared polysaccharide-based two-component hydrogels according to the ratios in Table 2 for performance testing and application.
- the precursor solution of the polysaccharide-based two-component hydrogel (the formula corresponding to sequence number 7) and the state after gelation are shown in FIG3 .
- the specific detection method is as follows: The shear strength of the hydrogels of different formulations on pig skin was measured by a standard lap shear test (ASTM F2255) using a tensile machine (Germany INSTRON). The pig skin was cut into rectangular pig skins of 10 mm and 40 mm. During the mechanical test, a transparent polymethyl methacrylate film was used as a hard backing for the tissue.
- polysaccharide-based two-component hydrogels of other formulations in the present invention can also be used for liver hemostasis.
- Example 22 Application of polysaccharide-based two-component hydrogel in femoral artery hemostasis
- the patch of Group a was not sutured; the patch of Group b was sutured interruptedly with 4-0 non-absorbable surgical sutures. After the skin was disinfected with 75% ethanol, it was sutured interruptedly with 3-0 non-absorbable surgical sutures.
- the abdominal cavity was opened 30 days after the operation to observe the adhesion between the abdominal viscera and the patch.
- the experimental results showed that the patch in group a had no obvious displacement, no intra-abdominal hernia, and no obvious adhesion between the patch in group a and the abdominal viscera; the patch in group b had no obvious displacement, and there was a little adhesion between the sutured part and the greater omentum in the abdominal cavity. It can be seen that the above polysaccharide-based membrane material can be used as a patch for abdominal hernia repair.
- Example 27 Application of polysaccharide-based powder materials in minimally invasive surgery for hemostasis
- the colon length statistics of normal mice, polysaccharide-based powder materials loaded with budesonide on the surface (group a), budesonide enema solution (group b) and blank group (group c) after treating acute enteritis in mice are shown in Figure 9.
- the statistical results show that the colon length of mice in group a is the longest compared with that in group b and group c. It can be seen that the polysaccharide-based powder materials loaded with budesonide can be used for the treatment of inflammation.
- polysaccharide-based sponge materials of other formulations in the present invention can also be used for spleen hemostasis.
- Example 34 Application of polysaccharide-based sponge material in hemostasis of non-compressive penetrating wounds
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Abstract
本发明涉及多糖基高分子交联剂、多糖基生物材料及制备方法与应用。本发明中多糖基高分子交联剂是邻苯二甲醛基团改性的多糖基高分子交联剂,该多糖基高分子交联剂不依赖于人工合成的亲水性高分子骨架和复杂的化学合成步骤。将本发明提供的多糖基高分子交联剂与含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的水溶性小分子或高分子在水性介质共同构成一种多糖基双组分水凝胶材料,具有可注射、低溶胀、强组织粘附的优势。此外,本发明提供的多糖基双组分水凝胶材料还可进一步制备成为膜、粉剂和海绵等形式的多糖基生物材料,可作为组织粘合剂、密封胶、止血剂、组织工程材料等,具有广泛的生物医学应用前景。
Description
本发明涉及属于生物材料技术领域,尤其是涉及多糖基高分子交联剂、多糖基生物材料及制备方法与应用。
水凝胶是一种高度含水的、具有三维交联网络结构的高分子材料,具有可调的物理化学性质,其高含水量、生物相容性和多功能性使其广泛应用于许多生物医学领域。其中,利用双组分水凝胶可原位成型固化的特性,在临床上可被用作止血剂、组织粘合剂和密封剂。例如,美国Confluent Surgical公司生产的DuraSeal胶以及美国百特公司生产的CoSeal胶,以聚乙二醇为骨架,基于端基上氨基或巯基与羧酸活性酯的反应实现交联,同时通过羧酸活性酯与组织表面的氨基等活性基团反应粘附在组织上,对创伤组织实施封闭;又如,中国专利CN111440310A、CN111440334A、CN 111574756A、CN 111621038A、CN113509591A、CN113694249A和CN114767920A公开了一系列邻苯二甲醛基团改性的聚乙二醇交联剂,通过邻苯二甲醛与含氨基的高分子交联制备的双组分水凝胶可用作组织密封剂。然而,由于聚乙二醇骨架亲水性极强,使得该类水凝胶溶胀率普遍较高(>100%),其高溶胀性不仅使水凝胶的机械性能大大降低,而且体积的膨胀会对周围组织造成压迫,同时凝胶具有脱落的风险,使得该类水凝胶在临床应用中存在安全性隐患。例如,以DuraSeal胶和CoSeal胶为代表的聚乙二醇类密封胶,常用在神经外科手术中的硬脑膜缝合后的辅助密封,以防止脑脊液的泄漏,然而在实际临床应用中,由于水凝胶吸收体液后体积溶胀压迫神经,引发了多起导致四肢瘫痪的不良事件(D Thavarajah,P De Lacy,R Hussain,RM Redfern,Spine.2010,35,25-26.)。
针对溶胀性问题,中国专利CN114907558A公开了一种通过对聚乙二醇高分子骨架的疏水性改性降低其亲水性,以实现制备聚乙二醇基低溶胀水凝胶的方法,然而,该方法基于对聚乙二醇骨架的复杂修饰,涉及多步化学合成。
发明内容
为解决现有技术中聚乙二醇基水凝胶普遍存在的溶胀率较高的问题,本发明提供多糖基高分子交联剂、多糖基生物材料及制备方法与应用。
具体而言,本发明提供多糖基高分子交联剂、多糖基高分子交联剂的制备方法、多糖基生物材料、多糖基生物材料的制备方法以及多糖基生物材料的应用。
本发明的目的可以通过以下技术方案来实现:
本发明的第一方面,提供一类多糖基高分子交联剂。
所述多糖基高分子交联剂为邻苯二甲醛基团改性的多糖基高分子交联剂,结构如式1所示:
式1中,P为天然多糖高分子或其修饰物或降解物,P选自透明质酸、纤维素、纤维素衍生物、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、卡拉胶、黄芪胶、黄原胶、结冷胶、瓜尔胶、***胶、刺槐豆胶、淀粉或其水解产物或衍生物等中的一种或几种;
式1中,n≥2,即表示单条多糖高分子链上的邻苯二甲醛官能团的平均个数大于或等于2;
式1中,邻苯二甲醛基团与P之间通过共价键连接。
在本发明的一些可实施方式中,P选自透明质酸、纤维素衍生物、海藻酸、肝素、硫酸软骨素、黄原胶、结冷胶、淀粉或其水解产物或衍生物。
其中,所述纤维素衍生物可以选自纤维素醚,包括但不限于甲基纤维素、羧甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素等;
优选地,所述纤维素衍生物选自羧甲基纤维素。
所述淀粉衍生物可以选自氧化淀粉、酯化淀粉、醚化淀粉或烷基化淀粉。
优选地,所述淀粉衍生物选自羧甲基淀粉。
在本发明的一些具体的可实施方式中,所述邻苯二甲醛基团改性的多糖基高分子交联剂选自以下结构中的一种:
其中,1≤r≤20,1≤s≤20,1≤t≤50,n≥2。优选的,1≤r≤6,1≤s≤10,1≤t≤30,n≥2。
本发明的第二方面,提供所述多糖基高分子交联剂的制备方法。
所述多糖基高分子交联剂的制备方法如下:
将醛基预保护的邻苯二甲醛前体衍生物与多糖高分子上的活性基团进行共价键连接,得到邻苯二甲醛前体衍生物修饰的多糖高分子,随后将邻苯二甲醛前体衍生物修饰的多糖高分子的醛基进行脱保护得到邻苯二甲醛基团改性的多糖基高分子交联剂。
所述的醛基预保护的邻苯二甲醛前体衍生物包含醛基被预先保护的邻苯二甲醛基团和可与多糖高分子上的活性基团连接的取代基R,结构如式2所示:
式2中,R包括但不限于羧基类取代基、乙烯基砜类取代基、环氧类取代基、卤代烷烃类取代基、异氰酸酯类取代基和胺基类取代基等。
式2中,可选的,R可与苯环直接相连,也可以通过单个或多个亚烷基链、烷氧基链连接到苯环上,所述多个亚烷基链、烷氧基链之间通过醚键、酰胺键、酯键、氨基甲酸酯键或脲键连接。
在本发明的一些具体的可实施方式中,所述醛基预保护的邻苯二甲醛前体衍生物选自以下化合物中的一种:
其中,1≤r≤20,1≤s≤20,1≤t≤50。优选的,1≤r≤6,1≤s≤10,1≤t≤30。
所述多糖高分子的活性基团既可以是多糖高分子自有的,也可以是多糖高分子被改性或降解后的具有反应活性的基团。
在本发明的一些可实施方式中,所述多糖高分子的活性基团选自羟基和羧基。
所述醛基预保护的邻苯二甲醛前体衍生物与多糖高分子上的活性基团进行共价键连接的方式选自醚键、酰胺键、酯键、氨基甲酸酯键或脲键连接,优选为醚键、酰胺键、酯键、氨基甲酸酯键连接。
更具体地,当所述多糖高分子的活性基团选自羟基时,所述的共价键连接为基于邻苯二甲醛前体衍生物上乙烯基砜类取代基、环氧类取代基或卤代烷烃类取代基与多糖高分子上的羟基之间的醚键连接,基于邻苯二甲醛前体衍生物上羧基类取代
基与多糖高分子上的羟基之间的酯键连接,基于邻苯二甲醛前体衍生物上异氰酸酯类取代基与多糖高分子上的羟基之间的氨基甲酸酯键连接;
当所述的多糖高分子活性基团选自羧基时,所述的共价键连接为基于邻苯二甲醛前体衍生物上胺基类取代基与多糖高分子上的羧基之间的酰胺键连接。
在本发明的一些具体的可实施方式中,所述共价键连接优选自基于邻苯二甲醛前体衍生物上乙烯基砜类取代基与多糖高分子上的羟基之间的醚键连接,基于邻苯二甲醛前体衍生物上环氧类取代基与多糖高分子上的羟基之间的醚键连接,基于邻苯二甲醛前体衍生物上羧基类取代基与多糖高分子上的羟基之间的酯键连接,以及基于邻苯二甲醛前体衍生物上胺基类取代基与多糖高分子上的羧基之间的酰胺键连接。
将邻苯二甲醛前体衍生物修饰的多糖高分子的醛基进行脱保护是指对多糖高分子上连接的醛基被预保护的邻苯二甲醛官能团在酸性条件下进行脱保护得到邻苯二甲醛基团改性的多糖基高分子交联剂。
本发明第一方面式1-1至式1-12提供的邻苯二甲醛基团改性的多糖基高分子交联剂的结构只是示例性的说明了上述涉及的醛基预保护的邻苯二甲醛前体衍生物与多糖高分子通过一定制备方法可获得的邻苯二甲醛基团改性的多糖基高分子交联剂。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物结构来实现所述邻苯二甲醛基团改性的多糖基高分子交联剂。
本发明的第三方面,提供多糖基双组分水凝胶的制备方法:将组分A和组分B分别溶于溶剂中得到组分A溶液和组分B溶液,组分A溶液和组分B溶液即为多糖基双组分水凝胶的双重组分;将组分A溶液和组分B溶液混合即得所述多糖基双组分水凝胶;
其中,所述组分A为邻苯二甲醛基团改性的多糖基高分子交联剂,如式1所示,n≥2;
所述组分B为含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的水溶性小分子、水溶性人工合成高分子、水溶性天然高分子(如蛋白质、核酸和多糖),且单个分子上含有的伯胺、联胺、酰肼、羟胺或巯基官能团数量不少于2。
在本发明的一些可实施方式中,优选的,所述组分B选自以下物质中的一种或几种:聚乙二醇衍生物、聚乙烯亚胺、聚氨基酸、蛋白、蛋白修饰物、蛋白改性
物、蛋白降解物、多糖、多糖修饰物或多糖降解物;且所述组分B选择的物质分子结构中含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团,且单个分子上含有的伯胺、联胺、酰肼、羟胺或巯基官能团数量不少于2;
优选地,所述聚乙二醇衍生物为伯胺、联胺、酰肼、羟胺或巯基改性的聚乙二醇衍生物,
优选地,所述蛋白包括胶原蛋白、血清蛋白、纤维蛋白原和纤维蛋白,所述蛋白降解物包括明胶或多肽;
优选地,所述多糖、多糖修饰物或多糖降解物选自:壳聚糖及壳聚糖修饰物和壳聚糖降解物;伯胺、联胺、酰肼、羟胺或巯基改性的透明质酸、海藻酸、硫酸软骨素、肝素、纤维素、甲壳素及其各自的修饰物和降解物。
进一步优选的,所述组分B选自胺基改性的聚乙二醇衍生物;酰肼改性的透明质酸;胶原蛋白;血清蛋白;明胶;多肽;聚氨基酸;壳聚糖。
在本发明的一些可实施方式中,所述溶剂选自水、生理盐水、缓冲溶液、脱细胞基质或细胞培养基溶液。
在本发明的一些可实施方式中,优选的,组分A溶液中,组分A的固含量为0.1-40wt%,优选为0.5-20wt%,进一步优选为0.5-10wt%;组分B溶液中,组分B的固含量为0.1-40wt%,优选为0.5-20wt%,进一步优选为0.5-10wt%。其中,提高多糖基双组分水凝胶中组分A的比例能够有效提高水凝胶的组织粘附性能与止血性能。
在本发明的一些可实施方式中,将组分A溶液和组分B溶液混合制备水凝胶的制备温度为0-80℃;制备pH为1-12。
本发明的第四方面,提供基于本发明第三方面的方法制备得到的多糖基双组分水凝胶。
本发明的第五方面,提供多种多糖基生物材料。
在本发明的一些可实施方式中,所述多糖基生物材料,是由本发明第四方面提供的多糖基双组分水凝胶干燥后制得的一种多糖基膜材料。
在在本发明的一些可实施方式中,所述干燥方法包括自然干燥和烘干。
优选的,烘干条件为30℃烘干12小时。
在本发明的一些可实施方式中,所述多糖基生物材料,是由上述多糖基膜材料机械球磨得到的一种多糖基粉剂材料。所述机械球磨是指将多糖基膜材料装入球磨
机内,物料处于强烈搅动的碾磨球之间,受到冲击力、碾磨力、剪切力和压力的反复作用,使之不断发生变形、破碎,得到微细的粉末。为了减少颗粒间的自粘力,防止其团聚,可加入液体表面活性剂和润滑剂,例如乙醇。要求液体添加剂不得腐蚀颗粒或与之发生化学反应。
在本发明的另一些可实施方式中,所述多糖基生物材料,是由本发明第三方面提供的组分A溶液和组分B溶液混合后通过乳化法、微流控方法和机械粉碎法等制备微凝胶颗粒,进一步通过干燥、过筛得到的一种多糖基粉剂材料。
优选的,上述微凝胶颗粒的制备方法为机械粉碎法:将组分A溶液和组分B溶液混合得到的多糖基水凝胶通过高速剪切的均质机切割成粒径分布均一的颗粒。优选的,上述微凝胶颗粒的粒径分布为1~1000μm。
在本发明的一些具体的实施方式中,所述干燥方法为真空冷冻干燥或烘干干燥。优选的冷冻干燥条件为-20℃冷冻6小时,随后-60℃冻干48小时;烘干条件为30℃烘干12小时。在本发明的一些具体的实施方式中,所述过筛为通过一种网孔状的工具(如振筛机)使经过粉碎后粗细相差悬殊的粉末分离出粗粉和细粉的操作过程。优选的,所述过筛后粉末的粒径分布为20目~500目。
在本发明的一些可实施方式中,所述多糖基生物材料,由本发明第三方面提供的组分A溶液、组分B溶液和制孔剂混合得到含有孔结构的多糖基水凝胶材料,进一步干燥得到的多糖基海绵材料。
其中,所述组分A为邻苯二甲醛基团改性的多糖基高分子交联剂,所述组分B为含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的水溶性小分子、水溶性人工合成高分子、水溶性天然高分子(如蛋白质、核酸和多糖),且单个分子上含有的伯胺、联胺、酰肼、羟胺或巯基官能团数量不少于2。
在本发明的一些可实施方式中,所述制孔剂是使材料中产生孔洞结构的添加剂,包括易分解为气体的物质、高分子微球、聚乙二醇、聚乙烯基吡咯烷酮、表面活性剂、水等。
其中,易分解为气体的物质如碳酸氢铵,其加入材料中受热会放出二氧化碳与氨气,从材料中溢出产生孔洞结构。高分子微球如聚甲基丙烯酸甲酯微球、二氧化硅微球和聚苯乙烯微球等。
优选地,制孔剂选为水,水凝胶通过冷冻干燥呈多孔蜂窝状海绵体结构。
优选地,冷冻干燥条件为-20℃冷冻6小时,随后-60℃冻干48小时。
本发明的第六方面,提供基于本发明第四方面的多糖基双组分水凝胶的应用,选自以下应用中的一种:
所述多糖基双组分水凝胶在制备组织修复产品中的应用;
所述多糖基双组分水凝胶在制备组织液渗漏封堵产品中的应用;
所述多糖基双组分水凝胶在制备组织漏气封堵产品中的应用;
所述多糖基双组分水凝胶在制备止血产品中的应用。
其中,组织修复包括皮肤修复、腹腔壁修复等。组织液渗漏封堵包括如胰液渗漏封堵、脑脊液渗漏封堵、肠漏封堵、胃漏封堵等。组织漏气封堵包括肺实质漏气封堵等。止血包括肝脏止血、肾脏止血、脾脏止血、胰止血、骨断面止血、动脉止血和心脏止血等。
本发明的第七方面,提供基于本发明第五方面的多糖基生物材料的应用。
当所述多糖基生物材料为多糖基膜材料时,所述多糖基膜材料的应用,选自以下应用中的一种:
所述的多糖基膜材料在制备手术伤口免缝合封闭产品中的应用;
所述的多糖基膜材料在制备补片产品中的应用;
其中,多糖基膜材料制备的补片产品可用于腹腔疝修补等。
当所述多糖基生物材料为多糖基粉剂材料时,所述多糖基粉剂材料的应用,选自以下应用中的一种:
所述多糖基粉剂材料在制备止血产品中的应用;
所述多糖基粉剂材料在制备细胞、因子、药物载体产品中的应用;
其中,多糖基粉剂材料制备的止血产品可用于微创手术止血、肝脏止血、肾脏止血、脾脏止血、胰止血、骨断面止血、动脉止血和心脏止血等;细胞、因子、药物载体包括干细胞载体、促生长因子载体、抗菌药物载体和抑炎药物载体等。
当所述多糖基生物材料为多糖基海绵材料时,所述多糖基海绵材料的应用,选自以下应用中的一种:
所述多糖基海绵材料在制备创面敷料产品中的应用;
所述多糖基海绵材料在制备止血产品中的应用。
当所述多糖基海绵材料制备止血产品时,可用于肝脏止血、肾脏止血、脾脏止
血、胰止血、骨断面止血、动脉止血、心脏止血和非压迫性贯穿伤止血等。
多糖是一类天然的水溶性高分子,来源广泛,具有良好的生物相容性。
本发明提供了一类邻苯二甲醛基团改性的多糖基高分子交联剂。本发明中邻苯二甲醛基团改性的多糖基高分子交联剂不依赖于人工合成的亲水性高分子骨架和复杂的化学合成步骤,本发明提供的多糖基高分子交联剂具有原料来源广泛和制备方法简单的优势。
本发明还将多糖基高分子交联剂与含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的小分子或高分子衍生物在水性介质中共同构成多糖基双组分水凝胶材料。该水凝胶材料由两组分交联构成:一是邻苯二甲醛基团改性的多糖基高分子交联剂,二是含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的水溶性小分子、水溶性人工合成高分子、水溶性天然高分子(如蛋白质、核酸和多糖)等,上述两组分各自含相应官能团数量不少于2。本发明提供的多糖基双组分水凝胶材料具有可注射、低溶胀、强组织粘附的优势,可作为组织粘合剂、密封胶、止血剂、组织工程材料等。
本发明还提供了基于多糖基高分子交联剂或水凝胶材料的多种不同形式的多糖基生物材料(如膜、粉剂和海绵),本发明提供的双组分水凝胶、膜、粉剂和海绵可作为组织粘合剂、密封胶、止血剂、组织工程材料等,具有广泛的生物医学应用前景,对于临床上的止血、组织粘合和密封具有重要意义。
图1为实施例二中透明质酸基交联剂(即组分A-1.2)的核磁共振氢谱。
图2为实施例三中羧甲基纤维素基交联剂(即组分A-2.2)的核磁共振氢谱。
图3为实施例十一中多糖基双组分水凝胶(配方7)的前体溶液及成胶后的照片。
图4为实施例十六中多糖基双组分水凝胶(组a)和缝合线(组b)应用于皮肤组织修复7d时的照片。
图5为实施例十八中多糖基双组分水凝胶(组a)应用于胰腺断端封堵胰液渗漏术后7d的照片。
图6为实施例十九中多糖基双组分水凝胶(组a)和骨蜡(组b)应用于脑脊
液渗漏封堵的照片。
图7为实施例二十四中多糖基膜材料应用于手术伤口免缝合封闭(组a)和缝合组(组b)术后10d的H&E染色结果对比照片。
图8为实施例二十六中的不同粒径的多糖基粉剂材料在显微镜下的微观形貌。
图9为实施例二十九中正常小鼠以及表面负载布***的多糖基粉剂材料(组a)、布***灌肠液(组b)和空白组(组c)治疗小鼠急性肠炎后的小鼠结肠长度统计图。
图10为实施例三十二中的海绵材料(组a)和商用可吸收止血纱(组b)应用于脾脏止血的对比照片。
图11为实施例三十三中的海绵材料(组a)应用于心脏止血的照片。
下面结合附图和具体实施例对本发明进行详细说明。
实施例一:醛基预保护的邻苯二甲醛前体衍生物(即化合物1~13)的合成
(一)化合物1~3的合成(s=2,t=7)
(1)化合物1的合成:合成过程参照文献Zhen Zhang,Chaoliang He,Yan Rong,Hui Ren,Tianran Wang,Zheng Zou,Xuesi Chen,National Science Review,Volume 8,Issue 4,April 2021,nwaa128.公开的方法。1H NMR(400MHz,DMSO-d6):δ=12.74(brs,1H),8.29(d,J=7.6Hz,1H),8.12(s,1H),7.65(d,J=7.6Hz,1H),6.30(s,1H),6.11(s,1H),3.40-3.30(m,6H).
(2)化合物2的合成:将化合物1(10g,45mmol)溶于10mL无水二氯甲烷(DCM),并加入1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺(EDC,10.38g,67mmol)和N-羟基琥珀酰亚胺(NHS,7.69g,67mmol),在室温下搅拌30分钟。将乙二胺(27.05g,0.45mmol)溶于无水DCM并搅拌,将上述反应体系快速滴
加至乙二胺溶液中,室温搅拌反应12h。反应完成后,除去大部分溶剂,残余化合物用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化合物2(9.0g,产率75%)。1H NMR(400MHz,DMSO-d6):δ=8.18(t,1H),8.07(d,1H),7.80(dd,1H),7.56(dd,1H),6.05(h,2H),4.59(dt,1H),4.25(dt,1H),3.38(tt,J=5.1Hz,2H),3.34(s,3H),3.03(tt,J=6.3,2H).
(3)化合物3的合成:将α,ω-二羧基聚乙二醇(COOH-PEG-COOH,t=7,8.26g)溶于100mL无水DCM,并加入EDC(3.52g,22.7mmol)和NHS(2.61g,22.7mmol),在室温下搅拌30分钟。将化合物2(5g,18.8mmol)溶于无水DCM(50mL)中,逐渐滴加至上述体系,在室温下搅拌反应12h。反应完成后,除去大部分溶剂,残余化合物用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化合物3(10.5g,产率79%)。1H NMR(400MHz,DMSO-d6):δ=8.86(s,1H),8.21(d,J=7.6Hz,1H),7.93(s,1H),7.61(d,J=7.6Hz,1H),6.38(s,1H),6.30(s,1H),3.80-3.48(m,28H),3.40-3.30(m,6H).
(二)化合物4~8的合成(r=2,s=6,t=7)
(1)化合物4的合成:合成过程参照文献Chun Ling Tung,Clarence T.T.Wong,Eva Yi Man Fung and Xuechen Li.Org.Lett.2016,18,11,2600-2603.公开的方法。1H NMR(400MHz,DMSO-d6):δ=11.82(s,1H),7.56(dq,1H),7.43(dd,1H),7.16(ddt,1H),6.05(m,1H),5.97(q,1H),3.53(dt,2H),3.40-3.30(m,6H).
(2)化合物5的合成:合成过程参照化合物2的合成。1H NMR(400MHz,DMSO-d6):δ=7.56(t,1H),7.48(m,2H),7.14(ddt,1H),6.06(s,1H),5.97(q,1H),3.40-3.30(m,6H),3.07(q,2H),2.90-2.72(m,4H),2.38(t,J=8.2Hz,2H),1.87(t,J=6.5Hz,2H),1.59-1.43(m,4H),1.46-1.30(m,4H).
(3)化合物6的合成:将化合物5(5g,14.3mmol)溶于100mL甲苯,加入丁二酸酐(1.5g,15mmol)和三乙胺(TEA,2.1mL,15mmol),室温搅拌4h。反应完成后,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化合物6(5.2g,产率80%)。1H NMR(400MHz,DMSO-d6):δ=11.87(s,1H),7.62(t,1H),7.56(t,1H),7.44-7.36(m,2H),7.14(ddt,1H),6.08-6.02(m,1H),5.97(q,1H),3.40-3.30(m,6H),3.19-3.03(m,4H),2.77(tt,J=8.7Hz,2H),2.55(dd,2H),2.48-2.34(m,4H),1.56-1.43(m,4H),1.40-1.27(m,4H).
(4)化合物7的合成:将α,ω-二氨基聚乙二醇(NH2-PEG-NH2,t=7,8.8g)溶于50mL无水DCM。将化合物4(5g,19.8mmol)溶于无水DCM(50mL)中,并加入EDC(4.65g,30mmol)和NHS(3.45g,30mmol),在室温下搅拌30分钟。将上述反应体系逐渐滴加至NH2-PEG-NH2溶液中,在室温下搅拌反应12h。反应完成后,除去大部分溶剂,残余化合物用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化合物7(10.4g,产率81%)。1H NMR(400MHz,DMSO-d6):δ=7.43-7.36(m,2H),7.14(ddt,1H),3.61-3.43(m,28H),3.36-3.26(m,6H),2.88-2.71(m,2H),2.54-2.36(m,2H).
(5)化合物8的合成:将六亚甲基二异氰酸酯(HDI,1.28g,7.6mmol)溶于无水四氢呋喃(THF,50mL)中。将化合物7(5g,7.6mmol)溶于无水THF(50mL)中,缓慢滴加至快速搅拌的HDI溶液中,室温下搅拌反应2h。经旋蒸除去溶剂后,用少量DCM重新溶解,倒入正戊烷中析出固体,重复2次后,抽干得到化合物8(5.5g,产率92%)。1H NMR(400MHz,DMSO-d6):δ=7.53(t,1H),7.44-7.36(m,2H),7.14(ddt,1H),6.047(s,1H),5.97(s,1H),5.87(t,1H),5.65(t,1H),3.63-3.51(m,32H),3.36-3.28(m,4H),3.39-3.32(m,6H),3.31-3.18(m,4H),3.10(tdd,J=5.7,4.7,1.0Hz,2H),2.90-2.71(m,4H),2.41(t,J=8.3Hz,2H),1.87(t,J=6.5Hz,2H),1.59-1.27(m,8H).
(三)化合物9~13的合成
(1)化合物9的合成:将中间体1(5g,25.5mmol)溶于无水DCM(40mL)中,加入0.2M NaOH溶液(85mL),随后加入四丁基溴化铵(TBAB,0.82g,2.55mmol),室温下搅拌30min。滴加1-溴-2-氯乙烷(8.41mL,0.102mol),室温下搅拌反应48h。随后,分离相,用盐水依次洗涤有机相,用无水硫酸钠干燥,过滤,减压浓缩,得到的粗产物经硅胶色谱柱纯化得到化合物9(5.6g,产率85%)。1H NMR(400MHz,DMSO-d6):δ=7.45(dd,1H),7.15(dd,1H),6.88(dd,1H),6.07-5.97(m,2H),4.24(q,J=2.2Hz,2H),3.81(t,J=2.2Hz,2H),3.37-3.34(s,6H).
(2)化合物10的合成:将HDI(6.43g,38.3mmol)溶于无水DCM中。将中间体1(5g,25.5mmol)溶于无水DCM中,并加入TEA(3.53mL,25.5mmol)。将上述混合体系缓慢滴加至快速搅拌的HDI溶液中,室温搅拌反应30min。经旋蒸除去溶剂后,用少量DCM重新溶解,倒入正戊烷中析出固体,重复2次后,得到化合物10(9.76g,产率70%)。1H NMR(400MHz,DMSO-d6):δ=7.56(dd,J=8.4,1H),7.40(s,1H),7.07(dd,J=8.3,1H),6.34(t,J=5.3Hz,1H),6.03–5.93(m,2H),3.38-3.31(s,6H),3.20-3.13(m,2H),3.06(q,J=5.5Hz,2H),1.67-1.27(m,8H).
(3)化合物11的合成:在无水无氧操作下,将中间体1(5g,25.5mmol)溶于无水DCM。在0℃冰浴条件下,向上述溶液中缓慢滴加2-氯乙烷磺酰氯(5g,30.6mmol),反应10min后,缓慢滴加无水TEA(4.23mL,30.6mmol),室温下反应12h。反应完成后,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化
合物11(6.9g,产率95%)。1H NMR(400MHz,DMSO-d6):δ=7.48-7.41(m,1H),7.35(s,1H),7.08(dd,J=8.2,1H),6.26(dd,J=18.5,1H),6.15(dd,J=18.4,1H),6.03(dq,J=2.9,1.7Hz,2H),3.41-3.33(s,6H).
(4)化合物12的合成:将中间体1(5g,25.5mmol)悬浊在30mL的水中,加入1.5M NaOH水溶液(10mL),体系逐渐变澄清。搅拌40分钟,加入环氧氯丙烷(7.1g,76.5mmol),室温搅拌24h。反应完成后,除去大部分溶剂,残余化合物用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,经旋蒸除去溶剂,得到的粗产物经硅胶色谱柱纯化得到化合物12(5.8g,产率90%)。1H NMR(400MHz,DMSO-d6):δ=7.45(s,1H),7.14(s,1H),6.91(dd,J=8.3,1H),6.07-5.99(m,2H),4.11(d,J=3.3Hz,2H),3.42(s,1H),3.38-3.32(m,6H),2.91-2.78(m,2H).
实施例二:邻苯二甲醛基团改性的透明质酸基交联剂代表性组分A-1.1~A-1.4的合成
(1)组分A-1.1的合成:将透明质酸(Hyaluronic acid,HA,5g,890kDa)溶于500mL的0.01mol/L 2-(N-吗啉)乙磺酸(MES)缓冲溶液(pH=5.2),搅拌至完全溶解,称取化合物2(0.54g,2mmol,s=2)溶于10mL二甲基亚砜(DMSO)后加入上述反应液,称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM,1.4g,5mmol)分3次加入上述反应体系,每次溶于3mL MES缓冲溶液,相隔1h,37℃下反应24h。反应结束后将pH调至8-9,搅拌1h,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-1.2。通过核磁氢谱图鉴定HA上化合物2的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物2的量,可计算化合物2的标记率大约为6.78%(w/w)。
(2)组分A-1.2的合成:将HA(5g,340kDa)溶于250mL MES缓冲溶液中(0.01M,pH)将化合物5(420mg,1.2mmol,r=2,s=6)溶于10mL DMSO,加入反应体系;透析时选择MWCO 7000的透析袋,其余合成过程参照组分A-1.1的合成。实施例二中代表性透明质酸基交联剂(即组分A-1.2)的核磁共振氢谱如图1所示,通过核磁氢谱图鉴定HA上化合物5的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物5的量,可计算化合物5的标记率大约为4.21%(w/w)。
(3)组分A-1.3的合成:将HA(5g,1.2MDa)溶于50mL的0.2M NaOH溶液中,搅拌至完全溶解。向上述体系中加入化合物11(343mg,1.2mmol),50℃反应6h。反应结束后,用稀盐酸中和pH至7,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-1.3。通过核磁氢谱图鉴定HA上化合物11的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物11的量,可计算化合物11的标记率大约为4.12%(w/w)。
(4)组分A-1.4的合成:将HA(5g,1.2MDa)溶于50mL的0.25M NaOH溶液中,搅拌至完全溶解。向上述体系中加入化合物12(302mg,1.2mmol),40℃反应12h。反应结束后,用稀盐酸中和pH至7,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-1.4。通过核磁氢谱图鉴定HA上化合物12的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物12的量,可计算化合物12的标记率大约为4.01%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的透明质酸基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他邻苯二甲醛保护衍生物来合成所述邻苯二甲醛基团改性的透明质酸基高分子交联剂。
实施例三:邻苯二甲醛基团改性的羧甲基纤维素基交联剂代表性组分A-2.1~A-2.4的合成
(1)组分A-2.1的合成:将羧甲基纤维素(Carboxymethyl Cellulose,CMC,5g,粘度(2%,25℃)为1200mPa·s,羧甲基取代度0.7)溶于500mL的去离子水中,搅拌至完全溶解。向上述溶液中依次加入化合物1(269mg,1.2mmol)、乙基-3-(3-二甲基氨基丙基)碳酰二亚胺(EDC,1.86g,12mmol)和二甲氨基吡啶对甲苯磺酸盐(DPTS,3g,12mmol)。室温反应24h。反应结束后用含稀盐
酸的氯化钠水溶液(pH=4)透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO14000),收集产物冷冻干燥,得到组分A-2.1。通过核磁氢谱图鉴定CMC上化合物1的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物1的量,可计算化合物1的标记率大约为2.48%(w/w)。
(2)组分A-2.2的合成:将CMC(5g,粘度(2%,25℃)为675mPa·s,羧甲基取代度0.7)溶于250mL的MES缓冲溶液(0.01M,pH=5.2),搅拌至完全溶解;称取化合物5(280mg,0.8mmol,r=2,s=6)溶于DMSO加入反应体系,其余合成过程参照组分A-1.2的合成。实施例三中代表性羧甲基纤维素基交联剂(即组分A-2.2)的核磁共振氢谱如图2所示,通过核磁氢谱图鉴定CMC上化合物5的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物5的量,可计算化合物5的标记率大约为3.31%(w/w)。
(3)组分A-2.3的合成:将CMC(5g,粘度(2%,25℃)为675mPa·s,羧甲基取代度0.7)溶于250mL的MES缓冲溶液(0.01M,pH=5.2),搅拌至完全溶解;化合物7(0.78g,1.2mmol,r=2,t=7)直接加入反应体系中;透析时选择
MWCO 7000的透析袋,其余合成过程参照组分A-2.1的合成。通过核磁氢谱图鉴定CMC上化合物7的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物7的量,可计算化合物7的标记率大约为3.67%(w/w)。
(4)组分A-2.4的合成:将CMC(5g,粘度(2%,25℃)为2000mPa·s,羧甲基取代度0.85)溶于50mL的0.25M NaOH溶液中,搅拌至完全溶解。向上述体系中加入化合物9(309mg,1.2mmol),40℃反应12h。反应结束后,用稀盐酸中和pH至7,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-2.4。通过核磁氢谱图鉴定CMC上化合物9的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物9的量,可计算化合物9的标记率大约为3.01%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的羧甲基纤维素基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的羧甲基纤维素基高分子交联剂。
实施例四:邻苯二甲醛基团改性的海藻酸基交联剂代表性组分A-3.1~A-3.3的合成
(1)组分A-3.1的合成:将海藻酸(Sodium Alginate,Alg,5g,粘度(2%,25℃)为50mPa·s,t=7)溶于250mL的去离子水中,搅拌至完全溶解;称取化合物3(0.65g,1mmol,s=2,t=7)、EDC(1.6g,10mmol)和DPTS(2.5g,10mmol)依次加入上述溶液;透析时选择MWCO 3500的透析袋,其余合成过程参照组分A-2.1的合成。通过核磁氢谱图鉴定Alg上化合物3的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物3的量,可计算化合物3的标记率大约为2.63%(w/w)。
(2)组分A-3.2的合成:将Alg(5g,粘度(2%,25℃)为980mPa·s)溶于250mL的MES缓冲溶液(0.01M,pH=5.2),搅拌至完全溶解。加入EDC(1.54g,10mmol)和NHS(1.14g,10mmol)室温下搅拌30分钟。称取化合物5(350mg,1mmol,r=2,s=6)加入上述反应体系,室温反应搅拌24h。反应结束后,用稀盐酸中和pH至7,用去离子水透析2-3d(MWCO 7000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO
7000),收集产物冷冻干燥,得到组分A-3.2。通过核磁氢谱图鉴定Alg上化合物5的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物5的量,可计算化合物5的标记率大约为2.57%(w/w)。
(3)组分A-3.3的合成:将Alg(5g,粘度(2%,25℃)为980mPa·s)溶于40mL的0.2M NaOH溶液中,搅拌至完全溶解;向上述体系中加入化合物11(286mg,1mmol),其余合成过程参照组分A-1.3的合成。通过核磁氢谱图鉴定Alg上化合物11的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物11的量,可计算化合物11的标记率大约为2.20%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的海藻酸基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的海藻酸基高分子交联剂。
实施例五:邻苯二甲醛基团改性的羧甲基淀粉基交联剂代表性组分A-4.1和A-4.2的合成
(1)组分A-4.1的合成:将羧甲基淀粉钠(Carboxymethyl Starch Sodium,CMS,A型,5g,pH为5.0-7.5)分散在250mL的去离子水中。向上述体系中依次加入化合物4(0.3g,1.2mmol,r=2)、EDC(1.86g,12mmol)和DPTS(3g,12mmol)。室温反应24h。反应结束后,用10倍体积无水乙醇重沉,析出白色粉末,收集固体后重新分散在250mL去离子水中,加入10%三氟乙酸,反应1h,将pH调至中性。用10倍体积无水乙醇重沉,析出白色粉末,即组分A-4.1。通过核磁氢谱图鉴定CMS上化合物4的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物4的量,可计算化合物4的标记率大约为2.15%(w/w)。
(2)组分A-4.2的合成:将CMS(A型,5g,pH为5.0-7.5)溶于40mL的0.25M NaOH溶液中;向上述体系中加入化合物12(0.3g,1.2mmol);最后用10
倍体积无水乙醇重沉,析出白色粉末,其余合成过程参照组分A-1.4的合成。通过核磁氢谱图鉴定CMS上化合物12的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物12的量,可计算化合物12的标记率大约为1.78%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的羧甲基淀粉基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到其他不同来源或不同结构的羧甲基淀粉同样可以用来合成所述邻苯二甲醛基团改性的羧甲基淀粉基高分子交联剂;同样也可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的羧甲基淀粉基高分子交联剂。
实施例六:邻苯二甲醛基团改性的羟乙基纤维素基交联剂代表性组分A-5.1和A-5.2的合成(m≥1)
(1)组分A-5.1的合成:将羟乙基纤维素(Hydroxyethyl Cellulose,HEC,Mw=1MDa,5g)溶于250mL无水DMSO中,搅拌至完全溶解,将化合物8(1.63g,2mmol,r=2,t=7)溶于5mL DMSO,加入上述体系,并加入二月桂酸二丁基锡(Dibutyltin Dilaurate,13μL,20μmol)作为催化剂。70℃搅拌反应24h,反应结束后,缓慢加入相同体积的冰水,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-5.1。通过核磁氢谱图鉴定HEC上化合物8的标记。收集反应体系上清液,根据高效液相色谱测定上清
液中残余化合物8的量,可计算化合物8的标记率大约为4.12%(w/w)。
(2)组分A-5.2的合成:将HEC(Mw=300kDa,5g)溶于250mL无水DMSO中,搅拌至完全溶解,将化合物10(0.73g,2mmol)溶于5mL DMSO,加入上述体系,并加入异辛酸锌(Zinc Octoate,6μL,20μmol)作为催化剂。70℃搅拌反应24h,反应结束后,缓慢加入相同体积的冰水,用去离子水透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 7000),收集产物冷冻干燥,得到组分A-5.2。通过核磁氢谱图鉴定HEC上化合物10的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物10的量,可计算化合物10的标记率大约为3.14%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的羟乙基纤维素基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的羟乙基纤维素基高分子交联剂。
实施例七:邻苯二甲醛基团改性的肝素基交联剂代表性组分A-6.1的合成
将肝素钠(Heparin sodium,Hep,5g,15kDa)溶于150mL的去离子水中,搅拌至完全溶解。向上述溶液中依次加入化合物6(0.97g,1.2mmol,r=2,t=6)、EDC(1.86g,12mmol)和DPTS(3g,12mmol)。室温反应24h。反应结束后用含稀盐酸的氯化钠水溶液(pH=4)透析2-3d(MWCO 14000),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO14000),收集产物冷冻干燥,得到组分A-6.1。通过核磁氢谱图鉴定Hep上化合物6的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物6的量,可计算化合物6的标记率大约为2.56%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的肝素基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的肝素基高分子交联剂。
实施例八:邻苯二甲醛基团改性的硫酸软骨素基交联剂代表性组分A-7.1的合成
将硫酸软骨素(Chondroitin sulfate,CS,5g,20kDa)溶于50mL的0.01mol/L的MES缓冲溶液(pH=5.2),搅拌、超声至完全溶解。加入EDC(1.54g,10mmol)和NHS(1.14g,10mmol)室温下搅拌30分钟。称取化合物5(350mg,1mmol,r=2,s=6)溶于10mL DMSO,加入反应体系,室温反应搅拌24h。反应结束后将pH调至8-9,搅拌1h,用去离子水透析2-3d(MWCO 3500),收集产物后加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 3500),收集产物冷冻干燥,得到组分A-7.1。通过核磁氢谱图鉴定CS上化合物5的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物5的量,可计算化合物5的标记率大约为1.87%(w/w)。
以上实施例提供了示例性的邻苯二甲醛基团改性的硫酸软骨素基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的硫酸软骨素基高分子交联剂。
实施例九:邻苯二甲醛基团改性的黄原胶基交联剂代表性组分A-8.1的合成
将黄原胶(Xanthan gum,XG,5g,1.2MDa)溶于500mL的1%的NaOH溶液(pH=5.2),搅拌至完全溶解。向上述体系中加入化合物12(302mg,1.2mmol),40℃反应12h。反应结束后,用稀盐酸中和pH至7,将上述体系缓慢倒入10倍体积的无水乙醇仲,收集白色沉淀。将白色沉淀重新溶解于500mL的去离子水中,并加入10%三氟乙酸,反应1h,再调至中性,随后将反应体系用去离子水透析1d(MWCO 14000),收集产物冷冻干燥,得到组分A-8.1。通过核磁氢谱图鉴定XG上化合物12的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物12的量,可计算化合物12的标记率大约为2.10%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的黄原胶基高分子
交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的黄原胶基高分子交联剂。
实施例十:邻苯二甲醛基团改性的结冷胶基交联剂代表性组分A-9.1的合成
将结冷胶(Gellan gum,GG,5g,500kDa)溶于500mL的0.01mol/L的MES缓冲溶液(pH=5.2),升温至80℃,搅拌至完全溶解,称取化合物2(266mg,1mmol,s=2)溶于10mL DMSO后加入上述反应液,称取DMTMM(7g,5mmol)分5次加入上述反应体系,每次溶于3mL MES缓冲溶液,相隔2h,60℃下反应24h。反应结束后将pH调至8-9,60℃下搅拌1h,在搅拌过程中倒入10倍体积的无水乙醇,收集沉淀后,加入500mL的去离子水,升温至60℃,搅拌至完全溶解后加入10%三氟乙酸,反应1h,再调至中性,随后在搅拌过程中倒入10倍体积的无水乙醇,收集沉淀并真空烘干,得到组分A-9.1。通过核磁氢谱图鉴定GG上化合物2的标记。收集反应体系上清液,根据高效液相色谱测定上清液中残余化合物2的量,可计算化合物2的标记率大约为1.98%(w/w)。
以上结构式和实施例提供了示例性的邻苯二甲醛基团改性的结冷胶基高分子交联剂的结构及其合成方法。本领域技术人员根据本申请的记载内容能够想到可以采用其他醛基预保护的邻苯二甲醛前体衍生物来合成所述邻苯二甲醛基团改性的结冷胶基高分子交联剂。
实施例十一:水凝胶组分配比
按照本发明方法,制得不同多糖基双组分水凝胶前体溶液(将组分A和B分别溶于磷酸盐缓冲液中,pH=7.4)。
表1
表1中的组分A-…是指实施例四~实施例五中涉及的组分A-3.1~组分A-4.4;
表1中的组分B-…分别是指组分B-4:聚赖氨酸(分子量5kDa),组分B-5:胶原蛋白,B-6:胺基改性的四臂聚乙二醇(分子量40kDa)。表1中的0.1-40wt%等是指优选的水凝胶前体溶液的质量浓度范围。
在本发明的其余实施例中,发明人按照表2中的配比制备多糖基双组分水凝胶,用于性能测试和应用。其中,多糖基双组分水凝胶(序号7对应的配方)的前体溶液及成胶后的状态如图3所示。
表2
实施例十二:水凝胶溶胀性能测试
为表明本发明制备的水凝胶,相比高溶胀(溶胀率>100%)的聚乙二醇骨架水凝胶具有低溶胀的性质,发明人按照表2中的配比制备多糖基双组分水凝胶,并对其进行溶胀率检测。并选取中国专利CN111440310A、CN111440334A、CN 111574756A、CN 111621038 A、CN113509591A、CN113694249A和CN114767920A、CN202010454896.6和CN202010455951.3公开的邻苯二甲醛基团改性的聚乙二醇交联剂用于本发明的对照组分A。
对照组分A
按照表3中的配比制备对照组的双组分水凝胶,用于溶胀率检测。
表3
具体检测方法如下:将表2和表3中涉及的各组分A溶液和组分B溶液通过双联混液器挤到聚四氟乙烯的模具中,固化10min后,得到直径为10mm,厚度为3mm的质量相近的圆柱体凝胶块。将上述凝胶块称重,记录质量为W0,并转移至50mL离心管中,加入pH为7.4的PBS缓冲溶液中(该溶液已提前加热至37±1℃),随后将离心管放入37±1℃培养箱内,每隔2小时取出样品,用滤纸吸去表面水分后称重,直至质量不再增加,记录此时的质量为Wt。结束试验,按下式计算凝胶溶胀率(n=3):
通过上述方法测试得到的溶胀率如下表:
通过上述方法测试得到的水凝胶溶胀率如表4所示:
表4
在上述配方中,相比于对照组聚乙二醇基的水凝胶(即配方37-40),本发明中的多糖基水凝胶在较宽的固含量范围下都具有低溶胀率(<50%)。
实施例十三:水凝胶组织粘附性能测试
发明人对本发明技术的多糖基双组分水凝胶进行了组织粘附性能测试,并选取商用Fibrin glue(纤维蛋白原胶)作为对照组。具体检测方法如下:利用拉力机(德国INSTRON)分别通过标准搭接剪切试验(ASTM F2255)测量上述不同配方的水凝胶在猪皮上的剪切强度。将猪皮剪裁成10mm和40mm的矩形猪皮。在机械测试期间,使用透明的聚甲基丙烯酸甲酯薄膜用作组织的硬背衬。将表2中的组分A溶液和组分B溶液或对照组Fibrin glue的双组分溶液通过双联混液器喷在一块猪皮上,面积为15mm×10mm,即粘附面积。立即将另一块猪皮按在喷了水凝胶前体溶液的猪皮上,用100kPa的力均匀按压10分钟,等待各配方水凝胶固化完毕后,进行拉伸测试。剪切强度通过以下公式计算,其中Fmax为最大力值。为确保数据的可靠性,对每个条件下的三个样本进行了测量。
通过上述方法测试得到的水凝胶粘附强度如表5所示:
表5
表5中的测试结果显示,与商用的Fibrin glue(纤维蛋白原胶)相比,本发明技术的多糖基双组分水凝胶在较宽的固含量范围下都具有优异的组织粘附性,可以实现组织粘合或密封应用。在配方1~配方5中,随着组分A增加,多糖基双组分水凝胶的组织粘附性增强。可见,提高多糖基双组分水凝胶中组分A的比例能够有效提高水凝胶的组织粘附性。
实施例十四:水凝胶体外止血性能测试
发明人对本发明技术中多糖基双组分水凝胶进行了体外止血性能测试,并选取商用Fibrin glue(纤维蛋白原胶)作为对照组。具体检测方法如下:将表2中的组分A溶液和组分B溶液或对照组Fibrin glue的双组分溶液通过双联混液器喷在洁净的96孔板中,等待固化10分钟,并置于37℃预热。在材料表面滴加20μL的37℃新鲜的EDTA抗凝绵羊血,空白对照组则直接将血液滴加在96孔板底部,于37℃静置5分钟。随后,用总量1mL的去离子水洗涤水凝胶表面的血液或血栓并轻微晃动,观察水凝胶表面残余的血凝块大小。吸取上清液检测540nm处的吸光度,并根据下方公式计算血栓形成指数。结果如表6所示。
通过上述方法测试得到的水凝胶血栓形成指数如表6所示:
表6
表6中的测试结果显示,与商用的Fibrin glue(纤维蛋白原胶)相比,本发明技术的多糖基双组分水凝胶在较宽的固含量范围下都具有优异的止血性能,可以实现止血应用。在配方1~配方5中,随着组分A增加,多糖基双组分水凝胶的体外凝血性能增强。可见,提高多糖基双组分水凝胶中组分A的比例能够有效提高水凝胶的止血效果。
实施例十五:基于以上实施例所得的产品配方,综合考虑溶胀性、组织粘附性和止血性能,选择配方5、6、7、10、14、22和30(即分别为序号5、6、7、10、14、22和30对应的配方)双组分水凝胶,以进一步实施具体的生物医学应用。
实施例十六:多糖基双组分水凝胶应用于皮肤创面修复
选用SD大鼠背部皮肤缺损创面,分两组进行皮肤创面修复实验:配方5(组a)和缝合组(组b)。在SD大鼠背部构造长10mm的皮肤缺损伤口。对于组a,将组分A溶液和组分B溶液通过双联混液器注射在皮肤缺损处,等待溶液充分填充和渗透,固化10分钟,水凝胶牢固粘附在创面上。对于组b,仅用4-0不可吸收手术缝合线对缺损处进行缝合。对各组创面进行观察,并记录7天内的修复效果。实验结果显示,相比于组b,组a修复速率更快,且没有明显的瘢痕组织生成。本实施例中,多糖基双组分水凝胶(组a)和缝合线(组b)应用于皮肤组织修复7d时的照片如图4所示。可见,上述多糖基双组分水凝胶可以应用于皮肤创面修复。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于皮肤创面修复。
实施例十七:多糖基双组分水凝胶应用于腹腔壁创面修复
选用SD大鼠腹腔壁磨损模型,分两组进行腹腔壁创面修复实验:配方5(组a)和空白组(组b)。将SD大鼠麻醉并固定,剃除其腹部毛发,暴露腹腔,在其
左右侧腹腔壁,用手术刀背来回刮擦数次直至出现渗血,即得到一直径为10mm左右的腹腔壁磨损模型。将组分A溶液和组分B溶液通过双联混液器注射在腹腔壁磨损处,等待溶液充分填充和渗透,固化10分钟。仅用生理盐水清洗组b大鼠腹腔壁创面。对创面及水凝胶进行观察,且记录各组创面在7天后的修复效果。实验结果显示组a的水凝胶牢固黏附在创面上,相比于组b,组a水凝胶处理的腹腔壁创面与腹腔内脏器无明显粘连,且修复速率更快。可见,上述多糖基双组分水凝胶可以应用于腹腔壁创面修复。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于腹腔壁创面修复。
实施例十八:多糖基双组分水凝胶应用于胰液渗漏封堵
选用SD大鼠胰漏模型,分两组进行胰漏渗液封堵实验:配方5(组a)和空白组(组b)。麻醉、固定SD大鼠,剃除其腹部毛发并用碘伏消毒,暴露其腹腔,分理出大网膜及胰腺,结扎脾脏部分血管,防止胰腺切除时造成不必要的出血。用手术刀切除胰-十二指肠末端,制造胰漏模型。对于组a,将组分A溶液和组分B溶液通过双联混液器注射在胰腺断端处,等待溶液充分填充和渗透,固化10分钟;组b不进行任何处理,直接关腹。术后第7天,收集SD大鼠的腹腔积液,并分析其蛋白酶含量;术后7天,对SD大鼠进行安乐死处理,观察其腹腔的粘连情况。实验结果显示,组b中的SD大鼠术后7天内的蛋白酶超过正常水平,证明了胰漏模型的成功建立。本实施例中,多糖基双组分水凝胶(配方5)应用在胰腺断端封堵胰液渗漏术后7d的照片如图5所示。相比于组b,组a大鼠腹腔内无明显积液和粘连,其胰腺断端仍能观察到水凝胶材料。生理盐水冲洗腹腔后,收集腹腔积液检测蛋白酶水平,实验结果表明,组a大鼠腹腔内胰蛋白酶含量处于正常水平。可见,上述多糖基双组分水凝胶可以应用于胰液渗漏封堵。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于胰液渗漏封堵。
实施例十九:多糖基双组分水凝胶应用于脑脊液渗漏封堵
选用SD大鼠脑脊液模型,分两组进行脑脊液渗漏封堵实验:配方5(组a)和骨蜡组(组b)。麻醉、固定SD大鼠,剃除背部毛发,以胸13、腰1为中心依次剪开皮肤、筋膜,暴露手术区肌肉。一侧用眼科剪紧贴棘突剪断与其相连的肌、肌腱,创造一切口,长度为以胸12~腰2为宜,深度以达到关节突为止。在该切口外侧约0.5cm剪开另一平行切口,长度、深度与前一切口基本一致,将两切口之间的肌肉剔除,暴露3对关节突(胸12~胸13、胸13~腰1和腰1~腰2)。一次暴
露椎管侧壁及椎间孔,平行截断椎管两侧壁,暴露脊髓,形成创面,观察到出血并伴随脑脊液渗漏,即为建模成功。随后,对于组a,立即将组分A溶液和组分B溶液通过双联混液器注射在脑脊液渗漏处,等待溶液充分填充和渗透,固化10分钟;对于组b,立即将骨蜡涂抹在脑脊液渗漏处,在使用过程中b组仍存在渗漏现象。本实施例中,多糖基双组分水凝胶(配方5,组a)和骨蜡(组b)应用于脑脊液渗漏封堵的照片如图6所示。将两组大鼠创面缝合。在术后2天时,组b大鼠全部死亡,a组大鼠全部存活;在术后7天时观察到水凝胶牢固粘附在组a大鼠的脊柱损伤处,且无明显渗漏。可见,上述多糖基双组分水凝胶可以应用于脑脊液渗漏封堵。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于脑脊液渗漏封堵。
实施例二十:多糖基双组分水凝胶应用于肺实质漏气封堵
选用新西兰白兔肺实质漏气模型,分两组进行肺实质漏气封堵实验,每组各三只:配方6(组a)和空白组(组b)。对新西兰白兔耳缘静脉注射1%戊巴比妥钠,剂量为3mL/kg,全麻气管插管,并用呼吸机辅助通气(VT 80mL,R 30bpm)。随后进行开胸,切除肺叶边缘组织,创面约1cm2,至少可见一处直径约1mm细支气管断端。对于组b,创面不做处理,直接关胸。对于组a,将组分A溶液和组分B溶液通过双联混液器注射在肺缺损部位,等待溶液充分填充和渗透,固化10分钟,确认水凝胶粘附在创面处后,逐层关胸,排除残气,使肺充分复张。组b中3只白兔在术后4小时内由于持续漏气导致呼吸衰竭死亡,组a中3只白兔肺部创面未见漏气。术后7、14天,解剖后观察,组a中水凝胶材料紧密附着于创面,未见积液和粘连。可见,上述多糖基双组分水凝胶可以应用于肺实质漏气封堵。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于肺实质漏气封堵。
实施例二十一:多糖基双组分水凝胶应用于肝脏止血
选用SD大鼠肝横断切面创伤模型,分三组进行肝脏止血实验:配方14(组a)、配方7(组b)和纱布组(组c)。将SD大鼠麻醉后,打开其腹腔,提起肝脏并放置在预先称重的滤纸上,然后在肝脏上建立一个直径10毫米的横断切面,造成出血。对于组a和组b,分别将组分A溶液和组分B溶液通过双联混液器注射在出血处,随着溶液的渗透,组a和组b在有血存在的情况下快速凝胶化,封堵出血口。对于组c,则用预先称重的纱布轻微按压在横断创面上。失血量通过滤纸(和纱布)的增重测量,止血时间通过计时器记录。实验过程中,相比于组c,组a和组b的
失血量大幅降低(组a为0.2g,组b为0.1g,组c为1.0g),且止血时间显著缩短(组a为7s,组b为5s,组c为50s)。可见,上述多糖基双组分水凝胶可以应用于肝脏止血。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于肝脏止血。
实施例二十二:多糖基双组分水凝胶应用于股动脉止血
选用SD大鼠股动脉出血模型,分三组进行股动脉止血实验:配方14(组a)、配方10(组b)和纱布组(组c)。将SD大鼠麻醉后,剃除其右侧后腿和下腹部毛发,暴露其股动脉、静脉及神经,小心剥离出股动脉,用止血钳轻轻夹闭两端动脉,用32G针头在动脉上扎孔。对于组a和组b,待上述动脉血液流尽后则立即将组分A溶液和组分B溶液通过双联混液器注射在出血处;对于组c,则立即将纱布轻微按压在出血处。实验结果显示,组a和组b在有血存在的情况下快速凝胶化,在两端止血钳去除后,水凝胶仍能够牢固粘附在出血点,实现稳定封堵,不再出血;组c大鼠则失血过多致死,未能实现止血。可见,上述多糖基双组分水凝胶可以应用于股动脉止血。
本发明中其他配方的多糖基双组分水凝胶同样可以应用于股动脉止血。
实施例二十三:多糖基膜材料的制备
以配方5为例,将组分A和B分别溶于磷酸盐缓冲溶液(pH=7.4)后得到组分A溶液和组分B溶液,将二者通过双联混液器涂抹在洁净平整的聚四氟乙烯板上,固化10分钟后,在含5%甘油的磷酸盐缓冲溶液(pH=7)中溶胀平衡,30℃恒温烘干,得到多糖基膜材料。
本发明中其他配方的前体溶液也可制备得到不同组分的多糖基膜材料。
实施例二十四:多糖基膜材料应用于手术伤口免缝合封闭
选用SD大鼠背部创面模型,分两组进行免缝合封闭手术伤口实验:实施例二十三中的膜材料(配方5,组a)和缝合组(组b)。将SD大鼠麻醉后,剃除其背部毛发,用手术刀在其背部制造一长1cm的皮肤切口。对于组a,将膜材料贴在切口处,使切口闭合。对于组b,将切口对齐后用4-0不可吸收手术缝合线进行缝合。术后3天、10天观察切口的愈合情况:组a膜材料未见明显脱落,切口上皮化较快,愈合速度快;组b愈合速度缓慢。本实施例中,多糖基膜材料应用于手术伤口免缝合封闭(组a)和缝合组(组b)术后10天的H&E染色结果对比照片如图7所示。H&E染色结果表明,组a创面完整愈合,新生组织与皮肤组织相近,而组
b创面未完全修复。可见,上述多糖基膜材料可以应用于手术伤口免缝合封闭。
本发明中其他配方的多糖基膜材料,同样可以应用于手术伤口免缝合封闭。
实施例二十五:多糖基膜材料作为补片应用于腹腔疝修补
选用SD大鼠急性腹壁疝模型,分两组进行腹壁疝修补实验:实施例二十三中的膜材料(配方5,组a)和Separmesh可吸收复合补片(巴德,组b)。将大鼠麻醉后,固定、备皮并消毒,于下腹部腹中线两侧各2cm的位置标记出大小1.2cm*1.2cm的正方形,逐层切开腹壁,建立一直径1.2cm的全腹壁缺损。两侧分别放置一2cm*2cm的正方形补片,组a补片不进行缝合;组b补片四周用4-0不可吸收手术缝合线间断缝合。皮肤用75%乙醇消毒后,用3-0不可吸收手术缝合线间断缝合。术后30天开腹腔,观察补片所在腹腔内脏器与补片的粘连情况。实验结果显示组a中补片无明显移位,无腹内疝发生,组a补片与腹腔内脏器无明显粘连;组b中补片无明显移位,缝合处与腹腔内大网膜存在少许粘连。可见,上述多糖基膜材料可以作为补片应用于腹腔疝修补。
本发明中其他配方的多糖基膜材料,同样可以作为补片应用于腹腔疝修补。
实施例二十六:多糖基粉剂材料的制备
以配方22为例,将组分A和B分别溶于磷酸盐缓冲溶液(pH=7.4)后得到组分A溶液和组分B溶液,将二者通过双联混液器涂抹在洁净平整的聚四氟乙烯板上,固化10分钟后,在磷酸盐缓冲溶液(pH=7)中溶胀平衡,30℃恒温烘干,将干燥后的材料装入球磨机内,过筛后得微细粉末(目数为60目~300目),即多糖基粉剂材料。本实施例中,不同粒径的多糖基粉剂材料在显微镜下的微观形貌如图8所示。或将固化后的水凝胶材料,加入一倍体积的磷酸盐缓冲溶液(pH=7),利用高速剪切搅拌将块状水凝胶切割成粒径较小的微凝胶。分离出微凝胶后,依次加入3倍体积的50%,75%和无水乙醇,与微凝胶中的水分进行置换。分离出微凝胶,30℃恒温真空烘干12h,过筛,得到目数为60目~300目的粉末,即多糖基粉剂材料。
本发明中其他配方的前体溶液也可制备得到不同组分的多糖基粉剂材料。
实施例二十七:多糖基粉剂材料应用于微创手术止血
选用巴马猪急性上消化道动脉出血模型,分两组进行微创手术止血实验:实施例二十六中的粉剂材料(配方22,组a)以及可吸收止血颗粒(ARISTA,组b)。将成年雌性巴马猪(体重20-25kg)麻醉,并在右股动脉插管以监测血压。随后在
5分钟内,监测所有动物的基线血压(收缩压)并将其调整为90-100mm Hg,然后静脉内施用肝素(10mg/kg)以实现全身肝素化。在内窥镜下,剥离黏膜,并分辨出胃中的黏膜下搏动动脉。然后用内窥镜刀切割动脉,诱导急性上消化道出血,并维持4分钟的自然流血。将组a和组b的止血粉分别通过导管应用于出血部位,观察出血部位,除非达到止血,否则重复止血程序,并记录止血时间和使用材料质量。实验结果显示,在手术过程中,组a的止血粉能够迅速粘附于创面,并形成胶状物封堵出血,止血时间较短(组a:80s,组b:160s),且使用的材料较少(组a:1.1g,组b:2g)可见,上述多糖基粉剂材料可以应用于微创手术止血。
本发明中其他配方的多糖基粉剂材料,同样可以应用于微创手术止血。
实施例二十八:多糖基粉剂材料作为抗菌药物载体应用于创面抗菌治疗
以配方14为例,通过实施例将组分A和B分别溶于磷酸盐缓冲溶液(pH=7.4)后得到组分A溶液和组分B溶液,将二者通过双联混液器涂抹在洁净平整的聚四氟乙烯板上,固化10分钟后,加入一倍体积的磷酸盐缓冲溶液(pH=7),利用高速剪切搅拌将块状水凝胶切割成粒径较小的微凝胶。将微凝胶分散在含苯扎氯铵(0.1%)的磷酸盐缓冲溶液中(pH=7.4),搅拌1h,由于静电吸附作用,含阳离子的苯扎氯铵会吸附在微凝胶表面,分离出微凝胶后,依次加入3倍体积的50%,75%和无水乙醇,与微凝胶中的水分进行置换。分离出微凝胶,30℃恒温真空烘干12h,过筛,得到负载苯扎氯铵的多糖基粉剂材料。
选用Balb/C小鼠背部全层切口感染创面模型,分三组进行体表创面抗菌实验:上述表面负载苯扎氯铵的多糖基粉剂材料(组a)、苯扎氯铵溶液组(组b)和空白组(组c)。在8–10周龄雌性BALB/C小鼠背部切下长20mm的全厚纵向切口,并将50μL大肠杆菌25922(1×108CFU mL-1)逐滴滴入伤口部位,建立原位急性致病菌感染模型。将组a的粉剂均匀喷洒到伤口处,伴随伤口渗液,粉剂逐渐凝胶化且牢固粘附在创面表面;组b则用0.01%的苯扎氯铵溶液消毒创面,组c不做任何处理。实验结果显示,组c感染区域开始扩散,血液循环不良,逐渐出现缺血,化脓等现象,组织损伤明显;组b在初期感染区域扩散速度有限,但在术后7天时仍出现化脓、缺血等现象;组a的恢复效果最佳,细菌增殖被抑制,创面无化脓、缺血等现象。可见,上述负载苯扎氯铵的多糖基粉剂材料可以应用于创面抗菌治疗。
本发明中其他配方的多糖基粉剂材料,同样可以作为负载抗菌类药物的载体,应用于创面抗菌治疗。
实施例二十九:多糖基粉剂材料作为抗炎药物载体应用于炎症治疗
糖皮质激素类药物适应症广泛,对全身各项生理功能都有较强的调节作用,在临床上广泛用于各种自身免疫性疾病、白血病、哮喘、过敏反应等等。然而,长时间非特异性的使用激素类药物可能会诱导多种疾病,具有严重的副作用,因此局部短时间小剂量使用激素类药物是临床上推荐的使用方法。以配方5为例,通过实施例将组分A和B分别溶于磷酸盐缓冲溶液(pH=7.4)后得到组分A溶液和组分B溶液,将二者通过双联混液器涂抹在洁净平整的聚四氟乙烯板上,固化10分钟后,加入一倍体积的磷酸盐缓冲溶液(pH=7),利用高速剪切搅拌将块状水凝胶切割成粒径较小的微凝胶。将微凝胶分散在含布***(20μg/mL)的磷酸盐缓冲溶液中(pH=7.4),搅拌1h,由于氢键和亲疏水相互作用,布***会吸附在微凝胶表面,分离出微凝胶后,依次加入3倍体积的50%,75%和无水乙醇,与微凝胶中的水分进行置换。分离出微凝胶,30℃恒温真空烘干12h,过筛,得到负载布***的多糖基粉剂材料。
选用Balb/C小鼠急性肠炎模型,分三组进行急性肠炎治疗实验:上述表面负载布***的多糖基粉剂材料(组a)、布***灌肠液(组b)和空白组(组c)。用无菌水配置3%的DSS饮用水,并用0.22μm的滤膜过滤,给小鼠连续7天引用,通过肠镜观察到小鼠组织局部水肿充血,有明显炎症现象,即为造模成功。组a通过肠镜将粉剂喷在炎症部位,组b则用布***灌肠液进行灌肠,组c不做任何处理。7、14天后,观察小鼠炎症部位情况,并解剖统计各组小鼠结肠长度。实验结果表明,组a中的粉剂材料牢固粘附在受损的炎症创面,相比于组b和组c,其创面水肿和溃疡情况减缓。本实施例中,正常小鼠以及表面负载布***的多糖基粉剂材料(组a)、布***灌肠液(组b)和空白组(组c)治疗小鼠急性肠炎后的小鼠结肠长度统计图如图9所示。统计结果表明,相比于组b和组c,组a小鼠的结肠长度最长。可见,上述负载布***的多糖基粉剂材料可以应用于炎症治疗。
本发明中其他配方的多糖基粉剂材料,同样可以作为负载抗炎类药物的载体,应用于炎症治疗。
实施例三十:多糖基海绵材料的制备
以配方6为例,将组分A和B分别溶于磷酸盐缓冲溶液(pH=7.4)后得到溶液A和溶液B,将二者通过双联混液器喷在模具中,固化10分钟后,在磷酸盐缓冲溶液(pH=7)中溶胀平衡,-20℃冷冻6小时,随后-60℃冻干48小时,得到多
糖基海绵材料。
本发明中其他配方的前体溶液也可制备得到不同组分的多糖基海绵材料。
实施例三十一:多糖基海绵材料作为创面敷料应用于创面治疗
选用SD大鼠背部缺损模型,分两组进行创面敷料实验:实施例三十中的海绵材料(配方14,组a)、商用明胶海绵组(组b)和空白组(组c)。在SD大鼠背部制造一直径10mm的圆形缺损创面。分别将组a和组b的海绵均匀覆盖在创面上,组c则不做任何处理,随后各组都用纱布和医用胶布覆盖。实验结果显示组a的海绵材料能牢固粘附在组织缺损部位,相比于组c,组a和组b创面恢复速率较快,新生组织和皮肤组织类似,无明显瘢痕组织生成。可见,上述多糖基海绵材料可以作为创面敷料应用于创面治疗。
本发明中其他配方的多糖基海绵材料,同样可以作为创面敷料应用于创面治疗。
实施例三十二:多糖基海绵材料应用于脾脏止血;
选用新西兰白兔脾脏出血模型,分两组进行脾脏止血实验:实施例三十中的海绵材料(配方6,组a)和商用可吸收止血纱(组b)。将新西兰白兔麻醉并固定,剃除其腹部毛发,用碘伏消毒后打开腹腔,暴露其脾脏。用手术刀在其脾脏上分别制造8mm长,1mm深的切口,造成出血创面。将止血材料轻轻按压在出血处,大概每10秒观察一次创面,出血完全停止后立即记录止血时间。本实施例中,多糖基海绵材料(组a)和商用可吸收止血纱(组b)应用于脾脏止血的照片对比如图10所示。止血材料在使用前后称重,差值即为总失血量。实验过程中,组a和组b材料都能牢固黏附在脾脏出血创面上,相比于组b,组a的止血时间较短(组a:120s,组b:180s)且失血量较少(组a:3g,组b:3.5g)。可见,上述多糖基海绵材料可以应用于脾脏止血。
本发明中其他配方的多糖基海绵材料,同样可以应用于脾脏止血。
实施例三十三:多糖基海绵材料应用于心脏止血;
选用SD大鼠心脏出血模型,分两组进行心脏止血实验:实施例三十中的海绵材料(配方30,组a)和纱布组(组b)。将SD大鼠麻醉并固定,剃除胸部毛发。打开胸腔并暴露心脏,使用细镊子去除心包。使用活检打孔器对心脏的左心室或右心室壁创造一直径2mm的损伤。随后,立即将止血材料应用于出血部位,并且施以相同的压力。大约每10秒观察一次创面,出血完全停止后立即记录止血时间。本实施例中,多糖基海绵材料(组a)应用于心脏止血的照片如图11所示。止血
材料在使用前后称重,差值即为总失血量。对于在300秒内未能形成止血的组别,通过放血对大鼠实施安乐死。实验过程中,组a的海绵牢固黏附心室创面上(如图11所示),相比于组b,组a止血时间短(组a:60s,组b大鼠未能在300s内成功止血)且失血量最少(组a:1.2g,组b在300s内失血2.5g),且组a大鼠成功在术后存活。可见,上述多糖基海绵材料可以应用于心脏止血。
本发明中其他配方的多糖基海绵材料,同样可以应用于心脏止血。
实施例三十四:多糖基海绵材料应用于非压迫性贯穿伤止血;
选用新西兰白兔肝脏穿孔模型,分两组组进行非压迫性贯穿伤止血实验:实施例三十中的海绵材料(配方6,组a)和纱布组(组b)。将新西兰白兔麻醉后,打开其腹腔,提起肝脏并放置在预先称重的纱布上,然后在肝脏上建立直径6毫米的贯穿创面,造成出血。随后,将不同组的止血材料填塞于贯穿创面处。失血量通过止血材料和纱布的增重测量。实验过程中,相比于组b,组a的失血量显著减少(组a:2.6g,组b:4.5g),且止血时间显著缩短(组a:35s,组b:96s)。可见,上述多糖基海绵材料可以应用于非压迫性贯穿伤止血。
本发明中其他配方的多糖基海绵材料,同样可以应用于非压迫性贯穿伤止血。
以上实施例十六至实施例二十二给出了具体配方的多糖基双组分水凝胶在组织修复、组织液渗漏封堵、组织漏气封堵、止血等方面的应用,这些应用中主要利用了多糖基双组分水凝胶组织粘附性能、止血性能,而根据实施例十二至实施例十四的记载可知,本发明实施例提供的多糖基双组分水凝胶配方1-36都具有良好的组织粘附性能、止血性能和较低的溶胀性,所以,本发明实施例提供的多糖基双组分水凝胶配方1-36都可在组织修复、组织液渗漏封堵、组织漏气封堵、止血等方面进行应用。
以上实施例二十三至实施例三十四给出了具体配方的多糖基膜材料、多糖基粉剂材料、多糖基海绵材料的制备以及相应的生物医学应用,本领域技术人员根据本申请的记载内容,可以根据需要将实施例提供的多糖基双组分水凝胶配方1-36也制备成多糖基膜材料、多糖基粉剂材料、多糖基海绵材料。同样的,本领域技术人员根据本申请的记载内容,可以根据需要将实施例提供的多糖基双组分水凝胶配方1-36制备成的多糖基膜材料用于手术伤口免缝合封闭、补片;或者根据需要将实施例提供的多糖基双组分水凝胶配方1-36制备成的多糖基粉剂材料用于止血,或作为细胞、因子、药物载体;或者,根据需要将实施例提供的多糖基双组分水凝胶
配方1-36制备成的多糖基海绵材料用于作为创面敷料产品或止血产品。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (19)
- 多糖基高分子交联剂,其特征在于,为邻苯二甲醛基团改性的多糖基高分子交联剂,结构如式1所示:
式1中,P为天然多糖高分子或其修饰物或降解物,P选自透明质酸、纤维素、纤维素衍生物、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、卡拉胶、黄芪胶、黄原胶、结冷胶、瓜尔胶、***胶、刺槐豆胶、淀粉、淀粉水解产物或淀粉衍生物中的一种或几种;式1中,n≥2;式1中,邻苯二甲醛基团与P之间通过共价键连接。 - 根据权利要求1所述的多糖基高分子交联剂,其特征在于,式1所示的多糖基高分子交联剂选自以下结构中的一种:
其中,1≤r≤20,1≤s≤20,1≤t≤50,n≥2;优选地,1≤r≤6,1≤s≤10,1≤t≤30,n≥2。 - 根据权利要求1所述的多糖基高分子交联剂,其特征在于,P选自透明质酸、纤维素衍生物、海藻酸、肝素、硫酸软骨素、黄原胶、结冷胶、淀粉或淀粉衍生物;其中,所述纤维素衍生物选自甲基纤维素、羧甲基纤维素、羟乙基纤维素、羟丙基纤维素或羟丙基甲基纤维素;优选地,所述纤维素衍生物选自羧甲基纤维素。所述淀粉衍生物选自氧化淀粉、酯化淀粉、醚化淀粉或烷基化淀粉;优选地,所述淀粉衍生物选自羧甲基淀粉。
- 权利要求1或2或3所述的多糖基高分子交联剂的制备方法,其特征在于,将醛基预保护的邻苯二甲醛前体衍生物与多糖高分子上的活性基团进行共价键连接,得到邻苯二甲醛前体衍生物修饰的多糖高分子,随后将邻苯二甲醛前体衍生物修饰的多糖高分子的醛基进行脱保护得到邻苯二甲醛基团改性的多糖基高分子交联剂。
- 根据权利要求4所述的多糖基高分子交联剂的制备方法,其特征在于,所述醛基预保护的邻苯二甲醛前体衍生物包含醛基被预先保护的邻苯二甲醛基团和可与多糖高分子上的活性基团连接的取代基R,结构如式2所示:
式2中,R选自羧基类取代基、乙烯基砜类取代基、环氧类取代基、卤代烷烃类取代基、异氰酸酯类取代基或胺基类取代基;式2中,R与苯环直接相连,或通过单个或多个亚烷基链、烷氧基链连接到苯环上,所述多个亚烷基链、烷氧基链之间通过醚键、酰胺键、酯键、氨基甲酸酯键或脲键连接。 - 根据权利要求5所述的多糖基高分子交联剂的制备方法,其特征在于,所述醛基预保护的邻苯二甲醛前体衍生物选自以下化合物中的一种:
其中,1≤r≤20,1≤s≤20,1≤t≤50;优选的,1≤r≤6,1≤s≤10,1≤t≤30。 - 根据权利要求4所述的多糖基高分子交联剂的制备方法,其特征在于,所述多糖高分子的活性基团是多糖高分子自有的活性基团,或是多糖高分子被改性或降解后的具有反应活性的基团;优选地,所述多糖高分子的活性基团选自羟基或羧基。
- 根据权利要求4所述的多糖基高分子交联剂的制备方法,其特征在于,所述醛基预保护的邻苯二甲醛前体衍生物与多糖高分子上的活性基团进行共价键连接的方式选自醚键、酰胺键、酯键、氨基甲酸酯键或脲键连接,优选为醚键、酰胺键、酯键、氨基甲酸酯键连接。
- 根据权利要求4所述的多糖基高分子交联剂的制备方法,其特征在于,当所述多糖高分子的活性基团选自羟基时,所述的共价键连接为基于邻苯二甲醛前体衍生物上乙烯基砜类取代基、环氧类取代基或卤代烷烃类取代基与多糖高分子上的羟基之间的醚键连接,基于邻苯二甲醛前体衍生物上羧基类取代基与多糖高分子上的羟基之间的酯键连接,基于邻苯二甲醛前体衍生物上异氰酸酯类取代基与多糖高分子上的羟基之间的氨基甲酸酯键连接;当所述的多糖高分子活性基团选自羧基时,所述的共价键连接为基于邻苯二甲醛前体衍生物上胺基类取代基与多糖高分子上的羧基之间的酰胺键连接。
- 根据权利要求4所述的多糖基高分子交联剂的制备方法,其特征在于,将邻苯二甲醛前体衍生物修饰的多糖高分子的醛基进行脱保护是指:对多糖高分子上连接的醛基被预保护的邻苯二甲醛官能团在酸性条件下进行脱保护得到邻苯二甲醛基团改性的多糖基高分子交联剂。
- 多糖基双组分水凝胶的制备方法,其特征在于,将组分A和组分B分别溶于溶剂中得到组分A溶液和组分B溶液,将组分A溶液和组分B溶液混合即得所述多糖基双组分水凝胶;其中,所述组分A为如权利要求1-3中任一项所述的邻苯二甲醛基团改性的多糖基高分子交联剂;所述组分B为含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团的水溶性小分子、水溶性人工合成高分子、水溶性天然高分子,且单个分子上含有的伯胺、联胺、酰肼、羟胺或巯基官能团数量不少于2;所述水溶性天然高分子包括蛋白质、核酸和多糖。
- 根据权利要求11所述的多糖基双组分水凝胶的制备方法,其特征在于,所述组分B选自以下物质中的一种或几种:聚乙二醇衍生物、聚乙烯亚胺、聚氨基酸、蛋白、蛋白修饰物、蛋白改性物、蛋白降解物、多糖、多糖修饰物或多糖降解物;且所述组分B选择的物质分子结构中含伯胺、联胺、酰肼、羟胺或巯基其中一种或多种基团,且单个分子上含有的伯胺、联胺、酰肼、羟胺或巯基官能团数量不少于2;优选地,所述聚乙二醇衍生物为伯胺、联胺、酰肼、羟胺或巯基改性的聚乙二醇衍生物,优选地,所述蛋白包括胶原蛋白、血清蛋白、纤维蛋白原和纤维蛋白,所述蛋白降解物包括明胶或多肽;优选地,所述多糖、多糖修饰物或多糖降解物选自:壳聚糖及壳聚糖修饰物和壳聚糖降解物;伯胺、联胺、酰肼、羟胺或巯基改性的透明质酸、海藻酸、硫酸软骨素、肝素、纤维素、甲壳素及其各自的修饰物和降解物。
- 根据权利要求11所述的多糖基双组分水凝胶的制备方法,其特征在于,所述组分B选自:胺基改性的聚乙二醇衍生物;酰肼改性的透明质酸;胶原蛋白;血清蛋白;明胶;多肽;聚氨基酸;壳聚糖。
- 根据权利要求11所述的多糖基双组分水凝胶的制备方法,其特征在于,组分A溶液中,组分A的固含量为0.1-40wt%,优选为0.5-20wt%,进一步优选为0.5-10wt%,组分B溶液中,组分B的固含量为0.1-40wt%,优选为0.5-20wt%,进一步优选为0.5-10wt%。
- 基于权利要求11或12或13或14所述制备方法制备得到的多糖基双组分水凝胶。
- 多糖基生物材料,其特征在于,选自以下生物材料中的一种:由权利要求15所述多糖基双组分水凝胶干燥后制得的一种多糖基膜材料;由所述多糖基膜材料进一步机械球磨制得的一种多糖基粉剂材料;或,由权利要求11中制备多糖基双组分水凝胶的组分A溶液、组分B溶液混合后通过乳化法、微流控方法或机械粉碎法制备的微凝胶颗粒,进一步通过干燥、过筛制得的一种多糖基粉剂材料;由权利要求11中制备多糖基双组分水凝胶的组分A溶液、组分B溶液和制孔剂混合得到含有孔结构的多糖基水凝胶材料,进一步干燥制得的一种多糖基海绵材料。
- 根据权利要求16所述多糖基生物材料,其特征在于,当多糖基生物材料选自多糖基海绵材料时,所述制孔剂是使材料中产生孔洞结构的添加剂,选择易分解为气体的物质、高分子微球、聚乙二醇、聚乙烯基吡咯烷酮、表面活性剂或水。
- 权利要求15所述多糖基双组分水凝胶的应用,其特征在于,选自以下应用中的一种:所述多糖基双组分水凝胶在制备组织修复产品中的应用;所述多糖基双组分水凝胶在制备组织液渗漏封堵产品中的应用;所述多糖基双组分水凝胶在制备组织漏气封堵产品中的应用;所述多糖基双组分水凝胶在制备止血产品中的应用;其中,所述组织修复包括皮肤修复、腹腔壁修复;所述组织液渗漏封堵包括胰液渗漏封堵、脑脊液渗漏封堵、肠漏封堵、胃漏封堵;所述组织漏气封堵包括肺实质漏气封堵;所述止血包括肝脏止血、肾脏止血、脾脏止血、胰止血、骨断面止血、动脉止血和心脏止血。
- 权利要求16所述多糖基生物材料的应用,其特征在于,当所述多糖基生物材料为多糖基膜材料时,所述多糖基膜材料的应用,选自以 下应用中的一种:所述的多糖基膜材料在制备手术伤口免缝合封闭产品中的应用;所述的多糖基膜材料在制备补片产品中的应用;当所述多糖基生物材料为多糖基粉剂材料时,所述多糖基粉剂材料的应用,选自以下应用中的一种:所述多糖基粉剂材料在制备止血产品中的应用;所述多糖基粉剂材料在制备细胞、因子、药物载体产品中的应用;所述的止血包括微创手术术中止血、肝脏止血、肾脏止血、脾脏止血、胰止血、骨断面止血、动脉止血和心脏止血;所述细胞、因子、药物载体包括干细胞载体、促生长因子载体、抗菌药物载体和抑炎药物载体;当所述多糖基生物材料为多糖基海绵材料时,所述多糖基海绵材料的应用,选自以下应用中的一种:所述多糖基海绵材料在制备创面敷料产品中的应用;所述多糖基海绵材料在制备止血产品中的应用;所述的止血包括肝脏止血、肾脏止血、脾脏止血、胰止血、骨断面止血、动脉止血、心脏止血和非压迫性贯穿伤止血。
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