Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B31/00—Preparation of derivatives of starch
  • C08B31/02—Esters
  • C08B31/04—Esters of organic acids, e.g. alkenyl-succinated starch
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
  • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
  • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus

Definitions

• the present invention relates to polymeric materials comprising chemically modified polysaccharides that form antibacterial hydrogels by crosslinking with each other, bioprinting matrices comprising the polymeric materials, and other uses.
• Bacterial infections have become one of the world's largest public healthcare challenges. Specifically, wound infections, one of the most commonly occurring infections, are a major cause of morbidity and mortality. Meanwhile, contamination in cell cultures by bacteria and other microorganisms remains a major concern for researchers, especially in 3D culture systems where detection by visual tracking is more complicated than in regular 2D cultures.
• One of the most common means to prevent bacterial contamination in vitro is the use of antibiotics. However, previous studies have raised concerns that antibiotics may induce changes in gene expression and regulation in cells.
• Chitosan a cationic polysaccharide derived from chitin
• Non-Patent Document 1 Non-Patent Document 1, etc.
• most of the sugar units of chitosan contain primary amino groups, it is insoluble in water, organic solvents, and alkaline solutions, although it is soluble in dilute acids.
• the present invention aims to provide a biomaterial, particularly a hydrogel material, that uses chitosan and has mechanical properties that can be used for a variety of purposes while maintaining the antibacterial properties of chitosan.
• the inventors discovered that by using a polymer material containing two types of polysaccharides, a hydrophilic chitosan derivative and a neutral hydrophilic polysaccharide capable of forming intermolecular hydrogen bonds with the hydrophilic chitosan derivative, it is possible to obtain a hydrogel that has mechanical properties applicable to a variety of uses by means of photocrosslinking and the like while maintaining the antibacterial properties of chitosan, and thus completed the present invention.
• the present invention provides ⁇ 1> A polymer material comprising: a) a first polysaccharide having a repeating unit including two types of sugar units, d-glucosamine and N-acetyl-d-glucosamine, the first polysaccharide having a structure in which at least a portion of the amino groups in the d-glucosamine are substituted with a site having a carboxyl group to form an amide bond; and b) a second polysaccharide having a structure in which at least a portion of the hydroxyl groups in the repeating unit are substituted with a functional group selected from the group consisting of an acryl group and a methacryl group, the first polysaccharide and the second polysaccharide both being water-soluble, and the first polysaccharide and the second polysaccharide being capable of forming a hydrogel by crosslinking with each other; ⁇ 2> The polymer material according to claim 1, wherein a hydrogen bond is formed
• the present invention relates to a bioprinting matrix comprising the above gel material and a use thereof, ⁇ 24> A matrix for bioprinting, comprising the polymer material according to any one of ⁇ 1> to ⁇ 23> above, wherein the first polysaccharide and the second polysaccharide are crosslinked with each other during bioprinting to form a hydrogel; ⁇ 25> The bioprinting matrix according to ⁇ 24> above, which has antibacterial activity and low toxicity; and ⁇ 26> use of the polymer material according to any one of ⁇ 1> to ⁇ 23> above or the matrix according to ⁇ 24> or ⁇ 25> above in bioprinting; encapsulation of proteins, particles, or exosomes; or drug delivery.
• an antibacterial composite hydrogel that has mechanical properties applicable to various applications by means of photocrosslinking or the like while maintaining the antibacterial properties of chitosan.
• the mechanical properties of such a hydrogel are improved by the formation of hydrogen bonds between the two types of polysaccharides contained in the polymer material.
• the polymer material of the present invention is biocompatible, water-soluble, and antibacterial, and can be easily gelled by light irradiation, etc., making it useful as a matrix for 3D bioprinting. These properties make it applicable to a wide range of applications, including encapsulation of proteins and drug delivery, tissue engineering, cell culture, drug discovery and screening, in vitro research, tissue regeneration, and regenerative medicine.
• FIG. 1 shows the FTIR spectra of chitosan (CH) and modified chitosan (LACH).
• Figure 2 is a graph showing the inhibition activity of E. coli growth in the presence of chitosan (CH) and modified chitosan (LACH). The final concentration of polysaccharide in the graph is in % wt/v.
• FIG. 3A is a graph showing the growth rate of bacteria in the presence of polysaccharides
• FIG. 3B is an image of CFUs on an agar plate after 24 hours of incubation.
• FIG. 4 is a graph showing the decomposition behavior of a hydrogel by an enzyme.
• FIG. 5 shows the printing properties of the LACH/DEXMA solution: FIG.
• FIG. 5A is an image of continuous filament formation (shear thinning action) as the precursor polymer solution is extruded;
• FIG. 5B is a screenshot of the print preview;
• FIG. 5C is an image of the bioprinting process;
• FIG. 5D is an image of the printed construct; and
• FIG. 5E is an image of the square area used to calculate the printing properties.
• FIG. 6 is a graph showing cell viability in gel-forming polysaccharides (gel precursor polymers).
• FIG. 7 is a graph showing cell viability in photocrosslinked gels.
• FIG. 8 is a flow diagram showing the procedure of the protein release assay in Example 7.
• FIG. 9 is a graph showing the kinetic profile of protein release from photocrosslinked gels.
• the polymer material of the present invention is characterized in that it contains a) a first polysaccharide and b) a second polysaccharide defined below, both of which are water-soluble and capable of forming a hydrogel by crosslinking with each other.
• the first polysaccharide of the present invention is a polysaccharide having repeating units containing two types of sugar units, d-glucosamine and N-acetyl-d-glucosamine.
• the first polysaccharide has a structure in which at least a part of the amino groups in the d-glucosamine is substituted with a site having a carboxyl group to form an amide bond. This chemical modification can increase the water solubility of the first polysaccharide.
• the "site having a carboxyl group” includes a sugar acid formed by oxidizing a monosaccharide and/or a disaccharide.
• a sugar acid may preferably include a galactosyl group.
• the sugar acid may be selected from the group consisting of lactobionic acid, threonic acid, xylonic acid, and gluconic acid derivatives having one or more sugar structures.
• the first polysaccharide can be a modified cationic polysaccharide.
• cationic polysaccharides can typically include, but are not limited to, chitosan or chitosan derivatives. In terms of having antibacterial activity, chitosan or chitosan derivatives are preferred.
• a non-limiting example of the first polysaccharide is a galactosylated chitosan that at least partially comprises the following repeating units:
• the introduction rate of the carboxyl group-containing moiety in the first polysaccharide can be preferably 1 to 10%. This can increase the water solubility of the first polysaccharide while maintaining the inherent properties of the first polysaccharide, such as antibacterial activity.
• introduction rate refers to the proportion of amino groups in the first polysaccharide that are substituted by the carboxyl group-containing moiety.
• the first polysaccharide preferably has a weight average molecular weight (Mw) in the range of 50 to 2000 kDa.
• the second polysaccharide in the present invention has a structure in which at least a part of the hydroxyl groups in the repeating unit is substituted with a functional group selected from the group consisting of an acrylic group and a methacrylic group.
• the functional group is a methacrylic group.
• the second polysaccharide is preferably a modified polysaccharide of a neutral water-soluble polysaccharide. That is, the first polysaccharide is preferably a cationic polysaccharide, whereas the second polysaccharide is preferably neutral and uncharged. This is preferable from the viewpoint of preventing electrostatic interactions with the first polysaccharide and avoiding pH dependency in solubility.
• the neutral water-soluble polysaccharide may be, for example, a polysaccharide containing a repeating unit selected from the group consisting of glucose, galactose, mannose, and combinations thereof. More specifically, the second polysaccharide may be selected from the group consisting of dextran, chitosan, locust bean gum, carrageenan, and derivatives thereof, and may have the above-mentioned functional groups. Preferably, the second polysaccharide may be dextran, chitosan, or a derivative thereof.
• a non-limiting example of the second polysaccharide may be a methacrylated dextran that includes, at least in part, the following repeating units: (In the formula, n is a natural number from 2 to 1000.)
• the second polysaccharide may include, but is not limited to, methacrylated chitosan, which at least in part comprises the following repeating units:
• the second polysaccharide may preferably have a weight average molecular weight (Mw) in the range of 4 to 2000 kDa.
• the first polysaccharide and the second polysaccharide are both water-soluble polysaccharides.
• the first polysaccharide is the above-mentioned galactosylated chitosan; and the second polysaccharide is methacrylated dextran or methacrylated chitosan.
• the first polysaccharide is a chitosan and the second polysaccharide is a dextran
• hydrogen bonds can be formed between the amino groups of the chitosan and the hydroxyl groups of the dextran. These hydrogen bonds are weaker than the electrostatic interactions of other polyanionic polymers.
• the antibacterial properties of chitosan are derived from the electrostatic interactions between the amino groups of the sugar moiety and the negatively charged cell walls of bacterial cells, so the antibacterial properties of chitosan can be maintained by using a neutral dextran or the like as the first polysaccharide.
• first polysaccharide and the second polysaccharide have the same polymer backbone and may have different chemical modifications.
• the first polysaccharide may be a galactosylated chitosan and the second polysaccharide may be a methacrylated chitosan.
• the molar ratio of the first polysaccharide to the second polysaccharide in the polymer material of the present invention is preferably in the range of 1:0.1 to 1:10.
• the molar ratio can be changed appropriately depending on the type of polysaccharide, etc., from the viewpoint of ease of forming a hydrogel, which will be described later.
• the first polysaccharide can have a concentration typically in the range of 10 to 100 mg/ml, preferably 25 to 50 mg/ml
• the second polysaccharide can have a concentration typically in the range of 30 to 200 mg/ml, preferably 50 to 100 mg/ml.
• the first polysaccharide and the second polysaccharide have the same polymer backbone and, optionally, different chemical modifications.
• the first polysaccharide and the second polysaccharide contained in the polymer material of the present invention can form a hydrogel by crosslinking with each other. Therefore, the polymer material of the present invention can contain an optional crosslinking agent in addition to the first and second polysaccharides.
• the crosslinking agent can be added at a concentration of preferably 1 to 10 mg/ml, more preferably 2 to 5 mg/ml.
• any agent known in the art can be used, for example, a photopolymerization initiator or a water-soluble azo polymerization initiator such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) or 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide (VA-086) can be used.
• a photopolymerization initiator or a water-soluble azo polymerization initiator such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) or 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide (VA-086) can be used.
• the crosslinking agent contained in the polymer material of the present invention is preferably a water-soluble photocrosslinking agent.
• the light irradiation time for photocrosslinking is not particularly limited, but typically can be in the range of 1 to 30 minutes.
• gel generally refers to a dispersion system of polymers that has high viscosity and has lost fluidity, and in which the storage modulus G' and loss modulus G" satisfy the relationship G' ⁇ G".
• a gel that uses water as a solvent is called a "hydrogel”.
• the polymeric material of the present invention can be applied to a wide range of applications, such as tissue engineering, cell culture, drug discovery and screening, in vitro research, tissue regeneration and regenerative medicine, etc. More specifically, such applications can include, for example, matrices in bioprinting; encapsulation of proteins, particles, or exosomes; or drug delivery.
• the polymer material of the present invention is biocompatible, water-soluble, and antibacterial, and can be easily gelled by light irradiation or the like, making it useful as a matrix for 3D bioprinting. Therefore, the present invention also provides a matrix for bioprinting that includes the above-mentioned polymer material and forms a hydrogel by crosslinking the first polysaccharide and the second polysaccharide with each other during bioprinting.
• the matrix is characterized by having antibacterial activity and low toxicity.
• the present invention provides the use of the polymeric material or matrix in bioprinting; encapsulation of proteins, particles or exosomes; or drug delivery.
• the polymer material of the present invention was prepared and a hydrogel was formed from the polymer material according to the following procedure.
• reaction 1 Synthesis of water-soluble chitosan
• a water-soluble chitosan material corresponding to the first polysaccharide was prepared by introducing a hydrophilic functional group into chitosan. Specifically, as shown in Scheme 1, chitosan was reacted with lactobionic acid (galactosylation reaction) to modify the amino groups in the chitosan molecule. This reaction yielded a soluble galactosylated chitosan that was soluble up to 60 mg/ml in a buffer in the physiological pH range.
• FIG. 1 shows the FTIR spectra of chitosan before (left panel: CH) and after modification (right panel: LACH) with lactobionic acid (LA).
• the most representative changes that confirm the successful implementation of chemical modification are the shift of the absorption band from 1653 cm -1 to 1625 cm -1 , corresponding to the stretching of the C-O bond of the acetamide group of chitosan, and the shift of the absorption band from 1597 cm -1 to 1532 cm -1 , corresponding to the amino group of the polysaccharide. These changes are due to the formation of new amide bonds between the amino group of CH and the carboxyl group of LA.
• the second polysaccharide of the present invention includes methacrylation by reaction of hydroxyl groups present in the starting polysaccharide with methacrylic anhydride (MA) or glycidyl methacrylate (GMA), which introduces double bond moieties into the second polysaccharide that can be converted to crosslinks by UV light activation.
• MA methacrylic anhydride
• GMA glycidyl methacrylate
• dextran (DEX) was reacted with glycidyl methacrylate (GMA) to obtain methacrylated dextran (DEXMA) as shown in Scheme 2.
• GMA glycidyl methacrylate
• the reaction was confirmed by NMR.
• reaction 4 Addition of photocrosslinker
• a water-soluble photocrosslinker was added to the mixture of the first and second polysaccharides, and the mixture was gelled by short-term irradiation with light.
• the photocrosslinker can be a compound that is activated by UV or visible light wavelengths.
• Chitosan is known to have antibacterial properties.
• LACH modified chitosan
• E. coli Escherichia coli
• the optical density (OD) measurement method of bacterial culture was used to estimate the density of cells in liquid culture in the presence or absence of polysaccharide samples at various time points. Specifically, bacteria were resuspended in LB medium at a concentration of 1x108 CFU/ml, and 300 ⁇ l aliquots of bacterial broth were added to 2700 ⁇ l of medium containing CH, LACH or control. The cultures were incubated at 37°C with moderate agitation.
• Hydrogels used in vivo must be degraded in a controlled manner to allow the target tissue to regenerate to its natural structure, morphology, and function.
• Chitosan is easily degraded by enzymes, particularly lysozyme, which is naturally present in various parts of the human body, via cleavage of glycosidic bonds.
• dextran is known to be susceptible to enzymatic degradation by lysozyme. Therefore, the degradability of the LACH/DEXMA gel of the present invention was examined in the presence of lysozyme.
• Hydrogels were formed by irradiating a gel precursor solution containing LACH/DEXMA with 5 mW/ cm2 UV light (365 nm) for 2 minutes at a distance of 5 cm from the light source.
• Low and medium molecular weight LACH were used.
• the composition of the gel precursor solution is as shown in Table 1 above.
• VA-086 (2 mg/ml) was added to the gel precursor solution (PBS solution) prior to UV crosslinking.
• a hydrogel consisting of only DEXMA without LACH was prepared.
• the degree of decomposition of the gel was calculated from the measured weight change of the gel sample according to the following formula.
• %DD is the degree of decomposition of the gel
• W0 is the initial weight of the gel
• W(t) is the weight of the gel at the time of measurement.
• hydrogel-based inks with shear-thinning properties are used to prevent excessive shear stress during the bioprinting process, which may affect cell viability.
• the LACH/DEXMA composite solution (gel precursor) of the present invention has a lower viscosity than the final hydrogel after gelation and exhibits shear-thinning behavior at an optimal composition, as shown in Figure 5A.
• the bioprinting test was carried out as follows: Bioprinting was performed using a 3d Cultures Tissue Scribe bioprinter. A polymer solution (composition 7 in Table 1) containing modified chitosan (LACH), modified dextran (DEXMA) and VA-086 was loaded into a 3 ml syringe (BD Luer-LokTM) with a nozzle (inner diameter 0.8 mm). A square object of 30 x 30 mm with a height of 5 mm was designed and loaded into the Repeater Host program (Figure 5B). The height was adjusted by scaling the Z axis to 0.1.
• composition 7 in Table 1 A polymer solution (composition 7 in Table 1) containing modified chitosan (LACH), modified dextran (DEXMA) and VA-086 was loaded into a 3 ml syringe (BD Luer-LokTM) with a nozzle (inner diameter 0.8 mm).
• the nozzle was 0.8 mm, the layer thickness was 0.8 mm, the initial layer and the filling layer were 0.5 mm, the filling speed was 2 mm/s and the filling rate was 60%.
• a printing temperature of 25 °C was used. A representative photograph of the printing process is shown in Figure 5C.
• the structures would exhibit a perfect square shape and the printing characteristic Pr would have a value of 1.
• a higher Pr value would result in a greater degree of gelation of the bioink, whereas a lower Pr value would result in a lesser degree of gelation of the bioink.
• a printing characteristic Pr in the range of 0.9 to 1.1 indicates that the bioink is suitable for use in bioprinting applications.
• the polymer material of the present invention has been demonstrated to be suitable as a bioink for 3D bioprinting applications.
• LACH modified chitosan
• DEXMA modified dextran
• Cells were plated in 96-well plates at a final density of 5x103 cells per well in 100 ⁇ L of DMEM containing 10% FBS and allowed to attach to the bottom of the well overnight. The medium was then replaced with DMEM containing 0.5% w/ v of the polymer sample (same concentration as in Example 3) under serum-free conditions. The cells were incubated for 48 hours at 37°C in 5% CO2. After the incubation period, XTT reagent (BIOTIUM, Cat: 10060y Lot: 17X0824) was added and the cells were incubated for another 2 hours.
• XTT reagent (BIOTIUM, Cat: 10060y Lot: 17X0824) was added and the cells were incubated for another 2 hours.
• a polymer material (precursor solution) containing LACH and DEXMA was prepared according to the composition in Table 1, and mesenchymal stem cells were encapsulated (1 x 106 /ml). Then, 30 ⁇ l droplets were dispensed into wells of a 96-well plate. As a comparative example, the same cell density was resuspended in methacrylated gelatin (Gelma), the most common photocrosslinking polymer used as bioink. Finally, the plate was irradiated with 5 mW/ cm2 UV light (365 nm) for 2 minutes at a distance of 5 cm from the light source. The cell viability was evaluated using the XXT assay described above.
• the obtained dynamic release profile is shown in Figure 9.
• a strong release of protein occurs, known as the burst effect.
• a sustained protein release is observed from 24 to 168 hours.
• the release of BSA becomes stable after 48 hours.
• the result of a burst effect value of approximately 30% suggests that the hydrogel of the present invention can provide both the targeted initial delivery of the drug at the required dose and the subsequent long-term maintenance of a constant therapeutic concentration in the internal environment.
• MACH methacrylated chitosan
• LACH (medium molecular weight) and MACH were dissolved in PBS and photocrosslinked in the presence of the crosslinker VA-086.
• Photocrosslinking was performed by irradiating a 30 ⁇ l drop of the polymer mixture with 365 nm light at an intensity of 5 mW/ cm2 and a distance of 5 cm to the light source. The results obtained using various polymer ratios are shown in Table 2.

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