CN114404648A - Preparation method of degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair - Google Patents
Preparation method of degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair Download PDFInfo
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Abstract
The invention discloses a preparation method of degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair, which is characterized in that Dopamine (DA) grafted oxidized natural polysaccharide and Jellyfish Collagen (JC) form hydrogel with a three-dimensional network structure through a cross-linking agent. The hydrogel prepared by the invention not only has excellent tissue adhesion performance, antibacterial performance and hemostatic performance, but also has strong water retention capacity, provides a moist environment for the healing of the diabetic wound and accelerates the healing of the wound. The invention has the advantages that: 1. the prepared diabetic wound repairing and degradable hydrogel with antibacterial and hemostatic capabilities does not need to be added with antibiotics when being applied to treatment of diabetic wounds, and drug resistance is avoided; 2. the collagen is derived from plankton in aquatic environment, and compared with animal-derived collagen, the collagen avoids outbreaks of zoonosis (mad cow disease, swine brucellosis, inhalation anthrax and the like) and risks of transmission of some potential viruses.
Description
Technical Field
The invention relates to the technical field of diabetic wound repair, in particular to a preparation method of degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair.
Background
Diabetic foot wounds, which are difficult to heal due to the damage of tiny blood vessels and the imbalance of the immune system, are the main reasons for amputation. Because the wound surface of a diabetic patient lacks an effective treatment means clinically, the death rate is high; this not only causes serious psychological disorders and economic burdens on patients, but also imposes a huge burden on social medical systems. Despite the continuous development of wound healing materials in clinical practice, the existing wound healing materials do not meet the expected requirements of modern medicine for perfect wound regeneration. Such as traditional wound dressing materials (bandages, cotton and gauze), are very dry on the surface, increasing necrosis of damaged tissue and slowing down the tissue repair mechanisms at the wound site. Furthermore, due to the stickiness of these materials, they feel extremely painful when removed from the patient's wound (biomater. sci.,2021, 9: 7705.). Therefore, the construction of degradable biological materials with the function of wound tissue adaptation and the function of promoting wound healing is always a research hotspot in the field of wound repair.
With the continuous and deep research on the healing of the diabetic wound surface, the 'moist wound healing theory' is accepted by the majority of clinicians and researchers. The hydrogel with high water content provides a continuous moist environment for wounds, and has an extracellular matrix structure, good air permeability, controllable mechanical properties, excellent cell compatibility and remarkable advantages in wound repair materials. At present, wound healing hydrogel (Shukangbo, Xuebijia, Kanghui et al) is also available in the market, but the price is too high, and the problems of wound infection, long healing time and the like still exist. Therefore, the development of novel hydrogel for resisting bacteria, stopping bleeding and promoting the healing of diabetic wounds is very meaningful.
Under the strategic arrangement of the national ocean Enhance, the development of marine biological resources is particularly important. With the global warming, the trend of the breeding outbreak of the jellyfish is more and more intensified, the structure of the marine ecosystem and the human life are seriously influenced, and the jellyfish becomes a novel offshore marine ecological disaster. How to relieve the harm caused by jellyfishes is a novel problem to be solved urgently. Earlier studies find that JC can activate VEGF and bFGF in wound healing, promote collagen fiber formation and collagen precipitation of the wound, accelerate angiogenesis, improve the rate of wound healing, and shorten the healing time (chinese.j. traumatol., 2019,22: 12). Therefore, the JC is an ideal raw material for preparing hydrogel with controllable mechanical property, antibacterial property, degradability, hemostasis and promotion of diabetic wound healing.
Disclosure of Invention
In order to overcome the defects of the existing materials and technologies for treating the diabetic wound, the invention provides a preparation method of degradable antibacterial hemostatic hydrogel for promoting the repair of the diabetic wound, wherein the degradable antibacterial hemostatic hydrogel for promoting the repair of the diabetic wound is formed by DA grafted oxidized natural polysaccharide and JC through a cross-linking agent.
The second purpose of the invention is to provide the degradable antibacterial hydrogel for promoting the repair of the diabetic wound surface, which is prepared by the preparation method, when the degradable antibacterial hydrogel is applied to the diabetic wound surface, antibiotics do not need to be added additionally, and drug resistance is avoided; and secondly, the used collagen is derived from plankton in an aquatic environment, and compared with animal collagen, the collagen avoids outbreaks of zoonosis (mad cow disease, swine brucellosis, inhalation anthrax and the like) and the risk of spreading some latent viruses.
In order to achieve the above object, the present invention adopts the following technical solutions:
the preparation method of the degradable antibacterial hemostatic hydrogel for promoting the repair of the diabetic wound comprises the following steps:
(1) preparing oxidized natural polysaccharide: stirring natural polysaccharide and completely dissolving in deionized water, adding sodium periodate (the molar ratio of the natural polysaccharide to the sodium periodate is 2:1), reacting for 12h in a dark place, adding a proper amount of glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and then freeze-drying to obtain oxidized natural polysaccharide;
(2) DA grafting and oxidizing natural polysaccharide: adding oxidized natural polysaccharide and DA into PBS, and reacting at 37 ℃ for 24h to obtain a target product;
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH value is adjusted to be neutral by using 0.1mol/L NaOH solution, and bubbles are removed through centrifugation to obtain JC mixed solution; and (3) preparing DA grafted oxidized natural polysaccharide in the step (2), adding deionized water to form a solution, adding a cross-linking agent, stirring for 30min, and transferring to a culture dish to stand at room temperature for a period of time to form the degradable antibacterial hemostatic hydrogel for promoting the repair of the diabetic wound.
As a preferable scheme: the natural polysaccharide in the step (1) is as follows: sodium alginate, chitosan, hyaluronic acid, quaternized chitosan, cellulose, and hydroxyethyl cellulose.
As a preferable scheme: in the step (2), DA accounts for 0.5-10% of the mass of the natural aldehyde group-oxidizing polysaccharide
As a preferable scheme: and (3) the cross-linking agent is glutaraldehyde, genipin, carbodiimide, ethylene oxide, epichlorohydrin or 1, 4-bis (3, 4-hydroxyphenyl) -2, 3-dimethylbutane.
As a preferable scheme: in the step (3), the cross-linking agent is genipin, the concentration of the cross-linking agent is 0.05-0.1%, and the volume ratio of the addition amount to the collagen of the jellyfish is 1: 1-1: 5.
As a preferable scheme: the time for forming the gel in the step (3) is 24-48 h.
As a preferable scheme: the concentration of DA grafted oxidized natural polysaccharide in the step (3) is 1-10 wt.%, and the concentration of jellyfish collagen is 1-5 wt.%.
As a preferable scheme: the volume ratio of the DA grafted oxidized natural polysaccharide to the JC in the step (3) is 1: 1-1: 10.
Compared with the prior art, the invention has the following beneficial effects:
(1) the method has mild conditions in the preparation process, does not use organic solvents, does not generate toxic substances in the degradation process, and the degradation product of the method is favorable for promoting cell proliferation, migration and granulation of wound tissues and accelerating wound healing.
(2) When the composition is used for diabetic wound surface, antibiotics do not need to be added additionally, and drug resistance is avoided.
(3) The collagen used is derived from plankton in aquatic environment, and compared with animal collagen, the collagen can avoid outbreaks of zoonosis (mad cow disease, swine brucellosis, inhalation anthrax and the like) and transmission risks of some latent viruses.
Drawings
FIG. 1 example 1OHEC @ DA/JC hydrogel inhibition of Staphylococcus aureus reproduction patterns;
FIG. 2 example 3OHEC @ DA/JC hydrogel rat tail-broken blood loss plot;
FIG. 3 example 2OHEC @ DA/JC hydrogel cultures the OD values of (a) human umbilical vein endothelial vascular cells and (b) human fibroblasts;
FIG. 4 fluorescence micrograph of example 3OHEC @ DA/JC hydrogel-loaded cells;
FIG. 5 scanning electron micrograph of OHEC @ DA/JC hydrogel-supported cell of example 3;
FIG. 6 is a graph of the effect of OHEC @ DA/JC hydrogel on the healing process of type II diabetic wounds in example 3.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist the person skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
(1) Preparation of Oxidized Hydroxyethylcellulose (OHEC): weighing (1.0g,16mmol) hydroxyethyl cellulose (HEC), stirring and completely dissolving in 300mL deionized water, adding (1.71g,8mmol) sodium periodate, reacting for 12h in a dark place, adding a proper amount of 1.5mL ethylene glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and then obtaining OHEC by freeze drying;
(2) DA grafted OHEC: adding 1g of OHEC and 0.05g of DA into PBS, and reacting at 37 ℃ for 24h to obtain a target product (OHEC @ DA);
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH is adjusted to be neutral by using 0.1mol/L NaOH solution, air bubbles are removed through centrifugation, and 2 wt.% JC mixed solution is obtained; and then adding deionized water into the OHEC @ DA to form a 2 wt.% solution, adding 1mL of 0.05% genipin into 5mL of JC mixed solution and 5mL of OHEC @ DA solution respectively, stirring for 30min, and transferring the mixture to a culture dish to stand at room temperature for 24h to form degradable, antibacterial and hemostatic (OHEC @ DA/JC) hydrogel for promoting the repair of the diabetic wound.
Example 2
(1) Preparation of an OHEC: weighing (1.0g,16mmol) HEC, stirring and completely dissolving in 300mL deionized water, adding (1.71g,8mmol) sodium periodate, reacting for 12h in a dark place, adding a proper amount of 1.5mL ethylene glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and then obtaining OHEC by freeze drying;
(2) DA grafted OHEC: adding 1g of OHEC and 0.05g of DA into PBS, and reacting at 37 ℃ for 24 hours to obtain OHEC @ DA;
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH is adjusted to be neutral by using 0.1mol/L NaOH solution, air bubbles are removed through centrifugation, and 2 wt.% JC mixed solution is obtained; and adding deionized water into the OHEC @ DA to form a 2 wt.% solution, adding 1mL of JC mixed solution and 5mL of OHEC @ DA solution into the OHEC @ DA solution respectively, stirring for 30min by 0.05% genipin, and transferring the mixture into a culture dish to stand at room temperature for 24h to form the OHEC @ DA/JC hydrogel.
Example 3
(1) Preparation of an OHEC: weighing (1.0g,16mmol) HEC, stirring and completely dissolving in 300mL deionized water, adding (1.71g,8mmol) sodium periodate, reacting for 12h in a dark place, adding a proper amount of 1.5mL ethylene glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and then obtaining OHEC by freeze drying;
(2) DA grafted OHEC: adding 1g of OHEC and 0.05g of DA into PBS, and reacting at 37 ℃ for 24 hours to obtain OHEC @ DA;
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH is adjusted to be neutral by using 0.1mol/L NaOH solution, air bubbles are removed through centrifugation, and 2 wt.% JC mixed solution is obtained; and adding deionized water into the OHEC @ DA to form a 2 wt.% solution, adding 1mL of JC mixed solution and 5mL of OHEC @ DA solution into 15mL of JC mixed solution and 0.05% of genipin, stirring for 30min, transferring to a culture dish, and standing at room temperature for 24h to form the OHEC @ DA/JC hydrogel.
Example 4
(1) Preparation of an OHEC: weighing (1.0g,16mmol) HEC, stirring and completely dissolving in 300mL deionized water, adding (1.71g,8mmol) sodium periodate, reacting for 12h in a dark place, adding a proper amount of 1.5mL ethylene glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and then obtaining OHEC by freeze drying;
(2) DA grafted OHEC: adding 1g of OHEC and 0.05g of DA into PBS, and reacting at 37 ℃ for 24 hours to obtain OHEC @ DA;
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH is adjusted to be neutral by using 0.1mol/L NaOH solution, air bubbles are removed through centrifugation, and 3 wt.% JC mixed solution is obtained; and adding deionized water into the OHEC @ DA to form a 2 wt.% solution, adding 1mL of JC mixed solution and 0.05% of genipin into 5mL of the OHEC @ DA solution respectively, stirring for 30min, transferring to a culture dish, and standing at room temperature for 24h to form the OHEC @ DA/JC hydrogel.
Comparative example 1
The comparative example is different from example 3 only in that sodium alginate is used for replacing HEC to be oxidized into aldehyde grafted DA to prepare hydrogel, and the hydrogel also has good hemostatic performance and biocompatibility.
Comparative example 2
This comparative example differs from example 3 only in that the hydrogel was prepared with a gelatin of porcine gelatin instead of JC, and various properties were inferior to OHEC @ DA/JC.
Compared with the comparative examples 1 and 2, the example 3 shows that the growth condition of the prepared material loaded cells is better than that of the porcine collagen, and compared with bovine or porcine collagen, JC is from plankton, so that the risk of zoonosis and potential infectious disease transmission is avoided, therefore, the degradable, antibacterial and hydrogel for promoting the repair of the diabetic wound has better development prospect in clinical application of treating the diabetic wound which is difficult to heal, and the like.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (8)
1. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting the repair of the diabetic wound is characterized by comprising the following steps:
(1) preparation of oxidized natural polysaccharide: stirring natural polysaccharide and completely dissolving in deionized water, adding sodium periodate, reacting for 12h in a dark place, adding a proper amount of ethylene glycol to terminate the reaction, dialyzing the reaction product by a dialysis machine, and freeze-drying to obtain oxidized natural polysaccharide;
(2) DA grafting and oxidizing natural polysaccharide: dissolving oxidized natural polysaccharide and DA in PBS, and reacting at 37 ℃ for 24h to obtain a target product;
(3) JC is dissolved in 0.1mol/L glacial acetic acid aqueous solution, the pH value is adjusted to be neutral by using 0.1mol/L NaOH solution, and bubbles are removed through centrifugation to obtain JC mixed solution; and (3) preparing dopamine grafted oxidized natural polysaccharide in the step (2), adding deionized water to form a solution, adding a cross-linking agent, stirring for 30min, and transferring the solution to a culture dish to be placed at room temperature for a period of time to form degradable, antibacterial and hemostatic hydrogel for promoting the repair of the diabetic wound.
2. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the natural polysaccharide in step (1) is: sodium alginate, chitosan, hyaluronic acid, quaternized chitosan, cellulose, and hydroxyethyl cellulose.
3. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein DA in the step (2) is 0.5-10% of the mass of the aldehyde-group-oxidized natural polysaccharide.
4. The method for preparing the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the cross-linking agent in step (3) is one of glutaraldehyde, genipin, carbodiimide, ethylene oxide, epichlorohydrin and 1, 4-bis (3, 4-hydroxyphenyl) -2, 3-dimethylbutane.
5. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the concentration of the cross-linking agent in the step (3) is 0.05% -0.1%, and the volume ratio of the cross-linking agent to the collagen hydrogel is 1: 1-1: 5.
6. The method for preparing the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the concentration of DA grafted oxidized natural polysaccharide in the step (3) is 1-10 wt.%, and the concentration of jellyfish collagen is 1-5 wt.%.
7. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the time for forming the gel in step (3) is 24-48 h.
8. The preparation method of the degradable antibacterial hemostatic hydrogel for promoting diabetic wound repair according to claim, wherein the volume ratio of DA grafted oxidized natural polysaccharide to JC added in step (3) is 1: 1-1: 10.
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