CN116440319A - Preparation method and application of medical repair hydrogel - Google Patents
Preparation method and application of medical repair hydrogel Download PDFInfo
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- CN116440319A CN116440319A CN202310540141.1A CN202310540141A CN116440319A CN 116440319 A CN116440319 A CN 116440319A CN 202310540141 A CN202310540141 A CN 202310540141A CN 116440319 A CN116440319 A CN 116440319A
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- purified water
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- lactic acid
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- A61L26/008—Hydrogels or hydrocolloids
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Abstract
The invention is applicable to the field of medical instruments, and provides a preparation method and application of medical repair hydrogel, wherein the preparation method of the medical repair hydrogel comprises the following steps: preparing materials; adding sodium hyaluronate into purified water for dissolution to prepare solution A; cooling the prepared solution A to room temperature, weighing polyethylene glycol and L-lactic acid, adding into the solution A, continuously stirring for dissolution, adjusting the pH value by sodium dihydrogen phosphate after all the solution is dissolved, and finally transferring the solution into a liquid preparation tank; weighing sodium carboxymethylcellulose, adding purified water, stirring for dissolving, transferring to a liquid preparation tank, supplementing purified water, and stirring uniformly to prepare solution B; the solution B is filtered, and the filtered material is placed in a clean storage tank to obtain the medical repair hydrogel.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a preparation method and application of medical repair hydrogel.
Background
The wound surface is the wound surface of skin, subcutaneous tissue and deep tissues after human body trauma, and is the first step of healing after human body trauma. The repair of wound surface is a long process, and is completed by the joint participation of various tissues of organism. The wound surface of any part of the human body can be generated to different degrees, and the wound surface has large range, large quantity and heavy degree. Clinically common wounds include open wounds and closed wounds. The open wound surface is an obvious infection focus, local infection is controlled after anti-infection treatment, but local skin still exists, and ulcers or scars are still formed after treatment such as dressing change, debridement, skin grafting and the like; whereas the occlusive wound surface mainly includes: fresh wound, old wound, wound after debridement or wound formed after healing of chronic ulcer. The non-chronic wound, also called asymptomatic ulcer, is mainly a kind of wound surface which is compared with chronic wound, and mainly refers to tissue injury which is not healed on the body surface for a long time or is difficult to heal. In daily life, the wound surface contacted by people is probably mainly a non-chronic wound surface, and the non-long-term wound surface is mainly used simply. The clinical manifestations of non-chronic wounds are various, mainly including the following: 1. persistent pain refers to pain that is felt continuously or repeatedly by the patient without other causes; 2. red swelling and pain due to heat: acute inflammation manifests as reddish swelling with pain; chronic inflammation is manifested by redness, tenderness, redness, fever, itching, etc.; 3. infection: refers to the increase of seepage or necrotic tissue caused by bacterial infection in the healing process of the wound, the purulent secretion on the surface of the necrotic tissue, and the like; 4. ulcers: refers to the wound caused by infection in the healing process, for example, the suture wound after operation can be recovered after a period of time after the suture, and the problems of wound ulcer and the like can not occur repeatedly for a long time, thus the wound belongs to the non-chronic wound. Also comprises mechanical wound surfaces, incised wound surfaces, burn and scald wound surfaces and the like, and the wound surfaces which can be recovered within a certain time belong to non-chronic wound surfaces.
Wound healing is a process involving the reconstitution and regeneration of ECM in synergy of various cells and their products. The whole process is as follows: the method comprises the steps of local matrix synthesis at a damaged part, platelet aggregation to form emboli, fibrin clotting, activation factor generation by platelets or surrounding cells to promote synthesis of HA (proprietary protein) by the blood cells, combination of the HA and the fibrin, filling into a network structure formed by the fibrin, formation of a loose network structure, matrix degradation formed by the HA and the fibrin, replacement by a matrix formed by collagen and sulfated glycosaminoglycan, formation of compact granular tissues and wound healing.
The existing medical gel is difficult to realize nursing of non-chronic wound surfaces and cannot provide microenvironment for wound surface healing. Therefore, in view of the above-mentioned situations, there is an urgent need to provide a preparation method and application of medical repair hydrogel, so as to overcome the shortcomings in the current practical application.
Disclosure of Invention
The invention aims to provide a preparation method and application of medical repair hydrogel, and aims to solve the problems in the background technology.
The invention is realized in such a way that a medical repair hydrogel preparation method and application thereof, the method comprises the following steps:
step 1: taking purified water, polyethylene glycol, sodium hyaluronate, L-lactic acid, sodium carboxymethylcellulose and disodium hydrogen phosphate for standby;
step 2: adding sodium hyaluronate into purified water for dissolution, and preparing solution A after all the sodium hyaluronate is dissolved;
step 3: cooling the solution A prepared in the step 2 to room temperature, weighing polyethylene glycol and L-lactic acid, adding the polyethylene glycol and the L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value of the solution A by sodium dihydrogen phosphate after the polyethylene glycol and the L-lactic acid are completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: weighing sodium carboxymethylcellulose, adding purified water, stirring for dissolving, transferring to a liquid preparation tank, supplementing purified water, and stirring uniformly to prepare solution B;
step 5: filtering the solution B, and placing the filtered material into a clean storage tank to obtain the medical repairing hydrogel.
As a further scheme of the invention: in the step 1, 40 to 95 weight parts of purified water, 1 to 15 weight parts of polyethylene glycol, 0.1 to 1 weight part of sodium hyaluronate, 0.1 to 35 weight parts of L-lactic acid, 0.1 to 15 weight parts of sodium carboxymethyl cellulose and 0.5 to 15 weight parts of disodium hydrogen phosphate are taken.
As a further scheme of the invention: in step 2, sodium hyaluronate and purified water were heated to 80 ℃ during dissolution and stirred.
As a further scheme of the invention: in step 3, the pH of the fully dissolved solution is adjusted to 4.5-7.5 by means of sodium dihydrogen phosphate.
As a further scheme of the invention: in the step 4, the pH value of the solution ranges from 4.5 to 7.5, and the stirring time is more than or equal to 30min.
As a further scheme of the invention: in step 5, the material in the tank is subjected to a wet heat sterilization treatment.
The medical repair hydrogel prepared by the preparation method of the medical repair hydrogel is applied to non-chronic wound care.
Compared with the prior art, the invention has the beneficial effects that:
the medical repair hydrogel prepared by the invention is prepared by a large number of experimental verification, has reasonable proportion and obvious synergy among the raw materials; the method comprises the steps that L-lactic acid is degraded into lactic acid monomers in vivo in a non-enzymatic hydrolysis mode, and is interacted with sodium carboxymethyl cellulose, hydrophilic groups hydroxyl in sodium carboxymethyl cellulose and carbonyl in lactic acid monomers are mutually combined in a hydrogen bond mode to form a complex network structure, a proper pH value is regulated under the action of phosphate buffer solution, so that a solution formed by sodium carboxymethyl cellulose and L-lactic acid keeps excellent stability, and meanwhile, the L-lactic acid continuously stimulates cell regeneration in a wound, accelerates collagen synthesis, regenerates fibrous tissues and promotes reconstruction of deep reticular fibrous structures, thereby achieving nursing of non-chronic wounds (such as superficial wounds, laser, photon, fruit acid skin replacement and micro-plastic postoperative wounds) and providing microenvironment for wound healing;
the sodium carboxymethylcellulose and lactic acid monomer added into the product prepared by the invention can form a complex network structure, thus being in line with the wet healing theory of modern wound care, and being in favor of the accelerated healing of the wound surface when the wound surface is placed in a closed and moist environment, preventing or reducing eschar which prevents the migration of wound surface repair cells, accelerating the recovery speed of the wound surface on the skin surface, and further achieving the effects of accelerating the healing of the wound surface and shrinking pores;
in the preparation process of the solution A, the temperature is firstly increased to 80 ℃ and then the solution A is completely dissolved, the temperature is reduced to room temperature and then the solution B is stirred for at least 30min, the temperature and the stirring time are strictly controlled in the whole preparation process of the product, and the stirring at the set temperature is favorable for reducing the evaporation of water in a reaction system and forming uniform and stable mixed solution, and meanwhile, the environment of the reaction system is improved, so that the liquid wound dressing is ensured to have excellent ductility and permeability;
the invention adopts high molecular weight sodium hyaluronate, because the low molecular weight hyaluronic acid can only form a broken lamellar network structure at low concentration, and the high molecular weight hyaluronic acid molecules can form a network structure covering the whole system; the high-concentration high-molecular sodium hyaluronate solution has strong film forming property, can form a natural protective film barrier on the surface of a wound, resists the injury of external bacteria and allergens, prevents infection, and indirectly generates antibacterial and anti-inflammatory effects; can obviously promote the healing of skin wounds after being combined with polyethylene glycol and other components, is beneficial to starting wound repair and accelerating wound healing.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Specific implementations of the invention are described in detail below in connection with specific embodiments.
The embodiment of the invention provides a preparation method of medical repair hydrogel, which comprises the following steps:
step 1: taking 40-95 parts by weight of purified water, 1-15 parts by weight of polyethylene glycol, 0.1-1 part by weight of sodium hyaluronate, 0.1-35 parts by weight of L-lactic acid, 0.1-15 parts by weight of sodium carboxymethylcellulose and 0.5-15 parts by weight of disodium hydrogen phosphate for standby;
step 2: adding sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble substances to prepare solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, weighing polyethylene glycol and L-lactic acid, slowly adding the polyethylene glycol and the L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value to be between 4.5 and 7.5 by sodium dihydrogen phosphate after the polyethylene glycol and the L-lactic acid are completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: weighing sodium carboxymethylcellulose, adding a proper amount of purified water, stirring for dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and carrying out damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel.
The medical repair hydrogel prepared by the preparation method of the medical repair hydrogel is applied to non-chronic wound care.
In the embodiment of the invention, the sodium hyaluronate is a main component of cells and cell stroma, can form a macromolecular network structure, plays roles of mechanical barrier and space barrier, has lubricating property, can avoid friction in the wound healing process, inhibit capillary bleeding and exudation, reduce the number of blood clots forming a permanent adhesion skeleton, inhibit the deposition of plasma fibrin, and has a certain effect on the mitosis of cells, namely can promote the separation of cells and stroma, and can promote wound healing and tissue regeneration; it is widely used in the fields of medicine, pharmacy, cosmetics, food, etc., and is used for beautifying and caring skin: 1. the skin care cream has good moisturizing performance, is one of the substances with the best moisturizing performance, can improve the nutrition metabolism of the skin, make the skin tender, smooth, remove wrinkles, increase elasticity, and inhibit the generation of melanin while keeping moisture, thereby achieving the whitening effect; 2. has good film forming property, forms a layer of film on the surface of the skin, and separates the skin from the external environment; 3. has strong hydrophilicity and lipophilicity, and can absorb water which is 50-100 times of the self weight; 4. has certain adhesiveness and diffusivity, can be adhered to the surface of a cell membrane and the surface of a microvascular endothelial, and can keep proper moisture of cells; 5. has good nutrition and protection effects on skin. When the sodium hyaluronate has good compatibility with human tissue, rejection reaction can not be generated; 6. can absorb ultraviolet rays and reduce damage to human skin tissues, and has effects of preventing skin aging, eliminating senile plaque and relieving wrinkles; the effect of sodium hyaluronate on mechanoreceptors is: the sodium hyaluronate solution prevents the conversion of mechanical energy to electric energy through the encapsulation of nerve endings in joints, blocks normal nerve impulse paths, and meanwhile, viscoelastic hyaluronic acid molecules can form a continuous molecular net structure in the solution, so that the biological barrier blocks the stimulation effect of various pain factors released at joints on receptors and reduces pain feeling of affected parts;
the molecular formula of the L-lactic acid is C 3 H 6 O 3 90% of the lactic acid is lactic acid with high optical activity (chirality) produced by biological fermentation technology by adopting carbohydrate similar to sugar as raw material; the finished product is colorless or light yellow clear viscous liquid and slightly sour; the water solution has moisture permeability and shows acid reaction; optionally mixing with water, ethanol or diethyl ether, and insoluble in chloroform; polymerization of the L-lactic acid, and connection of the L-lactic acid to a long chain is poly L-lactic acid (PLLA); PLLA is the main component of the young needle and can induce the synthesis of collagen fibers; PLLA is the main component of regenerative injection filler-childhood skin needle, and is different from hyaluronic acid static filler, PLLA can achieve the effects of increasing tissue volume and improving skin texture by inducing synthetic collagen fiber; the PLLA has good curative effect and safety and is widely applied to the medical field; from the effect, after the polylactic acid is injected subcutaneously through the dermis layer, the collagen and elastic fiber proliferation can be stimulated, and the problems of facial relaxation, wrinkles and the like can be effectively improved; from the safety aspect, the natural plant material is prepared by fermenting cereal or plant straws, has good biocompatibility, is a synthetic polymer which can be absorbed by human bodies and automatically degraded, can be hydrolyzed into lactic acid in the human bodies, and is completely decomposed into carbon dioxide and water. PLLA has been used in clinical medicine for over 30 years, including surgical sutures, intra-osseous packing materials, soft tissue packing materials, and the like. In recent years, with the production of poly-L-lactic acidThe clinical treatment scheme is gradually improved and perfected, and the indication is gradually relaxed to the partial facial or somatic depression atrophy caused by various reasons;
polyethylene glycol (PEG), a high molecular polymer, is widely used as a solvent or cosolvent for pharmaceutical agents; it belongs to polyvinyl alcohol, is a mixture formed by condensation polymerization of ethylene oxide and water, and has hydrophilicity and film forming property. The PEG material has the advantages of solubility, good biocompatibility, no toxicity, low immunogenicity and the like, and can be widely applied to medical instrument materials such as adhesion, hemostasis, antiseep, anti-adhesion and the like of wounds in various surgical operations of human bodies; meanwhile, the PEG material can also be used as a raw material for implanting human medical instruments to replace plant sources, animal sources and human source materials which are widely applied at present, so that the PEG material has extremely wide medical application; when PEG meets PLLA, the PEG becomes a new copolymer, the problem of PLLA aggregation when meeting water is solved, and the PLLA is not required to be made into freeze-dried powder, namely gel, so that the PEG has an immediate effect and can stimulate collagen regeneration;
sodium carboxymethyl cellulose (CMC-Na) is the carboxymethylated derivative of cellulose, the most predominant ionic cellulose gum; sodium carboxymethyl cellulose is usually an anionic high molecular compound prepared by reacting natural cellulose with caustic alkali and monochloroacetic acid, and has a molecular weight of thousands to millions; CMC-Na is white fibrous or granular powder, odorless, tasteless, hygroscopic, easy to disperse in water to form transparent colloid solution, which can be used as adhesive, thickener, suspending agent, emulsifier, dispersant, stabilizer, sizing agent, etc.; CMC dressing is used for dressing change treatment of chronic refractory wound surfaces such as pressure sores, diabetic feet, nutritional ulcers, burns and the like in clinic, and the common conclusion is that CMC accelerates the healing of the chronic wound surfaces, relieves the pain of dressing change, shortens the treatment time of patients, lightens the workload of nurses and saves the treatment cost as a whole. It helps PLLA disperse suspension and act on the site where improvement of the skin is needed, but is not used for space filling, progressively inducing regenerative replenishment of collagen (type I and type iii);
the medical repair hydrogel prepared by the invention is prepared by a large number of experimental verification, has reasonable proportion and obvious synergy among the raw materials; the method comprises the steps that L-lactic acid is degraded into lactic acid monomers in vivo in a non-enzymatic hydrolysis mode, and is interacted with sodium carboxymethyl cellulose, hydrophilic groups hydroxyl in sodium carboxymethyl cellulose and carbonyl in lactic acid monomers are mutually combined in a hydrogen bond mode to form a complex network structure, a proper pH value is regulated under the action of phosphate buffer solution, so that a solution formed by sodium carboxymethyl cellulose and L-lactic acid keeps excellent stability, and meanwhile, the L-lactic acid continuously stimulates cell regeneration in a wound, accelerates collagen synthesis, regenerates fibrous tissues and promotes reconstruction of deep reticular fibrous structures, thereby achieving nursing of non-chronic wounds (such as superficial wounds, laser, photon, fruit acid skin replacement and micro-plastic postoperative wounds) and providing microenvironment for wound healing;
the sodium carboxymethyl cellulose added into the product prepared by the invention can form a complex network structure with lactic acid monomers, and caters to the wet healing theory of modern wound care, which considers that the wound surface is placed in a closed and moist environment, thereby being beneficial to the accelerated healing of the wound surface. The principle is as follows: (1) The wound surface is kept moist, so that the formation of eschar which prevents the migration of wound surface repair cells can be prevented or reduced, and the speed of epithelial migration into the wound surface is facilitated; (2) facilitating the formation and granulation of healthy granulation tissue; (3) The closed moist environment increases the temperature of the wound surface, so that the autolytic debridement process of the wound surface is more active; (4) The exudate retained in the wound contains a number of cytokines that contribute to epithelial crawling and connective tissue proliferation. The "wet healing theory" is different from the traditional "wet-to-dry" mode of wound dressing, which emphasizes keeping the wound surface dry, is prone to damage of the new epithelium, and is not beneficial to isolate the migration of the infectious source. In a word, the wound surface is healed in a closed and moist environment, so that the formation of eschar which prevents the migration of wound repair cells is prevented or reduced, the recovery speed of the wound surface of the skin is increased, and the effects of accelerating the wound healing and shrinking pores are achieved;
in the preparation process of the solution A, the temperature is firstly increased to 80 ℃ and then the solution A is completely dissolved, the temperature is reduced to room temperature and then the solution B is stirred for at least 30min, the temperature and the stirring time are strictly controlled in the whole preparation process of the product, and the stirring at the set temperature is favorable for reducing the evaporation of water in a reaction system and forming uniform and stable mixed solution, and meanwhile, the environment of the reaction system is improved, so that the liquid wound dressing is ensured to have excellent ductility and permeability;
the biodegradable material polylactic acid (PLA) takes plant starch as a raw material, is a common bio-based polymer material, has good biocompatibility, biodegradability, biocompatibility, excellent mechanical strength, transparency and processability, but has large brittleness and poor toughness, so the application range is limited. In order to improve the ductility and impact toughness of polylactic acid, on the basis of keeping the green and environment-friendly properties of the polylactic acid material, the polylactic acid is often subjected to melt blending modification with a plasticizer or biodegradable flexible polyester; polyethylene glycol (PEG) is a commonly used plasticizer; aiming at the problems that the plasticizing modified polylactic acid has low strength, the low molecular weight polyethylene glycol is easy to migrate, the high molecular weight polyethylene glycol can be slowly crystallized, phase separation occurs between the polylactic acid and the polylactic acid, and the compatibility between PLA and biodegradable flexible polyester is poor;
the invention adopts high molecular weight sodium hyaluronate, because the low molecular weight hyaluronic acid can only form a broken lamellar network structure at low concentration, and the high molecular weight hyaluronic acid molecules can form a network structure covering the whole system; the high-concentration high-molecular sodium hyaluronate solution has strong film forming property, can form a natural protective film barrier on the surface of a wound, resists the injury of external bacteria and allergens, prevents infection, and indirectly generates antibacterial and anti-inflammatory effects; can obviously promote the healing of skin wounds after being combined with polyethylene glycol and other components, is beneficial to starting wound repair and accelerating wound healing.
The following is further described in connection with specific experiments:
test one
Embodiment 1.1 the preparation method of medical repair hydrogel provided by the embodiment of the invention comprises the following steps:
step 1: taking 2.5g of polyethylene glycol, 5g of L-lactic acid, 0.3g of sodium hyaluronate, 5g of sodium carboxymethylcellulose, 2g of disodium hydrogen phosphate and 85.2g of purified water for later use;
step 2: adding 0.3g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 2.5g of polyethylene glycol and 5g of L-lactic acid into the solution A, continuously stirring for dissolution, adjusting the pH value to be between 4.5 and 7.5 by using 2g of disodium hydrogen phosphate after the solution A is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 5g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare a solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and the stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and carrying out damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel.
Comparative example 1.1 the same procedure as in example 1.1 was used, except that the polyethylene glycol of example 1.1 was removed and the other conditions were kept consistent.
Comparative example 1.2 the same procedure as in example 1.1 was used, except that the L-lactic acid in example 1.1 was removed and the other conditions were kept the same.
Comparative example 1.3 the same procedure as in example 1.1 was used, except that sodium hyaluronate in example 1.1 was removed and the other conditions were kept identical.
Comparative example 1.4 the same procedure as in example 1.1 was used, except that sodium carboxymethyl cellulose in example 1.1 was removed and the other conditions were kept consistent.
1. Experimental population: subjects treated with the lattice laser were selected and 100 female volunteers aged 20-50 years old were randomized and equally divided into 5 groups of 20 subjects each.
2. Experimental instrument: the facial image analyzer VISIA-CR tests heme.
3. The experimental method comprises the following steps: applying the product to the nose, lip and eyes, squeezing air, removing the membrane after 30min, and applying the rest liquid to the face for absorption without cleaning; the first week is used for 7 days continuously, the second week is used for 3 times on average, and the continuous use is carried out for 4 weeks;
before testing, the tested group starts to measure after sitting still for 30 minutes in a constant temperature and humidity laboratory (temperature 20+/-1 ℃ and humidity 55+/-3), a region of 4 x 4cm in the middle of the right face of each tested person is selected, the average heme content of 5 positions in total in four corners and the middle of the region is tested, and then the average heme content of each group of groups of people is tested according to the method when repair dressing 1, 3, 7 and 16 times are used.
4. Evaluation method
4.1 objective evaluation: evaluating by both observers and subjects based on the photographs; subjective evaluation indexes are scores of symptoms of questionnaires at each time point;
4.2 by instrumental testing of the average heme content of the skin, a decrease in content indicates an effect and an increase or invariance indicates an ineffectiveness.
5. Experimental results
5.1 subjective symptom improvement Condition
After dressing is used for 30min after laser operation, pain is improved after 1-3 days; after dressing is used for 30min after laser operation, erythema is gradually reduced after 1-5 days; skin dryness was gradually reduced 1-7 days after laser surgery.
The heme content results are shown in Table 1:
table 1 shows the results of comparing the effects of the products prepared in example 1.1 with those of comparative examples 1.1 to 1.4
The experimental results show that: the samples of the example 1.1 and the comparative examples 1.1-1.4 can reduce skin heme, but the sample of the example 1.1 is more obvious in skin heme reduction in the same time than the sample of the comparative examples 1.1-1.4, which shows that the medical repair hydrogel prepared in the example 1.1 has obvious repair effect on medical and artistic after-treatment, can effectively promote the growth of damaged cells, lighten color spots and lead the repaired skin to be smooth and tender after long-term use.
Experiment II
Cell migration includes a healing effect on minor wounds in physiological activities in the body, similar to the purpose of lightening skin texture, promoting healing of skin lesions. Meanwhile, fibroblasts are the main cell components of loose connective tissue in dermis layers, and the results of a human fibroblast model have a certain reference to in vivo actions. Therefore, the cell migration test is carried out by selecting the human fibroblast, and the repairing effect of the product can be evaluated.
1. Reagents and materials
And (3) cells: human fibroblasts (expanded to P7 generation for assay);
phosphate Buffered Saline (PBS): GIBCO;
pancreatin (0.25%): GIBCO;
neonatal Bovine Serum (NBS): zhejiang Tianzhou biotechnology limited;
cell culture (DMEM, low sugar): GIBCO;
cell culture flask: corning;
serum pipette: falcon;
centrifuge tube: corning;
cell culture plate: corning;
2. instrument for measuring and controlling the intensity of light
Inverted microscope: the camera has a shooting function;
a carbon dioxide incubator;
the dividing value of the electronic balance is 0.1mg;
a horizontal low speed centrifuge;
pipetting: the measuring range comprises 100-1000ul, 20-200ul and 2-20ul;
a biosafety cabinet;
a microplate oscillator;
and (3) a computer: imageJ software can be run;
determination of the healing rate of the in-vitro scratch wound of the human fibroblast under the action of the medical repair hydrogel: an in vitro cell scoring method is adopted.
3. According to the experimental requirements, 4 groups (group I: 10 mu l/mL medical repair hydrogel, group II: 50 mu l/mL medical repair hydrogel, group III: 100 mu l/mL medical repair hydrogel) are arranged in the control group and the experimental group, and each group is provided with 2 holes.
The method comprises the following specific steps:
the center of the bottom of the 24-hole cell culture plate is marked in a cross shape;
the conventional method is to inoculate human fibroblasts in equal quantity on a culture plate;
conventional culture;
at the time of cell monolayer fusion, the medium 1640 with the concentration of 1% NBS is cultured overnight;
perpendicular scratches of a gun head of a sterile 200 mu L pipette on a cell layer, establishing an in-vitro cell wound model, and repeatedly flushing with PBS until the scratch area is clean;
the experimental group is prepared according to groups and 250 mu L of 1640 culture medium of 1% NBS of medical repair hydrogel with different concentrations is added, and the control group is added with 1640 culture medium of 1% NBS with equal volume concentration;
photographing and recording under an inverted microscope at points of 0h, 16h and 24h, wherein the photographing area is a scratch area in the range of 1.00mm with the midpoint of the mark as a starting point and a microscopic scale;
calculating the healing area of the designated scratch area by using ImageTool software, and counting the healing rate= (initial scratch area-current scratch area)/initial scratch area multiplied by 100%;
the experiment was repeated 5 times.
4. The statistical processing data adopts SPSS17.0 statistical software to carry out variance analysis, and the group comparison adopts LSD-t test or Dunnett's T3 test; p <0.05 indicates that the difference has a statistical significance, and P < 0.01 indicates that the difference has a significant statistical significance; p.gtoreq.0.05 indicates that the difference is not statistically significant.
5. Experimental results
The healing rate of the cells of the medical repair hydrogel culture group at each concentration is obviously higher than that of the control group (t value is 10.250-23.414, P is less than 0.01) 24 hours after the scratch; the cell healing rate of the II group and the III group is obviously higher than that of the I group (t value is 7.238, 8.399 and P is less than 0.01), the cell healing rate difference of the II group is not obvious compared with that of the III group (t=1.391 and P is more than 0.05), and the cell healing rate difference has no statistical significance; the difference of cell healing rates was not statistically significant (t values 0.981 to 1.584, P > 0.05) compared with 48h after scoring in each group.
Third experiment
Embodiment 3.1, the preparation method of the medical repair hydrogel provided by the embodiment of the invention comprises the following steps:
step 1: taking 2.5g of polyethylene glycol, 5g of L-lactic acid, 0.3g of sodium hyaluronate, 5g of sodium carboxymethylcellulose, 2g of disodium hydrogen phosphate and 85.2g of purified water for later use;
step 2: adding 0.3g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 2.5g of polyethylene glycol and 5g of L-lactic acid into the solution A, continuously stirring for dissolution, adjusting the pH value to be between 4.5 and 7.5 by using 2g of disodium hydrogen phosphate after the solution A is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 5g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare a solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and the stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and performing damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel A1.
Embodiment 3.2, the preparation method of the medical repair hydrogel provided by the embodiment of the invention comprises the following steps:
step 1: taking 5g of polyethylene glycol, 10g of L-lactic acid, 0.6g of sodium hyaluronate, 10g of sodium carboxymethylcellulose, 2.5g of disodium hydrogen phosphate and 71.9g of purified water for later use;
step 2: adding 0.6g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 5g of polyethylene glycol and 10g of L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value to be between 4.5 and 7.5 by using 2.5g of disodium hydrogen phosphate after the solution A is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 10g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare a solution B, and stirring for more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and performing damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel A2.
Embodiment 3.3 the preparation method of the medical repair hydrogel provided by the embodiment of the invention comprises the following steps:
step 1: 10g of polyethylene glycol, 15g of L-lactic acid, 1g of sodium hyaluronate, 15g of sodium carboxymethylcellulose, 3g of disodium hydrogen phosphate and 56g of purified water are taken for standby;
step 2: adding 1g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 10g of polyethylene glycol and 15g of L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value to be between 4.5 and 7.5 by using 3g of disodium hydrogen phosphate after the solution is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 15g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, uniformly stirring to prepare a solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and the stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and performing damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel A3.
Comparative example 3.1 the embodiment of the invention provides a preparation method of medical repair hydrogel, which comprises the following steps:
step 1: 10g of polyethylene glycol, 25g of L-lactic acid, 12g of sodium hyaluronate, 5g of sodium carboxymethylcellulose, 4g of disodium hydrogen phosphate and 56g of purified water are taken for standby;
step 2: adding 12g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 10g of polyethylene glycol and 25g of L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value to be between 4.5 and 7.5 by using 4g of disodium hydrogen phosphate after the solution is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 5g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare a solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and the stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and performing damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel B1.
Comparative example 3.2 the embodiment of the invention provides a preparation method of medical repair hydrogel, which comprises the following steps:
step 1: 15g of polyethylene glycol, 30g of L-lactic acid, 20g of sodium hyaluronate, 10g of sodium carboxymethylcellulose, 6g of disodium hydrogen phosphate and 19g of purified water are taken for standby;
step 2: adding 20g of sodium hyaluronate into purified water for dissolution, heating and stirring at 80 ℃, and after all the sodium hyaluronate is dissolved, visually observing no insoluble matters to prepare a solution A;
step 3: cooling the solution A prepared in the step 2 to room temperature, slowly adding 15g of polyethylene glycol and 30g of L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value to be between 4.5 and 7.5 by using 6g of disodium hydrogen phosphate after the solution is completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: taking 10g of sodium carboxymethylcellulose, adding a proper amount of purified water, stirring and dissolving, transferring to a liquid preparation tank, supplementing the purified water, stirring uniformly to prepare a solution B, wherein the pH value of the solution is in the range of 4.5-7.5, and stirring time is more than or equal to 30min;
step 5: filtering the solution B, putting the filtered material into a clean storage tank, and performing damp-heat sterilization treatment on the material in the storage tank to obtain the medical repair hydrogel B2.
The results are analyzed with reference to table 2 below:
table 2 shows the results of comparing the effects of the products prepared in examples 3.1 to 3.3 with those of comparative examples 3.1 to 3.2
| Examples numbering | Moisturizing effect | Skin feel |
| A1 | Very good | Fine and smooth |
| A2 | Very good | Fine and smooth |
| A3 | Very good | Fine and smooth |
| B1 | Difference of difference | Very sticky |
| B2 | Difference of difference | Very sticky |
The medical repair hydrogel A1-A3 prepared in the preferred range of the invention has better performance in all aspects than B1 and B2, so that the hydrogel has excellent moisturizing performance and fine skin feel.
In the examples of the present invention, wound healing is a process involving the reconstitution and regeneration of ECM in synergy of various cells and their products, the entire process being as follows: the method comprises the steps of local matrix synthesis at a damaged part, platelet aggregation to form emboli, fibrin clotting, activation factor generation by platelets or surrounding cells to promote synthesis of HA (proprietary protein) by the blood cells, combination of the HA and the fibrin, filling into a network structure formed by the fibrin, formation of a loose network structure, matrix degradation formed by the HA and the fibrin, replacement by a matrix formed by collagen and sulfated glycosaminoglycan, formation of compact granular tissues and wound healing. The matrix plays a role of a template in the skin healing process due to the double-layer polymeric membrane formed by the glycosaminoglycan and the collagen fibers, and has important significance for wound healing. In the early stage of tissue injury, HA is the most important aminodextran existing on wound surfaces, and HAs not only a structural function but also a regulating function. Although the mechanism of action cannot be elucidated at the molecular level, many cues have suggested that HA binds to fibrin and forms an intercellular matrix framework, thereby regulating fibroblast proliferation and granular tissue formation. Animal studies have shown that HA accelerates migration of injured animal epithelial cells, promoting the mobilization of macrophages necessary for wound healing. In addition, HA also transports certain proteins and polypeptides such as growth factors, etc. to the wound site, which have an important role in wound healing. The HA increase in the injured part of the cornea of the eye, which is caused by the operation, is similar to that of the fibroblast during the healing process. Other experiments have also shown that this equal binding of HA to fibroblasts is one of the reasons for scar-free repair of the injured site. Research shows that the HA solution with concentration of 0.2% -2% HAs obvious promoting effect on wound healing. The main mode is as follows: 1. sodium hyaluronate is acidic mucopolysaccharide in vivo, and has inhibiting effect on microorganisms; 2. sodium hyaluronate has an inhibitory effect on collagen synthase; 3. sodium hyaluronate can promote wound healing and prevent infection; 4. sodium hyaluronate has protective effect on tissue cells; 5. sodium hyaluronate can reduce capillary permeability.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (7)
1. The preparation method of the medical repair hydrogel is characterized by comprising the following steps of:
step 1: taking purified water, polyethylene glycol, sodium hyaluronate, L-lactic acid, sodium carboxymethylcellulose and disodium hydrogen phosphate for standby;
step 2: adding sodium hyaluronate into purified water for dissolution, and preparing solution A after all the sodium hyaluronate is dissolved;
step 3: cooling the solution A prepared in the step 2 to room temperature, weighing polyethylene glycol and L-lactic acid, adding the polyethylene glycol and the L-lactic acid into the solution A, continuously stirring and dissolving, adjusting the pH value of the solution A by sodium dihydrogen phosphate after the polyethylene glycol and the L-lactic acid are completely dissolved, and finally transferring the solution into a liquid preparation tank;
step 4: weighing sodium carboxymethylcellulose, adding purified water, stirring for dissolving, transferring to a liquid preparation tank, supplementing purified water, and stirring uniformly to prepare solution B;
step 5: filtering the solution B, and placing the filtered material into a clean storage tank to obtain the medical repairing hydrogel.
2. The method for preparing a medical repair hydrogel according to claim 1, wherein in step 1, 40-95 parts by weight of purified water, 1-15 parts by weight of polyethylene glycol, 0.1-1 parts by weight of sodium hyaluronate, 0.1-35 parts by weight of l-lactic acid, 0.1-15 parts by weight of sodium carboxymethyl cellulose and 0.5-15 parts by weight of disodium hydrogen phosphate are taken.
3. The method for preparing a medical repair hydrogel according to claim 1, wherein in step 2, sodium hyaluronate and purified water are heated to 80 ℃ during dissolution and stirred.
4. The method for preparing a medical repair hydrogel according to claim 1, wherein in step 3, the pH of the totally dissolved solution is adjusted to 4.5-7.5 by sodium dihydrogen phosphate.
5. The method for preparing a medical repair hydrogel according to claim 1, wherein in step 4, the pH value of the solution is in the range of 4.5-7.5, and the stirring time is not less than 30min.
6. The method for producing a medical repairing hydrogel according to claim 1, wherein in step 5, the material in the reservoir is subjected to a wet heat sterilization treatment.
7. The use of a medical repair hydrogel prepared by the method for preparing a medical repair hydrogel according to any one of claims 1 to 6 in non-chronic wound care.
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