Injectable composite hydrogel as well as preparation method and application thereof

Abstract

The invention is applicable to the technical field of biomedical materials, and provides injectable composite hydrogel as well as a preparation method and application thereof. According to the invention, groups such as catechol are introduced into a hydrogel skeleton to form hydrogen bonds with amino groups and hydroxyl groups on the tissue surface, so that the hydrogel is ensured to be tightly adhered to a wound part to protect the wound from being influenced by complex microenvironments such as gastric acid. Meanwhile, metal ions and a nano material are introduced, so that the mechanical strength, deformation resistance and degradation rate of the hydrogel are enhanced, and the hydrogel can better adapt to a complex gastrointestinal tract environment. Besides, the composite hydrogel constructed by the invention can slowly release substances with special biological activity, such as metal ions with Fenton-like reaction activity and metal or metal oxide nanoparticles with superoxide dismutase-like and catalase-like activities, in wound parts and nearby microenvironments; through synergistic catalytic degradation of local excessive hydrogen peroxide, inflammatory response is relieved, antibacterial activity is enhanced, and healing of gastrointestinal tract postoperative wounds is effectively promoted.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and in particular relates to an injectable composite hydrogel and a preparation method and application thereof. Background Art

[0002] Due to its special anatomical position and the presence of gastric acid and intestinal contents, gastrointestinal postoperative wounds are prone to complications such as bleeding and perforation, which makes wound healing difficult. In severe cases, it can also cause septic shock or even death. At the same time, overexpressed reactive oxygen species near the wound can damage cell proteins (such as cytoskeletal proteins), destroy the gastrointestinal barrier, and cause a variety of inflammatory gastrointestinal diseases. At present, the main treatments for gastrointestinal postoperative wounds are oral drugs that inhibit gastric acid secretion (such as proton pump inhibitors, etc.) and endoscopic hemostatic clips to close the wound, but these methods cannot prevent complications such as bleeding and perforation, nor can they remove overexpressed reactive oxygen species in the microenvironment near the wound, and the efficacy is often very limited. Therefore, it is urgent to develop a new treatment platform for gastrointestinal postoperative wounds, which can isolate gastric acid and gastrointestinal contents by adhering to the wound, prevent bleeding and perforation, and efficiently remove overexpressed reactive oxygen species around the wound, reduce inflammatory response, and promote wound healing.

[0003] In recent years, hydrogels have attracted extensive attention in the biomedical field, especially in the application of wound adhesives, due to their unique physicochemical properties and good biocompatibility. The three-dimensional cross-linked network structure of hydrogels enables them to effectively absorb exudates from the wound site, maintain the moist environment of the wound, and accelerate the coagulation process by increasing the concentration of local platelets and coagulation factors, thereby promoting wound healing. However, when it comes to the treatment of postoperative wounds of the gastrointestinal tract, existing hydrogel technology has encountered challenges. Compared with the skin epidermis, wounds in the internal digestive system have more complex physiological structures and microenvironments, especially extreme conditions such as gastric acid, which not only limits the applicability and effect of hydrogels, but also makes it difficult to accurately control the gelation and degradation rates. In addition, the functions of most hydrogel materials are relatively single, and they cannot effectively deal with common complications of postoperative wounds of the gastrointestinal tract, such as bleeding, perforation, inflammation and infection. Therefore, it is urgent to develop hydrogel materials with convenient drug delivery, acid resistance and multi-modal combined treatment functions.

[0004] Nanomedicines have great potential in antibacterial, anti-inflammatory and wound healing due to their convenient preparation, controllable particle size, diverse functions and easy large-scale production. However, nanomaterials still face problems such as difficulty in drug administration and poor drug efficacy in the treatment of gastrointestinal wounds.

[0005] In order to solve the above problems, the present invention provides an injectable composite hydrogel and a preparation method and application thereof. Summary of the invention

[0006] The purpose of the present invention is to provide an injectable composite hydrogel and a preparation method and application thereof, aiming to solve the problems raised in the above background technology.

[0007] To achieve the above object, the present invention provides the following technical solutions: A method for preparing an injectable composite hydrogel comprises the following steps: Construct a library of self-healing hydrogel substrate materials that can coordinate with metal ions, a library of molecules containing coordination groups, a library of metal ions, and a library of nanoparticle materials with superoxide dismutase-like and catalase-like activities; The self-healing hydrogel substrate is CMCS / OSD hydrogel, the molecule containing the coordination group is dopamine, and the metal ion is Fe 3+ The nanoparticles are cerium dioxide nanoparticles (CeO2 NPs), and the specific preparation steps are as follows: Step S1: oxidizing sodium alginate (SA) to oxidized sodium alginate (OSA) by sodium periodate (NaIO4), and grafting dopamine (DA) to prepare oxidized sodium alginate catechol (OSD) having a phenolic hydroxyl unit; Step S2: mixing carboxymethyl chitosan (CMCS) with OSD to form CMCS / OSD hydrogel; Step S3: Introduction of Fe into CMCS / OSD hydrogel precursor solution 3+ and CeO2 NPs to form CMCS / OSD / Fe 3+ / CeO2 composite hydrogel.

[0008] Furthermore, the specific operation of step S1 is as follows: first, 1 g of SA is dissolved in 100 mL of deionized water, and magnetically stirred until completely dissolved to prepare a 1 wt% solution; 0.22 g of NalO4 is added, and the mixture is reacted at 25 °C in the dark for 4 h, and 3 mL of ethylene glycol is added and stirred for 2 h to terminate the reaction; 1 g of sodium chloride is added, and dialyzed for 3 d, with the water changed 3 to 4 times a day; the product is freeze-dried to obtain white OSA; then 1 g of OSA is dissolved in 100 mL of deionized water, and 0.91 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 0.54 g of N-hydroxysuccinimide (NHS) are added; the mixture is reacted under nitrogen protection for 15 min, and then 0.71 g of DA is added to initiate an amidation reaction; after reacting at 25 °C for 12 h, the mixture is dialyzed in a hydrochloric acid solution with a pH of 5.5 for 3 d to remove residual reaction substrates; the product is freeze-dried to obtain OSD having a phenolic hydroxyl unit.

[0009] Furthermore, the specific operation of step S2 is: mixing 0.6 mL of 3 wt% carboxymethyl chitosan solution and 0.3 mL of 6 wt% oxidized sodium alginate catechol solution, vibrating and mixing, and standing for 5 min until the solution does not flow to form CMCS / OSD hydrogel.

[0010] Furthermore, the specific operation of step S3 is: adding 0.05 mL of 0.1 mM Fe 3+ CMCS / OSD / Fe was formed when the solution was left to stand for 5 min until it stopped flowing. 3+ Hydrogel; in CMCS / OSD / Fe 3+ 0.05 mL of 20 mg / mL CeO2NPs dispersion was mixed into the hydrogel precursor solution and allowed to stand for 5 min until the solution stopped flowing to form CMCS / OSD / Fe 3+ / CeO2 composite hydrogel.

[0011] An injectable composite hydrogel prepared according to the above-mentioned method for preparing the injectable composite hydrogel.

[0012] An application of the injectable composite hydrogel described above in the preparation of a product for promoting wound healing after gastrointestinal surgery.

[0013] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention introduces catechol and other groups into the hydrogel skeleton through molecular design. These groups form hydrogen bonds with amino and hydroxyl groups on the tissue surface, ensuring that the hydrogel can adhere tightly to the wound site, protecting the wound from the influence of complex microenvironments such as gastric acid, and providing a stable basis for the treatment of postoperative wounds of the gastrointestinal tract.

[0014] 2. The present invention introduces metal ions (such as Fe 3+ ) and nanomaterials (such as CeO2NPs), by utilizing their multiple coordination effects with carboxyl and phenolic hydroxyl groups, the mechanical strength of the hydrogel is enhanced, making the hydrogel have stronger deformation resistance and degradation rate, so that it can better adapt to the complex gastrointestinal environment.

[0015] 3. The composite hydrogel constructed by the present invention not only has strong adhesion and strong acid resistance, but also can slowly release substances with special biological activity in the wound site and the nearby microenvironment, such as metal ions with Fenton reaction activity and metal or metal oxide nanoparticles with both superoxide dismutase and catalase activities. These substances can work synergistically to catalyze the degradation of local excess hydrogen peroxide, reduce inflammatory reactions, and enhance antibacterial activity, thereby effectively promoting the healing of postoperative wounds of the gastrointestinal tract. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 For CMCS / OSD / Fe 3+ Schematic diagram of the preparation route and cross-linking mechanism of / CeO2 composite hydrogel; wherein CMCS is carboxymethyl chitosan, SA is sodium alginate, OSA is oxidized sodium alginate, OSD is oxidized sodium alginate catechol, NaIO4 is sodium periodate, EDC is 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and NHS is N-hydroxysuccinimide.

[0017] Figure 2 It is a library of molecules containing coordination groups.

[0018] Figure 3 For SA, OSA and OSD 1 H NMR spectra.

[0019] Figure 4 This is the gelation process of CMCS / OSD hydrogel.

[0020] Figure 5 For CMCS / OSD / Fe 3+ The gelation process of hydrogel.

[0021] Figure 6 CMCS / OSD, CMCS / OSD / Fe 3+ , CMCS / OSD / CeO2, CMCS / OSD / Fe 3+ / CeO2 hydrogel structure and performance characterization; (a) is the scanning electron microscope image of CMCS / OSD hydrogel; (b) is the scanning electron microscope image of CMCS / OSD / CeO2 hydrogel; (c) is the scanning electron microscope image of CMCS / OSD / Fe 3+ Scanning electron microscopy images of hydrogels; (d) CMCS / OSD / Fe 3+ / CeO2 composite hydrogel; (e) CMCS / OSD / Fe 3+ Self-healing image of CMCS / OSD / Fe / CeO2 composite hydrogel on pig skin under dynamic conditions; (f) 3+ Adhesion of CMCS / OSD / Fe / CeO2 composite hydrogels; (g) 3+ / CeO2 composite hydrogel was injected into a culture dish using a syringe; (h) CMCS / OSD / Fe 3+ Injectable images of / CeO2 composite hydrogel; Figure 7 CMCS / OSD, CMCS / OSD / Fe 3+ , CMCS / OSD / CeO2, CMCS / OSD / Fe 3+Swelling curve of / CeO2 hydrogel and degradation curve in buffer solution with pH 2.2; where (a) is the swelling curve of the hydrogel; (b) is the degradation curve of the hydrogel in buffer solution with pH 2.2.

[0022] Figure 8 For Buffer (pH=4), CMCS and CMCS / OSD / Fe 3+ Determination of the active oxygen scavenging ability of / CeO2 composite hydrogel. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0024] The specific implementation of the present invention is described in detail below in conjunction with specific embodiments.

[0025] The present invention aims to develop a method for preparing a multifunctional injectable composite hydrogel with a simple preparation process and a precisely controllable structure, and to introduce binary or multi-components into the hydrogel skeleton and three-dimensional structure by using molecular design, nanofabrication and assembly technology, and to construct a multimodal combined treatment platform with the help of multiple forces such as covalency, coordination, and hydrogen bonding.

[0026] One embodiment of the present invention provides a method for preparing an injectable composite hydrogel, comprising the following steps: (1) Construct a library of self-healing hydrogel substrate materials that can coordinate with metal ions; The first category: chemical self-healing hydrogel substrates, which are mainly based on multiple dynamic covalent bonds to rebuild or strengthen their three-dimensional network structure, including Schiff base reaction (such as CMCS / OSD, CMCS / OSA hydrogels), acylhydrazone (such as polyacrylamide / diacetone acrylamide hydrogels), disulfide bonds (such as cystamine / acrylamide hydrogels), phenylboronic acid esters (such as hydrogels based on phenylboronic acid / cis-diol derivatives), reversible Diels-Alder cycloaddition reactions (such as furan-modified hyaluronic acid / bismaleimide polyethylene glycol hydrogels) and dynamic coordination bonds (such as alginate / metal ion hydrogels, phosphate-terminated polyethylene glycol / trivalent metal ion polymer hydrogels), etc.

[0027] The second category: physical self-healing hydrogel substrates, which mainly reconstruct their three-dimensional network structures based on non-covalent interactions, including host-guest interactions, hydrophobic interactions, hydrogen bonds, electrostatic interactions, crystallization, etc. Among them, the main units based on the host-guest interaction include cyclodextrin, cucurbituril, calixarene, pillararene, oblique arene, geminal arene, biphenylarene, prismatic arene, triphenylamine[3]arene, molecular cages, and extended aromatic molecules based on the above macrocycles, etc., which have special skeleton and cavity structures; the guest units include molecules that can be specifically complexed with the above main molecules or other molecules containing related group fragments.

[0028] (2) Constructing a molecular library containing coordination groups: mainly refers to groups such as hydroxyl, carboxyl, phosphate, etc. that can coordinate with metal ions or nanomaterials, such as molecules containing catechol units (such as grafted dopamine, methyldopa, caffeic acid, etc.); molecules containing pyrogallol units (such as grafted gallic acid, methyl gallate, tannic acid, etc.), etc. ( Figure 2 ).

[0029] (3) Construction of metal ion library: metal ions with coordination and therapeutic functions, including but not limited to Fe with Fenton-like reaction activity 3+ , Mn 2+ , which has the function of promoting epidermal cell migration 2+ , Zn, which promotes wound healing 2+ , Ca with hemostatic function 2+ , which has the effect of promoting cell proliferation 2+ , and Ag with antibacterial effect + wait.

[0030] (4) Construct a library of nanoparticle materials with superoxide dismutase-like and catalase-like activities: including but not limited to CeO2 nanoparticles, Cu x O nanoparticles, MnO2 nanosheets, etc., CuS nanoparticles, FeS nanoparticles, Au nanoclusters, Pt nanoparticles and Ag nanowires with antibacterial effects, etc.

[0031] Among them, CMCS / OSD hydrogel was used as the self-healing hydrogel substrate, combined with molecular dopamine containing coordination groups and metal ions Fe with Fenton-like reaction activity. 3+ , transition metal oxide CeO2 NPs with superoxide dismutase-like and catalase-like activities were used as examples to prepare injectable composite hydrogels. First, Fe 3+ On the one hand, by using phenolic hydroxyl groups and Fe 3+The coordination effect of CeO2NPs increases the cross-linking strength of the hydrogel; on the other hand, the Fenton-like reaction characteristics are used to degrade the overexpressed hydrogen peroxide in the wound site, reduce oxidative stress, and generate free radicals for antibacterial purposes. Secondly, with the multiple coordination effects of carboxyl and phenolic hydroxyl groups on CeO2NPs, the CMCS / OSD / Fe 3+ / CeO2 composite hydrogel ( Figure 1 ).

[0032] The specific preparation steps are as follows: Step S1: SA is oxidized to OSA by NaIO4, and an aldehyde group is introduced; then DA is grafted onto the aldehyde group to synthesize OSD having a phenolic hydroxyl unit, and a catechol group is introduced as a coordination active site. 1 H NMR Figure 3 As shown in the figure, the peak at δ=5.0 ppm is the characteristic peak of the aldehyde group, which proves the successful synthesis of OSA, and the peak at δ=6.8 ppm is the characteristic peak of the benzene ring, which proves the successful grafting of dopamine. The specific operation of step S1 is as follows: First, 1 g of SA was dissolved in 100 mL of deionized water and stirred magnetically until completely dissolved to prepare a 1 wt% solution; 0.22 g of NaIO4 was added, and the reaction was allowed to proceed at 25 °C in the dark for 4 h, and 3 mL of ethylene glycol was added and stirred for 2 h to terminate the reaction; 1 g of sodium chloride was added and dialyzed for 3 d, with the water changed 3 to 4 times a day; the product was freeze-dried to obtain white OSA; then 1 g of OSA was dissolved in 100 mL of deionized water, and 0.91 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 0.54 g of N-hydroxysuccinimide (NHS) were added; the reaction was allowed to proceed under nitrogen protection for 15 min, and then 0.71 g of DA was added to initiate the amidation reaction; after reacting at 25 °C for 12 h, the reaction was dialyzed in a hydrochloric acid solution with a pH of 5.5 for 3 d to remove the residual reaction substrate; the product was freeze-dried to obtain OSD with phenolic hydroxyl units.

[0033] Step S2: CMCS and OSD are mixed to form a CMCS / OSD hydrogel, wherein the amino groups of CMCS and the aldehyde groups of OSD are cross-linked to form a Schiff base bond. The specific operation of step S2 is as follows: 0.6 mL of 3 wt% carboxymethyl chitosan solution was mixed with 0.3 mL of 6 wt% oxidized sodium alginate catechol solution and then vibrated to mix well. The solution was allowed to stand for 5 min until it stopped flowing to form CMCS / OSD hydrogel ( Figure 4 ). This method has good applicability and high reproducibility for hydrogel grafting of monomers such as caffeic acid, tannic acid, and gallic acid, and provides a general preparation strategy for constructing hydrogel substrates that can coordinate with metal ions.

[0034] Step S3: Introduction of Fe into CMCS / OSD hydrogel precursor solution 3+ and CeO2 NPs, Fe 3+ Multiple coordination effects occur with catechol groups, carboxyl groups / phenolic hydroxyl groups on CeO2 NPs, and hydrogen bonds are formed between phenolic hydroxyl groups to construct CMCS / OSD / Fe 3 + / CeO2 composite hydrogel. The specific operation of step S3 is as follows: Add 0.05 mL of 0.1 mM Fe 3+ CMCS / OSD / Fe was formed when the solution was left to stand for 5 min until it stopped flowing. 3+ Hydrogel ( Figure 5 ), Fe 3+ The addition of has no obvious effect on the gelation rate, but it can significantly enhance the mechanical properties of the hydrogel. At the same time, the color of the hydrogel deepens from brown to dark brown. 0.05 mL of 20 mg / mL CeO2NPs dispersion was mixed into the CMCS / OSD hydrogel precursor solution and allowed to stand for 5 min until the solution stopped flowing to form the CMCS / OSD / CeO2 composite hydrogel. 3+ 0.05 mL of 20 mg / mL CeO2NPs dispersion was mixed into the hydrogel precursor solution and allowed to stand for 5 min until the solution stopped flowing to form CMCS / OSD / Fe 3+ / CeO2 composite hydrogel.

[0035] Scanning electron microscopy characterization proved that CMCS / OSD hydrogel, CMCS / OSD / Fe 3+ Hydrogel, CMCS / OSD / CeO2 hydrogel, CMCS / OSD / Fe 3+ / CeO2 composite hydrogel has a porous structure ( Figure 6 (a)-(d)). The CMCS / OSD / Fe 3+ / CeO2 composite hydrogel is injectable and self-healing, can strongly adhere to pig skin, and will not fall off or break after repeated twisting ( Figure 6 (e) and (f)). 3+ After the precursor of CMCS / OSD / Fe / CeO2 composite hydrogel was mixed, it was injected into the culture dish with a syringe. It can be seen that the hydrogel can be formed quickly and maintain a good morphology. 3+ Injectability of / CeO2 composite hydrogels ( Figure 6 (g) and (h)).

[0036] The swelling experiment showed that the swelling rate of the hydrogel was lower in acidic buffer and higher in neutral buffer. 3+ The swelling rate of the composite hydrogel in both acidic and neutral buffers decreased. 3+ The degradation rate of the composite hydrogel was lower due to the Fe 3+ The coordination effect makes the cross-linked network of the hydrogel more dense, reduces the swelling rate and swelling ratio of the hydrogel, and enables it to maintain good adhesion and toughness in extreme microenvironments such as gastric acid ( Figure 7 (a) and (b)).

[0037] Example 1: Study on CMCS / OSD / Fe 3+ / CeO2 composite hydrogel's active oxygen scavenging ability; The hydroxyl radicals produced by the degradation of H2O2 by CeO2 were used to oxidize TMB into blue oxTMB, and the solution after centrifugation to remove CeO2 was used as an indicator. Sodium acetate-acetate buffer (Buffer, pH=4), CMCS and CMCS / OSD / Fe were studied respectively. 3+ / CeO2 composite hydrogel system. Experiments show that only CMCS / OSD / Fe 3+ / CeO2 composite hydrogel system can quickly (within 30 min) remove reactive oxygen species, changing the system from blue to colorless, while the other control groups showed no significant changes, proving that CMCS / OSD / Fe 3+ The CeO2 composite hydrogel system has a highly efficient free radical scavenging function, which can degrade hydrogen peroxide to relieve inflammation and promptly remove free radicals with high biological toxicity. It has great application potential in relieving wound inflammation and promoting healing. Figure 8 ).

[0038] The above are only preferred embodiments of the present invention. It should be pointed out that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention. These should also be regarded as the protection scope of the present invention. These will not affect the effect of the implementation of the present invention and the practicality of the patent.

Claims

1. A method for preparing an injectable composite hydrogel, characterized in that: The following steps are involved: Construct a library of self-healing hydrogel substrate materials that can coordinate with metal ions, a library of molecules containing coordination groups, a library of metal ions, and a library of nanoparticle materials with superoxide dismutase-like and catalase-like activities; The self-healing hydrogel substrate is CMCS / OSD hydrogel, the molecule containing the coordination group is dopamine, and the metal ion is Fe 3 + , the nanoparticles are cerium dioxide nanoparticles, and the specific preparation steps are as follows: Step S1: oxidizing sodium alginate to oxidized sodium alginate by sodium periodate, and grafting dopamine to prepare oxidized sodium alginate catechol having a phenolic hydroxyl unit; Step S2: mixing carboxymethyl chitosan with oxidized sodium alginate catechol to form CMCS / OSD hydrogel; Step S3: Introduction of Fe into CMCS / OSD hydrogel precursor solution 3+ and ceria nanoparticles to form CMCS / OSD / Fe 3+ / CeO2 composite hydrogel.

2. The method for preparing the injectable composite hydrogel according to claim 1, characterized in that: The specific operation of step S1 is as follows: first, 1 g of sodium alginate is dissolved in 100 mL of deionized water, and magnetic stirring is performed until it is completely dissolved to prepare a 1 wt% solution; 0.22 g of sodium periodate is added, and the reaction is carried out at 25°C in the dark for 4 h, and 3 mL of ethylene glycol is added and stirred for 2 h to terminate the reaction; 1 g of sodium chloride is added, and dialyzed for 3 d, and the water is changed 3 to 4 times a day; the product is freeze-dried to obtain white oxidized sodium alginate; then 1 g of oxidized sodium alginate is dissolved in 100 mL of deionized water, and 0.91 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.54 g of N-hydroxysuccinimide are added; the reaction is carried out under nitrogen protection for 15 min, and then 0.71 g of dopamine is added to initiate an amidation reaction; after reacting at 25°C for 12 h, the solution is dialyzed in a hydrochloric acid solution with a pH of 5.5 for 3 d, to remove the residual reaction substrate; the product is freeze-dried to obtain oxidized sodium alginate catechol having phenolic hydroxyl units.

3. The method for preparing the injectable composite hydrogel according to claim 2, characterized in that: The specific operation of step S2 is: 0.6 mL of 3 wt% carboxymethyl chitosan solution and 0.3 mL of 6 wt% oxidized sodium alginate catechol solution are mixed and then shaken to mix well, and the mixture is allowed to stand for 5 min until the solution does not flow to form a CMCS / OSD hydrogel.

4. The method for preparing the injectable composite hydrogel according to claim 3, characterized in that: The specific operation of step S3 is: add 0.05 mL of 0.1 mM Fe 3+ CMCS / OSD / Fe was formed when the solution was left to stand for 5 min until it stopped flowing. 3+ Hydrogel; in CMCS / OSD / Fe 3+ 0.05 mL of 20 mg / mL cerium dioxide nanoparticle dispersion was mixed into the hydrogel precursor solution and allowed to stand for 5 min until the solution stopped flowing to form CMCS / OSD / Fe 3+ / CeO2 composite hydrogel.

5. An injectable composite hydrogel prepared according to the method for preparing an injectable composite hydrogel according to any one of claims 1 to 4.

6. Use of the injectable composite hydrogel according to claim 5 in the preparation of a product for promoting wound healing after gastrointestinal surgery.

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