CN106267305B

CN106267305B - Hemostatic material

Info

Publication number: CN106267305B
Application number: CN201610644176.XA
Authority: CN
Inventors: 周应山; 徐礼勤; 龚祖光; 杨柳清; 王立平; 蒋锐
Original assignee: Shanghai New Valve Medical Devices Co Ltd; Jiangsu Li Nova Medical Products Co Ltd
Current assignee: Shanghai New Valve Medical Devices Co Ltd; Jiangsu Li Nova Medical Products Co Ltd
Priority date: 2016-08-08
Filing date: 2016-08-08
Publication date: 2019-08-06
Anticipated expiration: 2036-08-08
Also published as: CN106267305A

Abstract

The object of the present invention is to provide the fibers of suitable clinical application, especially application in terms of hemostasis, burn and scald, chronic wound.The present invention is a kind of hemostatic material, wherein including fiber, which has biodegradability, which is characterized in that the fiber includes polymer represented by following structural formula:Wherein the R is from-NH₂、‑OCH₂CH₂OH、‑OCH₂CH₂CH₂OH ,-OH ,-ONa ,-OK, select in group composed by-OCa it is at least one kind of；M, n and p respectively indicates the number percent that repetitive unit is corresponded in polymer molecule, and meets following relationship: m+n+p=1, p/ (m+n+p)=0.05~0.30；Degree of substitution D is defined as m/ (m+n+p), the overall degree of substitution of fiber is defined as Ds, the degree of substitution of the polymer of fiber cross section central point is defined as Do, when the degree of substitution of the polymer at fiber cross section edge is defined as Dx, meet following relationship: Ds=0.09~0.8, Do/Dx=0~0.7.

Description

Hemostatic material

Technical Field

The present invention relates to a hemostatic material, and in particular, to a hemostatic material comprising fibers that are liquid-absorbent by swelling and that are degradable in the human body.

Background

The chitin has the characteristics of good biocompatibility, biodegradability, hemostasis, wound healing promotion and the like, so that the chitin has wide application prospects in various tissue engineering scaffold materials such as absorbable surgical operation sutures, wound dressings, drug carrier materials, artificial skin and the like.

Dissolving chitin in organic acid or inorganic acid to form viscous colloid, spinning, coagulating, washing, drying, etc. to obtain chitin fiber for preparing wound dressing. Chinese patent document CN1129748A (deacetylated chitin fiber and its production method and application), chinese patent document CN1149093A (chitin fiber and its production method), chinese patent document CN101250759A (medical chitosan fiber and its production method), and the like successively disclose a production method of chitin fiber. However, the chitin fibers prepared by the methods have the defects of weak antibacterial property, poor liquid absorption and the like in medical clinical application, and particularly have unsatisfactory effects when being applied to treatment of chronic healing wounds such as easily infected burn wounds with more exudates, bedsores and the like.

For example, in chinese patent document CN1715465A (carboxymethyl chitin fiber, and a method for producing the same and an application thereof), the chitin fiber is alkalized and then modified with ethylene oxide to obtain hydroxyethyl chitin fiber, and in chinese patent document CN101368328A (a method for producing hydroxyethyl chitosan fiber) and the like. However, these modification methods are, on the one hand, harsh in reaction conditions, complicated in steps and difficult to control; on the other hand, the distribution position and the number of the substituent groups on the molecular chain of the product obtained by the reaction are uncertain, so that the liquid absorption performance of the product is difficult to control effectively. In addition, the above products also have no antibacterial properties. These problems can greatly limit the application of the dressing prepared from chitin fiber in clinical treatment, especially in treatment of burn and scald and chronic wound.

In particular, in conventional chitin fibers, the degree of substitution is often controlled to control the liquid absorption performance of the fibers, but the present inventors have found that the degree of substitution is too low, the liquid absorption capacity of the fibers is insufficient, the degree of substitution is too high, and the liquid absorption capacity is significantly increased, but the fiber morphology is difficult to maintain, that is, the fibers are dissolved or dispersed by the absorbed liquid. At this time, the liquid outflow may cause a certain degree of liquid-absorbing function to be lost.

Disclosure of Invention

In order to solve the above problems, the present inventors have conducted extensive studies and surprisingly found that by controlling the ratio of repeating units having different substituents in the polymer contained in the fiber and making the degree of substitution on the outer side (edge) of the fiber greater than the degree of substitution on the inner side (center) of the fiber, the fiber can maintain a good form and also maintain sufficient liquid-absorbing ability, thereby improving the antibacterial and liquid-absorbing properties of the fiber, and providing a fiber suitable for clinical use, particularly, for applications in hemostasis, burn and scald, treatment of chronic wounds, and the like.

The invention is realized by the following technical scheme:

1. a hemostatic material, which contains fiber and is characterized in that the material has biodegradability,

the fibers comprise a polymer represented by the following structural formula:

wherein

Said R is selected from-NH₂、-OCH2CH₂OH、-OCH₂CH₂CH₂At least 1 selected from the group consisting of OH, -ONa, -OK, and-OCa;

m, n and p respectively represent the number percentage of the corresponding repeating units in the polymer molecule and satisfy the following relational expressions:

m+n+p＝1，

p/(m+n+p)＝0.05～0.30；

when the degree of substitution D is defined as m/(m + n + p), the overall degree of substitution of the fiber is defined as Ds, the degree of substitution of the polymer at the center point of the cross section of the fiber is defined as Do, and the degree of substitution of the polymer at the edge of the cross section of the fiber is defined as Dx, the following relationships are satisfied:

Ds＝0.09～0.8，

Do/Dx＝0～0.7。

the invention has the following effects:

(1) the fibers of the present invention can be prepared by only ordinary solution modification (as in example 1) without the use of expensive raw materials and equipment, and without the need for severe reaction conditions, etc. In other words, the liquid-absorbing fiber can be prepared by a method with simple process, mild reaction conditions and low cost.

(2) The prepared fiber has good liquid absorption performance and antibacterial performance. The modification of the invention does not affect the original antibacterial and liquid-absorbing capacity of chitin, and on the basis, after the modification is carried out in a way of satisfying the above conditions, the surface modification degree of the fiber is greater than that of the central part, during liquid absorption, the modification degree of the central part is smaller, the liquid absorption amount is reduced, the fiber is not easy to dissolve, the molecular morphology is strictly maintained, the fiber plays a role of a skeleton, the edge part still maintains larger modification degree and liquid absorption amount, meanwhile, the outer part of the fiber can be well attached to the skeleton of the central part through intermolecular force, and the structure can not be lost due to dissolution even if the liquid absorption amount is larger. According to this, can make the fibre that makes still can keep better form after a large amount of imbibitions, the swelling range is big promptly, and the difficult liquid that absorbs dissolves, and at this moment, the liquid of absorption is locked in the fibre, can not appear excessive imbibition back, and the fibre excessively dissolves and leads to losing original structure to the phenomenon that the liquid that makes the absorption is discharged from the fibre again.

(3) The "skeleton" of the central portion does not swell substantially at the time of liquid absorption, and thus maintains the original length, and therefore the outer structure of the fiber attached to the skeleton is difficult to elongate by the constraint of the skeleton at the time of liquid absorption, whereby the fiber obtained can be expanded and thickened only in the radial direction of the fiber as much as possible at the time of liquid absorption and swelling, that is, not elongated by liquid absorption swelling and stretching, and not expanded uniformly in all directions.

Based on the characteristics, the fiber has a plurality of applications in the field of medical materials, for example, the fiber can be made into fiber clusters or non-woven fabrics by opening, carding, lapping, needle punching and other processes, can also be made into woven fabrics by twisting, spinning and other processes, and can also be made into powder by crushing and other processes, and the fiber is used for hemostasis, wound treatment and the like.

Specifically, the fibers which can maintain a good shape when absorbing a large amount of liquid, are not adhered to the wound due to the absorption of liquid after being stained with blood after being attached to the wound, do not hinder the healing of the wound and are easy to detach. And the radial expansion fiber can fill the gaps among the fibers in the original fiber fabric when expanding after imbibing, thereby enhancing the hemostatic effect and avoiding the problem of performance reduction of preventing wound adhesion caused by fiber length stretching. In addition, when the length of the fiber is not changed, the position of a contact point of the cross-contacted fiber in the formed fabric is not moved before and after liquid absorption, so that the fabric integrally keeps the original shape, and the condition that the fabric or the fiber is moved into a wound and adhered to the wound to hinder the wound healing is avoided.

In particular, when used as a hemostatic material, the fibers absorb liquid and then gel, and the material originally having voids is brought into a substantially sealed state while absorbing liquid outside the wound, which is more advantageous for blocking wound bleeding.

In addition, the hemostatic material exhibits excellent vertical absorption performance, so that absorbed liquid is locked in the vicinity of the area of the hemostatic material in contact with bleeding points, the liquid absorption amount of fibers in the area is further increased, and the liquid absorption is radially expanded, and in addition to the above-mentioned improvement in sealability, the hemostatic material bulges (increases in thickness) in the direction perpendicular to the surface where the wound is located, thereby generating a vertical force, and the hemostatic material can press the wound more tightly and has a better hemostatic effect.

In addition, in the process, the surface effect can help the red blood cells and the blood platelets to be enriched while high-power imbibing, so that the aim of stopping bleeding by enabling the blood to be coagulated nearby the wound more quickly is fulfilled. Specifically, the fiber absorbs liquid but does not absorb red blood cells and platelets, and meanwhile, because the amino groups on the surface of the fiber have positive charges, the fiber can attract the red blood cells and platelets with negative charges to stay near the surface of the fiber, and near the contact surface of the fiber and a wound, on one hand, because the fiber absorbs liquid which can dissolve the red blood cells and platelets, on the other hand, because the fiber expands, the distance between the fibers is reduced, the void volume of the fiber is reduced, the liquid volume and the volume in the region are both reduced, the total amount of the red blood cells and the platelets is unchanged, and the concentration is remarkably increased, so that a good blood coagulation effect is achieved.

For these reasons, the hemostatic material can exert its hemostatic effect effectively and the time required for hemostasis is significantly shortened.

Drawings

FIG. 1 is a micrograph showing the microstructure of a fiber of the present invention.

FIG. 2 is a schematic diagram showing the liquid-absorbed morphologies of the fibers of different degrees of substitution of the present invention. Specifically, single fibers are placed in 0.9% physiological saline, taken out and fixed on a glass sheet at 37 ℃ for 30min, and the shape change of the fiber imbibition is observed under an optical microscope.

FIG. 3 is a schematic view showing the liquid-absorbed morphology of a fiber bundle of fibers having different degrees of substitution according to the present invention. Specifically, the fiber bundle is placed in 0.9% physiological saline and observed for the shape change of the imbibition of the fiber bundle at 37 ℃ for 30 min.

The letters in FIGS. 2 and 3 indicate the following meanings

a is an unmodified fiber; b to g are fibers of examples 1 to 6, and subscripts 1 and 2 represent forms before and after liquid absorption (e.g., a)₁Shows the form of the fiber a before liquid absorption, a₂Showing the shape of the fiber a after imbibition, and so on)

Detailed Description

The aspects and effects of the present invention will be described in further detail below with reference to preferred embodiments and examples, but the present invention is not limited to the following embodiments or examples.

[ fibers used as raw materials ]

As described above, in the case of ordinary chitin fibers, if the substitution degree is controlled to control the liquid absorption performance of the fibers, there arises a problem that the substitution degree is too low, the liquid absorption amount of the fibers is insufficient, the substitution degree is too high, and although the liquid absorption amount is significantly increased, the fiber morphology is difficult to maintain, that is, the fibers are dissolved or dispersed by the absorbed liquid.

For example, when the fibers in the following table are immersed in physiological saline and the liquid absorption amounts are measured as multiples of the dry weight of the fibers, the liquid absorption amounts are small when the substitution degree is low, the practical value is not large, and when the substitution degree is too large, the fibers excessively absorb liquid, so that the original structure is lost, and the originally absorbed water returns to the environment, and the liquid absorption amounts cannot be measured.

In view of the above, the present inventors have surprisingly found that, when the degree of substitution in the central portion of the fiber is reduced to maintain the fiber in a satisfactory form, the structure of the outer portion of the fiber is attached to the skeleton by intermolecular forces, and the fiber is not easily detached and dispersed, and the basic fiber form can be maintained even after a large amount of liquid absorption, and thus the present invention has been completed.

The liquid-absorbent fibers of the present invention comprise a polymer represented by the following structural formula:

wherein

Said R is selected from-NH₂、-OCH₂CH₂OH、-OCH₂CH₂CH₂At least 1 selected from the group consisting of OH, -ONa, -OK, and-OCa;

m+n+p＝1，

p/(m + n + p) is 0.05-0.30; the lower limit is preferably 0.10 or more, more preferably 0.15 or more, and the upper limit is more preferably 0.25 or less, more preferably 0.20 or less.

If the p value is too large, the liquid absorption of the fibers is lowered. If the P value is too small, the fibers are dissolved after contacting with the liquid, and the morphology is difficult to maintain.

the total degree of substitution Ds of the fiber is 0.09-0.8,

Do/Dx＝0～0.7。

the lower limit of Ds is preferably 0.2 or more, more preferably 0.3 or more, still more preferably 0.4 or more, and the upper limit is preferably 0.7 or less, more preferably 0.6 or less, still more preferably 0.5 or less.

If the Ds value is too large, it is not preferable to maintain the fiber form, and if it is too small, the amount of the fiber liquid absorbed is lowered.

The lower limit of Do/Dx is more preferably 0.05 or more, still more preferably 0.1 or more, yet more preferably 0.15 or more, and the upper limit is more preferably 0.6 or less, still more preferably 0.5 or less, yet more preferably 0.4 or less.

Too large a Do/Dx may cause the fibers to dissolve when exposed to liquids, and may not maintain the basic morphology of the fibers, affecting their performance characteristics and preventing their removal from the wound. When the substitution degree is too small, the ratio of the expansion rate of the fiber diameter to the expansion rate of the fiber length is insufficient, and the amount of the absorbed fiber is reduced, and at the same time, the fiber is easily adhered to the wound, which is not favorable for removal from the wound.

The smaller the value of Do, the better the center form of the fiber is maintained, and the more easily the center portion functions as a skeleton, and for example, Do may be 0.02 or less, 0.05 or less, 0.1 or less, 0.2 or less, 0.25 or less, 0.3 or less, or 0.35 or less.

The center point of the fiber in the invention is the geometric center of the cross section when the cross section of the fiber is in a regular pattern, and is the geometric center of gravity of the cross section when the cross section of the fiber is in an irregular pattern.

The fiber edge in the present invention refers to the position on the cross section of the fiber farthest from the center point of the fiber.

The shape of the fiber cross section is not particularly limited, for example, circular, elliptical, clover, triangular, polygonal, etc., but circular or elliptical is preferable from the viewpoint of uniform modification, and circular is most preferable.

The diameter of the cross section of the fiber is not particularly limited, but is preferably 1 to 1000. mu.m, the lower limit is more preferably 5 μm or more, more preferably 10 μm or more, still more preferably 15 μm or more, and the upper limit is more preferably 500 μm or less, still more preferably 200 μm or less, still more preferably 100 μm or less.

The diameter of the fibers is mainly related to the application, for example, the fibers may be thicker when used externally or in a position with bleeding and large fluid output, and may be thinner when used internally or in a position with bleeding and small fluid output.

The length of the fiber is not particularly limited, but is preferably 1 to 10cm, the lower limit is more preferably 2cm or more, more preferably 3cm or more, still more preferably 5cm or more, and the upper limit is more preferably 9cm or less, still more preferably 8cm or less, still more preferably 7cm or less.

If the length of the fiber is too short, the cutting or the preparation of the fabric is not facilitated, and if the length of the fiber is too long, the fiber is easy to bend when forming the fabric, the opening and carding of the fiber are not facilitated, and the subsequent processing of the fabric or the non-woven fabric is difficult.

The polymer used in the fiber has 3 kinds of repeating units having different structures as shown in the above figure, but the molecular formula represents only the kind of the repeating unit contained in the polymer, and the arrangement order of the repeating units may be arbitrary. In other words, as long as the ratio of the repeating units meets the requirement of the present invention, the arrangement order does not affect the object of the present invention.

The viscosity average molecular weight of the polymer of the present invention is preferably 5 to 1000 ten thousand, the lower limit is preferably 10 ten thousand or more, more preferably 20 ten thousand or more, more preferably 50 ten thousand or more, more preferably 100 ten thousand or more, and the upper limit is preferably 900 ten thousand or less, more preferably 800 ten thousand or less, more preferably 700 ten thousand or less, more preferably 600 ten thousand or less.

When the viscosity-average molecular weight is too large, the molecular chain is in a curled state, and the reactive groups on the molecular chain are easily wrapped, so that the reaction is not facilitated, and the total substitution degree is too low. When the viscosity-average molecular weight is too small, the molecular chain is short, the reactive group is easy to expose, and the reactive reagent and the hydrolytic reagent are easier to penetrate through the gaps of the molecular chain and have the effect on the molecular chain, so that the total substitution degree is greatly increased, the difference between the center point and the edge substitution degree of the cross section of the fiber is small, the fiber is dissolved after contacting with liquid, the fiber form cannot be maintained, and the service performance of the fiber is influenced.

The groups R of the polymeric species are preferably more than 2, i.e. comprise at least R1 and R2, more preferably R is only R1 and R2,

r1 is selected from-NH₂、-OCH₂CH₂OH、-OCH₂CH₂CH₂At least one selected from the group consisting of OH,

r2 is at least one selected from the group consisting of-OH, -ONa, OK, and-OCa.

The content of R1 is preferably 0 to 95%, the lower limit is preferably 5% or more, more preferably 10% or more, and still more preferably 20% or more, and the upper limit is preferably 90% or less, more preferably 80% or less, and still more preferably 70% or less, with respect to the total amount of R.

The content of R2 is preferably 5 to 100%, the lower limit is more preferably 10% or more, more preferably 20% or more, and more preferably 30% or more, and the upper limit is preferably 90% or less, more preferably 80% or less, and more preferably 70% or less, with respect to the total amount of R.

The fibers preferably have a good liquid-absorbing capacity, and the amount of liquid absorbed is preferably 2 times or more, more preferably 5 times or more, still more preferably 10 times or more, based on the weight (dry weight) of the fibers themselves, based on the absorption of physiological saline (0.9% sodium chloride solution), and the upper limit is not particularly limited. Preferably 20 times or less.

More preferably, the fibers are as thick as possible without lengthening upon imbibition swelling, i.e., the fiber diameter expansion ratio is much larger than the fiber length expansion ratio, preferably the fiber diameter expansion ratio/fiber length expansion ratio is more than 5 times, more preferably more than 10 times, more preferably more than 20 times, and more preferably more than 30 times. The larger the ratio, the more favorable the retention of the fiber morphology, i.e., the swelling upon imbibition, without being completely dissolved or dispersed by the absorbed liquid.

The fiber diameter of the present invention means a diameter of a circle when the cross section of the fiber is circular, and a line connecting two points located at the farthest distance from each other on the edge of the cross section of the fiber when the cross section of the fiber is not circular.

The expansion ratio of the fiber length means:

(Length after fiber imbibition-Length before fiber imbibition)/Length before fiber imbibition X100%

The expansion ratio of the fiber diameter means:

(diameter after fiber imbibition-diameter before fiber imbibition)/diameter before fiber imbibition X100%

[ hemostatic Material ]

The hemostatic material of the invention is any 1 or more of needle-punched non-woven fabric, spunlace non-woven fabric, woven fabric or non-woven fabric, yarn, loosely combined multi-layer non-woven fabric or loose fiber mass made of fibers.

When woven or nonwoven fabric is used, the grammage is preferably 1 to 500gsm, the lower limit is more preferably 5gsm, more preferably 20gsm, more preferably 50gsm, and the upper limit is more preferably 450gsm, more preferably 400gsm, more preferably 350 gsm.

The hemostatic material absorbs 5-40 times of the dry weight of the hemostatic material of physiological saline containing 0.9% of sodium chloride. In the formed hemostatic material, in addition to the liquid absorption of the fibers themselves, the fiber internal space sealed by the expansion of the parallel fibers can store a large amount of water. Thus, the shaped hemostatic material may achieve better liquid absorbency than the fibers themselves.

Preferably, the hemostatic material is degradable in vivo for no more than 30 days, more preferably no more than 15 days.

The method of forming the fibers is not particularly limited, and the fibers can be formed into various forms such as woven fabrics and nonwoven fabrics by a known method.

Examples

1. Method for determining parameters of fiber material

1.1 measurement of m, n, p

The type of the instrument used for the measurement: model AMX600M NMR spectrometer manufactured by Bruker of Germany

The desired content relationship can be calculated from the measured values, for example, m/(m + n + p), p/(m + n + p) equivalents.

The specific operation method comprises dissolving fiber in 1% CD₃D of COOD₂In O, the characteristic group of each repeating unit is determined (for example, m corresponds to-NCH in its repeating unit)₂-、-OCH₂-; p for-NCOCH in its repeating unit₃-) and calculating the ratio of each repeating unit according to the ratio of the area size of the proton peak area.

1.2 determination of the degree of substitution at a certain point on the fiber cross-section (e.g.a point on the center or on the edge)

Soaking the liquid absorption fiber in water/ethanol (v/v-20/80) solution containing 30% (w/v) KOH at 60 ℃ for 5 hours, taking out the liquid absorption fiber, repeatedly washing the liquid absorption fiber with 80% (v/v) ethanol water solution for 8 times, drying the liquid absorption fiber at 40 ℃ for 24 hours after removing the washing liquid, quenching the dried fiber in liquid nitrogen, testing by an energy spectrometer (EDS) to obtain the K content of the center point of the cross section of the fiber and the K content of the edge of the fiber, calculating the substitution degree of each point according to the K content, and taking the ratio of the K content of the center point of the cross section of the fiber to the K content of the edge of the fiber as the substitution degree ratio.

1.3 absorbency Performance test

1.3.1 liquid absorption

20 liquid-absorbing fibers were taken and measured for dry weight W (g) with an analytical balance. Soaking nylon cloth in 0.9% sodium chloride normal saline for 30min, taking out, drying, wrapping with the nylon cloth, and weighing W₁(g) In that respect Weighing enough physiological saline containing 0.9% sodium chloride 500 times more than 20 fibers, placing the fiber wrapped with nylon cloth therein, standing at 37 deg.C for 30min, taking out the nylon cloth bag, spin-drying, and weighing as W₂(g) In that respect The absorption capacity of the individual fibers is (W)₂-W₁)/W。

1.3.2 expansion ratio of fiber diameter to Length

And taking out the spun fiber, fixing the spun fiber on a glass sheet, and measuring the diameter and the length of the imbibed fiber under a microscope. Additionally, dry fibers were fixed on a glass slide and their diameters and lengths were measured under a microscope.

The measurement results of the above data are summarized in tables 1 and 2 below.

Method for measuring viscosity average molecular weight: the measurement is carried out by the Ubbelohde viscosity method. Taking a certain amount of fiber, dissolving in 0.1mol · L^-1CH₃COOH-0.2mol·L^-1The viscosity-average molecular weight of NaCl was calculated by measuring the flow-out time of NaCl in a constant-temperature water bath at (25. + -. 0.05). degree.C.by means of an Ubbelohde viscometer.

2. Method for measuring parameters of hemostatic material

2.1 liquid absorption

A quantity of hemostatic material is measured as W (g) dry weight. The nylon cloth was soaked in 0.9% sodium chloride in physiological saline for 30 minutes, taken out, spun-dried, and the needle-punched non-woven fabric was wrapped with the nylon cloth and weighed as W1 (g). Weighing normal saline containing 0.9% sodium chloride 400 times the weight of the hemostatic material, placing the hemostatic material wrapped with nylon cloth therein, standing at 37 deg.C for 30min, taking out the nylon cloth bag, spin-drying, and weighing w2 (g). The absorption rate of the hemostatic material under physiological saline is (W2-W1)/W.

2.2 in vivo degradation absorption test

The in vivo degradation test adopts a rat liver embedding material degradation model.

Male SPF grade SD rats were selected 24. Two days prior to the experiment, rats were treated for abdominal dehairing with sodium sulfide solution. 3% sodium pentobarbital (30mg/kg) was used for intraperitoneal injection for anesthesia during the experiment.

After the rat is completely anesthetized, the rat is fixed on the experimental rat board in the supine position, and the four limbs and the head are fixed well. Disinfecting the abdomen of rat with 75% alcohol and medical iodophor, cutting the middle incision of the upper abdomen for about 5cm, cutting skin and abdominal muscles, cutting wall peritoneum, exposing left lobe of liver, and placing iodophor gauze under the left lobe. A liver tissue with the length of 1cm multiplied by 0.3cm is cut at the outer edge of the left lobe of the liver to form the acute bleeding wound surface of the liver. After the wound surface bleeds freely for 10s, the dry weight is m₁(g) The dressing is spread on the surface of the wound edge, the material is taken out after light pressure, the bleeding condition of the wound surface is observed after light pressure for 1min, and the pressure is repeatedly applied until the wound surface has no active bleeding. Then, an absorbable suture is used for sewing a needle perpendicular to the dressing and the left-lobe liver wound edge, the dressing is fixed on the liver wound edge, after no active bleeding is detected, the abdominal cavity is sewn in a layered and discontinuous mode, the abdomen is disinfected again by iodophor, the elastic bandage is properly pressed and fixed after sterile gauze is applied inside, and then the cultivation is performed in a cage. The bandage was removed on day 2 post-surgery and the survival rate of the rats was recorded. The activity of the rats was observed daily after the operation. At time points of 7, 14, 21, 28 days, respectively, 6 rats were each removed, the abdominal cavity opened, the dressing removed, lyophilized and weighed m₂(g) In that respect Has a degradation absorption rate of (m)₁-m₂)/m₁。

2.3 in vivo liver hemostasis test in animals

The study was carried out using an in vivo rabbit liver bleeding model.

24 healthy New Zealand rabbits (3 months old) with half male and female parts and 2.5kg body weight. The test group and the control group (common gauze) are randomly divided, and 6 pieces of the test group and the control group are respectively selected. Two days before the experiment, the belly of the rabbit is depilated by sodium sulfide solution. Pentobarbital sodium (30mg/kg) was slowly injected into the rabbit ear vein with 3% pentobarbital sodium.

After the rabbits are completely anesthetized, the rabbits are in a supine position, the two upper limbs are abducted and properly fixed on a laboratory table, the abdomen of the rats is disinfected by 75% alcohol and medical iodophor, an incision is designed under the left costal margin and is about 5cm long, the skin margin and the edge of a disinfection gauze pad are sutured, the larger blood vessels in each muscle layer of the abdomen are avoided during incision, the abdominal muscles are incised to the abdominal wall, the peritoneum of the wall layer is lifted and cut, the abdominal cavity is entered, and the abdominal viscera are prevented from being damaged. Exposing the liver, manufacturing a cross opening at the center of the left lobe of the liver by using a scalpel at 1cm (length) × 1cm (width) × 0.4cm (depth), causing acute liver hemorrhage, respectively covering groups of dressings with the size of 2cm × 2cm on the surface of a wound after the wound freely bleeds for 10s, then externally applying sterile gauze with the size of 3cm × 3cm, vertically compressing the wound with a weight of 20g for hemostasis, observing the wound every 20 seconds after 1min of hemostasis, taking down the weight after the wound has no bleeding, recording the hemostasis time, and recording as success of hemostasis after observing that the wound has no bleeding again within 5 min.

Example 1

Weighing 5g of chitin fiber with the length of 6cm and the p/(M + n + p) of 0.25, dispersing the chitin fiber in 50mL of isopropanol, adding 2.54g of acrylic acid-2-hydroxyethyl ester, oscillating uniformly at room temperature, reacting for 48h in a thermostatic water bath at 50 ℃, separating the reacted chitin fiber from a reaction mixed solution, washing for 2 times by using an 80% (v/v) methanol aqueous solution, taking out the fiber, drying by spinning, dispersing in an 80% (v/v) methanol aqueous solution, dropwise adding a 30% (w/v) potassium hydroxide aqueous solution, adjusting the pH of the methanol-potassium hydroxide aqueous solution mixed solution to 11.0, soaking for 1 h, separating the soaked fiber from the mixed solution, washing for 3 times by using an 80% (v/v) methanol aqueous solution, dehydrating, and drying at 40 ℃ to obtain the liquid absorption fiber with the viscosity-average molecular weight (M η) of 300 ten thousand and the substitution degree of the total mass of acryloyl substances of 0.17.

Dissolving the imbibing fiber in 1% CD₃D of COOD₂In O, nuclear magnetic hydrogen spectrometry is used to respectively measure-NCH₂-、-OCH₂-proton peak area in (a), whereby the content of R2-OK in the substituted acryloyl group was calculated to be 22%; then R1 is-OCH₂CH₂The OH content was 78%.

Example 2

5g of chitin fiber with the length of 6cm and the p/(m + n + p) of 0.10 is weighed and dispersed in 50mL of isopropanol, adding 7.09g of acrylic acid-2-hydroxypropyl ester, oscillating uniformly at room temperature, reacting in constant temperature water bath at 70 deg.C for 48 hr, separating chitin fiber from reaction mixture, washing with 80% (v/v) methanol water solution for 2 times, taking out fiber, drying, dispersing in 80% (v/v) methanol water solution, dripping 30% (w/v) potassium hydroxide aqueous solution, adjusting pH of the mixed solution of methanol and potassium hydroxide aqueous solution to 11.0, soaking for 1 hr, separating the soaked fiber from the mixed solution, washing with 80% (v/v) methanol water solution for 3 times, dewatering, drying at 40 ℃ gave a liquid-absorbent fiber having a viscosity average molecular weight of 300 ten thousand and a degree of substitution of the amount of the total acryloyl groups of 0.30.

Dissolving the imbibing fiber in 1% CD₃D of COOD₂In O, nuclear magnetic hydrogen spectrometry is used to respectively measure-NCH₂-、-OCH₂-proton peak area in (a), whereby the content of R2-OK in the substituted acryloyl group was calculated to be 35%; then R1 is-OCH₂CH₂CH₂The OH content was 65%.

Example 3

Weighing 5g of chitin fiber with the length of 6cm and the p/(m + n + p) of 0.10, dispersing the chitin fiber in S0mL isopropanol, adding 14.17g of acrylic acid-2-hydroxypropyl, oscillating uniformly at room temperature, reacting in a constant-temperature water bath at 70 ℃ for 48h, and separating the reacted chitin fiber from the reaction mixed solutionWashing with 80% (v/v) methanol water solution for 2 times, taking out fiber, drying, dispersing in 80% (v/v) methanol water solution, dripping 30% (w/v) potassium hydroxide water solution, adjusting pH of the mixed solution of methanol and potassium hydroxide water solution to 11.5, soaking for 1 hr, separating the soaked fiber from the mixed solution, drying, placing in saturated CaCl₂The solution was immersed for 1 hour, and the fiber was taken out, washed 3 times with an aqueous 80% (v/v) methanol solution, dehydrated, and dried at 40 ℃ to obtain a liquid-absorbent fiber having a viscosity average molecular weight of 50 ten thousand and a degree of substitution of the amount of the total acryloyl groups of 0.49.

Dissolving the liquid absorption fiber in D20 of 1% CD3COOD, and respectively measuring proton peak areas in-NCH 2-, -OCH 2-by nuclear magnetic hydrogen spectrometry to calculate the content of R2-OCa in the substituted acryloyl groups to be 39%; the content of R1 being-OCH 2CH2CH2OH is 61%.

Example 4

Weighing 5g of chitin fiber with the length of 6cm and the p/(m + n + p) of 0.25, dispersing the chitin fiber in 50mL of isopropanol, adding 5.08g of acrylic acid-2-hydroxyethyl ester, oscillating uniformly at room temperature, reacting for 58h in a constant-temperature water bath at 55 ℃, separating the reacted chitin fiber from a reaction mixed solution, washing for 2 times by using an 80% (v/v) methanol aqueous solution, taking out the fiber, drying by spinning, dispersing in an 80% (v/v) methanol aqueous solution, dripping a 30% (w/v) potassium hydroxide aqueous solution, adjusting the pH of the methanol and potassium hydroxide aqueous solution mixed solution to 11.5, soaking for 1 h, separating the soaked fiber from the mixed solution, drying by spinning, and placing in saturated CaCl₂The solution was immersed for 1 hour, washed with 80% (v/v) aqueous methanol solution 3 times, dehydrated, and dried at 40 ℃ to obtain a liquid-absorbent fiber having a viscosity average molecular weight of 50 ten thousand and a degree of substitution of the amount of the total acryloyl groups of 0.55.

Dissolving the imbibing fiber in 1% CD₃D of COOD₂In O, nuclear magnetic hydrogen spectrometry is used to respectively measure-NCH₂-、-OCH₂Peak area of proton in-whereby R2 is-OCa in the substituted acryloyl group was calculatedThe content of (A) is 27%; then R1 is-OCH₂CH₂CH₂The OH content was 73%.

Example 5

Weighing 5g of chitin fiber with the length of 6cm and the p/(m + n + p) of 0.25, dispersing the chitin fiber in 50mL of isopropanol, adding 6.30g of acrylic acid, uniformly oscillating at room temperature, reacting for 40h in a constant-temperature water bath at 70 ℃, separating the reacted chitin fiber from a reaction mixed solution, washing for 2 times by using 80% (v/v) methanol aqueous solution, taking out the fiber, drying, washing for 3 times by using 80% (v/v) methanol aqueous solution after drying, dehydrating, and drying at 40 ℃ to obtain the liquid-absorbing fiber with the viscosity-average molecular weight of 8 ten thousand and the quantity substitution degree of the total acryloyl substances of 0.75.

Dissolving the imbibing fiber in 1% CD₃D of COOD₂And O, performing nuclear magnetic hydrogen spectrum test. The results show that compared with chitin fiber raw material, the liquid absorption fiber only has two new absorption peaks with chemical shifts of 2.3 and 3.1, and the absorption peaks are assigned to-NCH₂CH₂CO-, indicating that R2 was-OH, the content was 100%, and the degree of substitution by amount of the total acryl group-derived substances was 0.75 by calculation.

Example 6

Weighing 5g of chitin fiber with the length of 6cm and the p/(m + n + p) of 0.10, dispersing the chitin fiber in 50mL of methanol, adding 1.91g of acrylamide, uniformly oscillating at room temperature, reacting for 72h in a constant-temperature water bath at 40 ℃, separating the reacted chitin fiber from a reaction mixed solution, washing for 2 times by using an 80% (v/v) methanol aqueous solution, taking out the chitin fiber, spin-drying, soaking in a 40 ℃ saturated sodium bicarbonate solution for 1 hour, taking out the fiber, washing for 3 times by using an 80% (v/v) methanol aqueous solution, dehydrating, and drying at 40 ℃ to obtain the liquid-absorbing fiber with the viscosity-average molecular weight of 900 ten thousand and the acryloyl total substance quantity substitution degree of 0.09.

Dissolving the imbibing fiber in 1% diluted acetic acid by sodium ion meterThe content of R2-ONa in the substituted acryloyl tested was 5%; then R1 is-NH₂The content of (B) is 95%.

Quenching the liquid absorption fiber in liquid nitrogen, and measuring the-CO-content of the center point of the cross section of the fiber and the content of the fiber edge by X-ray photoelectron spectroscopy (XPS), so as to calculate to obtain the substitution degrees of the acryloyl groups at the center point of the cross section of the fiber and the fiber edge to be 0 and 0.12 respectively.

TABLE 1 basic fiber parameters

In the above table, the calculation process of each embodiment is as follows:

and testing the substitution degree of acryloyl groups at different sites of the cross section of the fiber by EDS, namely completely hydrolyzing the liquid absorption fiber into potassium carboxylate by using a KOH solution, completely cleaning and drying, wherein the amount of K is equal to that of carboxylate radical substances, and calculating to obtain the amount of the carboxylate radical substances by obtaining the content of K through the EDS test, thereby calculating to obtain the substitution degree of the acryloyl groups.

For example 6, since the grafted acrylamide was not hydrolyzed to generate carboxyl groups, the-CO-content thereof was obtained using XPS test to calculate the degree of substitution at different sites.

TABLE 2 absorbency Properties of the fibers

Comparative example

A series of fibers having the same degree of substitution (Do/Dx ═ 1) from the center point of the cross section of the fiber to the edge of the fiber were prepared, and the morphology after liquid absorption was examined by the following method, and the state of retention of the morphology of the fibers after the fibers were contacted with the liquid was observed.

Weighing 8.3g NaCl and 0.277g CaCl₂Adding distilled water to fully dissolve, placing in a volumetric flask, and adding distilled water to a constant volume of 1000mL to obtain a solution A specified in British pharmacopoeia. The solution simulates the content of main metal ions in human blood.

Morphological contrast of imbibed fibers

Taking 1 fiber, fixing two ends of the fiber on a glass sheet by using a double-sided adhesive tape, dripping 0.25mL of solution A into the middle part of the fiber, standing the fiber for 30min at 37 ℃, taking out the fiber, and observing the shape change of the fiber after imbibing the liquid under an optical microscope.

TABLE 3 determination of the absorbency of the fibers

As a result, it was difficult to measure the exact liquid absorption amount since the fiber of comparative example 1 had a poor intact form, and it was presumed that the liquid absorption amount was lower than that of the present invention in comparative example 2, although it could be measured, the microstructure of the uniformly substituted fiber was maintained after liquid absorption at the same substitution degree, but the microstructure was not strong enough to bind water since it was slightly dissolved compared with the present invention, and the water was partially lost after spinning and drying.

Example 7

The fibers of example 1 were subjected to opening, carding, lapping, needling, and heat sealing to produce a needled nonwoven fabric having a grammage of 100 gsm.

Example 8

The chitin fibers used in example 2 were first processed into a spunlace nonwoven having a grammage of 20gsm and then modified in the same manner as in example 2.

Example 9

The fibers of example 3 are subjected to opening, carding, single-layer lapping, needling, single-layer net needling composite and other processes to form the loosely-combined multi-layer non-woven fabric with the gram weight of 200 gsm.

Example 10

The fibers of example 4 were subjected to opening, carding, etc. to make a loose fiber mass with a grammage of 5 gsm.

Example 11

The fibers of example 5 were subjected to opening, carding, drawing, twisting, and the like to obtain a yarn.

Example 12

The fibers in example 6 are subjected to opening, carding, drawing, twisting and other processes to obtain yarns. The yarn is knitted to obtain the woven fabric

The hemostatic materials prepared in examples 7-12 were tested and the results are shown below.

TABLE 4 absorbency of hemostatic materials

Examples	W(g)	W₁(g)	W₂(g)	(W₂-W₁)/W	Liver hemostasis time (second)
						7	1.0	1.5	19.4	17.9	136
8	1.0	1.5	18.6	17.1	144
						9	1.0	1.5	30.0	28.5	95
10	1.0	1.5	41.5	40.0	108
						11	1.0	1.5	36.1	34.6	121
12	1.0	1.5	6.5	5.0	139

In the same experiment, the hemostatic time of the medical gauze is about 400 seconds, and thus, the hemostatic material provided by the invention obviously reduces the time required for hemostasis.

TABLE 5 in vivo degradation and absorption Performance test of hemostatic materials

Claims

1. A hemostatic material, which comprises fibers, and is characterized in that the time required for the fibers to degrade in a human body or a white mouse is less than 30 days;

the fibers comprise a polymer represented by the following structural formula:

wherein

The above-mentionedR is selected from-NH₂、-OCH₂CH₂OH、-OCH₂CH₂CH₂At least 1 selected from the group consisting of OH, -ONa, -OK, and-OCa;

m+n+p＝1，

p/(m+n+p)＝0.05～0.30；

Ds＝0.2～0.7，

Do/Dx＝0～0.6。

2. the hemostatic material according to claim 1, wherein the R contains 0 to 95% of R1 and 5 to 100% of R2,

wherein,

r2 is at least one selected from the group consisting of-OH, -ONa, -OK, and-OCa.

3. The hemostatic material of claim 1, wherein the overall degree of substitution Ds of the fibers is 0.3 to 0.6.

4. Hemostatic material according to claim 1, wherein the total degree of substitution Ds ═ 0.4 to 0.5 for the fibers

5. The hemostatic material of claim 1, wherein Do/Dx is 0-0.5.

6. The hemostatic material of claim 1, wherein Do/Dx is 0-0.4.

7. Hemostatic material according to claim 1, wherein the polymer has a viscosity average molecular weight M η in the range of 5 to 1000 ten thousand.

8. Hemostatic material according to claim 1, wherein the fibers absorb 0.9% sodium chloride in physiological saline 5-20 times the dry weight of the fibers.

9. Hemostatic material according to claim 1, wherein the fibers, after imbibing, expand in radial direction of the fibers by a percentage more than 5 times the percentage of expansion in axial direction of the fibers

The radial direction of the fiber means a direction from the center of the cross section of the fiber to the edge of the cross section of the fiber,

the fiber axial direction refers to a direction perpendicular to the cross section of the fiber.

10. The hemostatic material of claim 1, wherein the hemostatic material is any 1 or more of a needle punched nonwoven, a hydro-entangled nonwoven, a woven fabric, a yarn, a loosely bonded multi-layer nonwoven, or a loose fiber mass made of fibers.

11. Hemostatic material according to claim 1, wherein the fibers have a diameter of 0.2 to 120 μm.

12. The hemostatic material according to claim 11, wherein the needle-punched nonwoven fabric, the spunlaced nonwoven fabric, the woven fabric, or the multi-layer nonwoven fabric has a grammage of 1 to 500 gsm.

13. The hemostatic material according to claim 1, wherein the hemostatic material absorbs 0.9% sodium chloride in physiological saline 5 to 40 times of the dry weight of the hemostatic material.