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Bio-Based Polymeric Hemostatic Material and Wound Dressing

Jianyun Lin , Shihe Luo , Chongling Yang , Ying Xiao , Liting Yang , Zhaoyang Wang

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 581 -595.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 581-595 DOI: 10.7536/PC200437
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Bio-Based Polymeric Hemostatic Material and Wound Dressing
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Abstract

The rapid hemostasis and healing of wounds have a very important effect on human life security and physical health. During the treatment process of wounds, careful, targeted, and effective treatment is required to prevent infection and accelerate tissue regeneration. Thus, the research on wound care materials attracted much attention. Among them, bio-based polymer materials extracted from animals and plants or synthesized from bio-based monomers, having the advantages of good physical properties, biological activity, biocompatibility, biodegradability and bioabsorbability, have been modified or drug-loaded by physical or chemical methods to produce hemostatic materials and wound dressings with functions of hemostasis, sterilization, protection and promotion of wound healing. Herein, we review the progress of domestic and foreign research on hemostatic materials and wound dressings based on common bio-based polymers, such as polylactic acid, chitosan, sodium alginate, hyaluronic acid, protein and polyphosphate in recent years from multiple angles of chemical composition, synthetic route, preparation method, material structure, evaluation model and biological activity. And the research level at home and abroad on these hemostatic materials from bio-sourced and renewable natural resources is also analyzed and compared. Predictably, the main research directions will still be further broadening the types of raw materials as well as making multifunctional and biomimetic materials.

Contents

1 Introduction

2 Polylactic acid materials

2.1 Polylactic acid

2.2 Polylactic acid-Polyethylene glycol

2.3 Poly(lactic acid-co-glycolic acid)

2.4 Other modified PLAs

3 Polysaccharides

3.1 Chitosans

3.2 Alginates

3.3 Hyaluronic acids

3.4 Celluloses

4 Proteins and polypeptides

5 Polyphosphates

6 Conclusion and outlook

Graphical abstract

Keywords

bio-based polymer / hemostatic material / wound dressing / polylactic acid / polysaccharides / polypeptides

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Jianyun Lin, Shihe Luo, Chongling Yang, Ying Xiao, Liting Yang, Zhaoyang Wang. Bio-Based Polymeric Hemostatic Material and Wound Dressing. Progress in Chemistry, 2021, 33(4): 581-595 DOI:10.7536/PC200437

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1 Introduction

Wounds can be divided into external wounds and internal wounds according to their location, and acute wounds and chronic wounds according to their healing speed. Different types of wounds need different dressings for symptomatic treatment[1,2]. Wound healing includes hemostasis, inflammation, re-epithelialization, angiogenesis, collagen deposition and matrix remodeling[1]. Therefore, the ideal wound dressing should support the whole process of wound healing to help achieve hemostasis, antibacterial, cell proliferation and tissue regeneration[3]. Uncontrolled bleeding from wounds, which accounts for 50% of all battlefield deaths and 39% of civilian trauma deaths, is the leading cause of trauma-related death and is one of the most challenging problems facing military and civilian medicine[4,5]. Soldiers can suffer from hemorrhagic shock within 10 minutes after trauma on the battlefield, and 35% of civilians die of hemorrhage within 15 minutes after admission, so early intervention to stop bleeding is very important[6,7]. In addition, the incidence of multiple complications such as diabetes and cancer is increasing, and the risk of wound healing dysfunction is also increasing, which makes wound treatment after hemostasis also particularly important[1,8].
Although wound dressings have been widely used in the battlefield and clinic, due to the limitations of many commercial dressings, such as irregularly shaped wounds deep in the body, which are not suitable for tourniquets, scientists and engineers have been working to develop more efficient, multi-functional and multi-target wound dressings[9][3,10]. At present, many kinds of wound dressings have been developed, such as foam, sponge, electrospun fiber film, film, powder particles and hydrogel, and the materials used are various. Among them, bio-based polymers such as polylactic acid (PLA), chitosan (CS), alginic acid (ALG), hyaluronic acid (HA), protein and polyphosphate (PolyP) have attracted much attention due to their good physical properties, bioactivity, biocompatibility, biodegradability and bioabsorbability[11,12]. Based on the research of our group in the synthesis and biomedical application of bio-based materials, especially the recent research of polylactic acid in hemostatic materials, as well as the latest research results at home and abroad, this paper focuses on the following aspects:In this paper, the composition, preparation methods, structure and biological activity of the biobased polymer hemostatic materials and wound dressings were reviewed and prospected, in order to provide a reference for the development of better hemostatic materials and wound dressings[13][14][15].

2 Polylactic acid

Polylactic acid (PLA) is a common bio-based polymer material, which is used to prepare wound dressings because of its excellent biodegradability, biosafety and easy modification[16,17][18⇓~20][21⇓~23][24][25]. In addition to pure polylactic acid (structure shown in Figure 1A) used in wound dressing research, common polylactic acid-polyethylene glycol (PLA-PEG, structure shown in Figure 1b) and poly (lactic acid-glycolic acid) (PLGA, structure shown in Fig. 1C) and more modified polylactic acid have attracted much attention in this field.

2.1 Pure polylactic acid

pure PLA fiber film can be used as wound dressing as Pure cotton gauze.Yagi et al.In Japan compared the hemostatic performance of non-woven PLA cloth developed by Toray Industries with that of common rayon gauze as wound dressing[26]。 When the two dressings were applied to the liver section of mice,it was found that the non-woven PLA cloth with a fiber diameter as low as 1μm was softer and More easily adhered to the wound surface than the rayon gauze with a fiber diameter of about 12μm.more importantly,the mean hemostasis time and mean blood loss were only 270 s and 0.7 G,respectively,for non-woven PLA cloth,and 495 s and 2.1 G,respectively,for rayon gauze.In addition,it was also observed under electron microscope that the adhesion of red blood cells on non-woven PLA cloth was significantly better than that on rayon gauze,indicating that pure PLA non-woven cloth can be used as a hemostatic material for incompressible bleeding sites such as minimally invasive liver surgery。
If the fiber size of the dressing is reduced from micron to nanometer,the degradation and absorption time of PLA hemostatic materials In vivo can be shortened,but it will bring the problem that PLA dressings are easy to burst.In order to overcome this shortcoming,Okamura et al.In Japan prepared a multilayer film of poly(L-lactic acid)(PLLA)and sodium alginate(ALG)alternately,and then eluted the ALG layer to prepare a multilayer PLLA nanosheet with high adhesion and good flexibility.the thickness of the nanosheet can be as low as 230 nm.When used as a hemostatic dressing,it can reduce tissue adhesion after liver injury[27]。
Ding Jianxun et al.,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,physically loaded 10 wt%atorvastatin on pure PLA,and the porous PLA membrane prepared could prevent the bridge connection of fibrin between damaged tissue and surrounding tissue,and could also effectively prevent peritoneal adhesion,which could prevent common postoperative complications such as organ dysfunction[28]。 Physical loading of conventional hemostatic agents not only prevents tissue adhesion,but also improves the hemostatic effect of PLA.Gong Guifen of Harbin University of Science and Technology and others loaded polysaccharide extracted from bletilla striata on PLA non-woven fabric dressing,and the bleeding time and blood loss of the dressing in rabbit ear artery bleeding model test were 19 min and 2 mL,while those of the saline control group were as high as 60 min and 7 mL,respectively[29]。
Schneider et al in Germany physically blended poly(L-lactic acid-co-racemic lactic acid)with adrenaline(AD)and tranexamic acid(TA)hemostatic agents respectively to prepare thin and soft electrospun fibrous membrane dressings[30]。 The test results showed that the loading of AD and TA on the dressing could be as high as 20 wt%and 50 wt%,respectively,and the release rate could reach 50%and 85%,respectively.The tensile strength of the dressing can reach more than 14 MPa,the cytotoxicity is low,the hemostasis speed is fast,and the dressing is especially suitable for the conditions that the operation passage is small and the wound dressing is difficult to fix in otorhinolaryngology surgery.Recent studies have shown that pure PLA fibers loaded with three-dimensional porous metal-organic framework Ag+ions can also continuously kill bacteria such as EC and SA,and significantly accelerate the healing of infected wounds in rats[31]。
On the basis of PLA fibers,hemostatic materials with other shapes can also be prepared.For example,Lee et al.In Korea prepared a gel particle by coating the electrospun PLA fiber with a mixture of hyaluronic acid and ferric chloride[32]。 the gel particle can target and aggregate at a bleeding position like platelets unde that action of an external magnetic field to generate a stable artificial thrombus,and can improve the modulus of the thrombus by 300%and the hardness of the thrombus by 50%,thereby playing a role similar to that of fibrin in increasing the strength of thrombus and contributing to the hemostasis proces。
American Lavik et al developed a hemostatic nanoparticle directly using pure PLA particles as the core and adhesive polypeptide as the shell[33]。 Compared with the blank group,the particles could reduce the amount of bleeding in the wound of mice and improve the survival rate of injured mice.More importantly,these particles can still maintain the original spherical powder of 100~500 nm after storage at 50℃for 7 days,and can still effectively stop bleeding and improve survival rate in rat liver injury model test,indicating that the PLA hemostatic material is expected to play a good hemostatic effect in harsh storage and use environments,such as the Afghan battlefield where the temperature is as high as 50℃。

2.2 Polylactic acid-polyethylene glycol

Due to the poor toughness,poor hydrophilicity and low degradation rate of pure PLA,in order to expand its application range,polyethylene glycol(PEG)with better hydrophilicity is used to modify PLA,which can make PEG-modified PLA blends or copolymers more widely used in the biomedical field than pure PLA[34][35][36][37]。
Blending is a common,simple and effective method.For example,Rashkov et al.in Bulgaria dissolved PLA and PEG2000 in a mixed solvent of dichloromethane(DCM)/dimethyl sulfoxide(DMSO)at a mass ratio of 80%:20%,and then added small molecule drugs such as diclofenac sodium(DS),lidocaine hydrochloride(LHC),benzalkonium chloride(BC)or DS/LHC,DS/LHC/BC combinations to prepare electrospun fiber membranes[38]。 the results of in vitro drug release test showed that the release rate of the samples loaded with combined drugs was slower than that of the samples loaded with single drug,which may be due to the ionic interaction between the drugs,which provided a new idea for adjusting the release rate of drugs on wound dressings。
Phaechamud in Thailand also carried out a similar blending study.They added 15 wt%gentamicin sulfate(GS)or 3 wt%metronidazole(MZ)to the DCM mixed solution with a mass ratio of PLLA:PEG400 of 40%:60%,and then evaporated the DCM at 60℃using a glass plate coating method to prepare a drug-loaded porous membrane[39]。 the pore size of the membrane was about 20μm,and the porosity was about 50%.the crystallization rate,water vapor/oxygen permeability,degradation rate and drug release ability of the membrane were improved compared with those of PLLA membrane.the GS-loaded porous membrane had inhibitory effect on Staphylococcus aureus(SA),Proteus mirabilis and Pseudomonas aeruginosa,and the MZ-loaded porous membrane had inhibitory effect on Bacteroides fragilis,and the antibacterial activity lasted for 7 days.Therefore,the PLA-based antibacterial porous film can be used as a dressing for wound treatment。
Moreover,Phaechamud et al.Also studied the pore formation mechanism of PLLA-PEG400 porous membrane[40]。 They found that When the volatile residual mass of DCM was 2.67 times that of PEG400,the PLLA-PEG400 solution began to phase separate.when the residual mass of DCM is equal to that of PEG400,the solvent phase begins to tend to a regular round pore shape.Therefore,the structure of the porous membrane can be controlled by adjusting the type,ratio and volatilization rate of the polymer and the solvent to obtain wound dressings with different air permeability,degradation rate and drug release rate。
the PLA-PEG block copolymer prepared by the chemical modification also has good biocompatibility,can not cause the dissolution of red blood cells or the change of the conformation of fibrinogen,and can be used for preparing wound dressings[41]。 For example,Xu Kaitian et al.of Shantou University grafted butanediol at the end Of PLA,and then reacted with PEG6000 terminated by hexamethylene diisocyanate to produce alternating block copolymers(alt)or random block copolymers(ran)[42]。 because the structure of alt is more regular,the test results show that the crystallization and mechanical properties of alt are better than those of ran.At the same time,the hydrophilicity,water absorption,cell compatibility and therapeutic efficacy of alt were also better than those of ran.the reason may be that the alternating structure can enhance the phase separation,which not only induces more PEG-segments to aggregate on the surface of the material,but also provides a rougher surface.Histological analysis of animal experiments shows that both alt and ran have better therapeutic effects than gauze when used as wound dressings,Because they can provide a well-hydrated environment without the risk of dehydration,which is conducive to cell attachment,survival and proliferation。

2.3 Poly(lactic-co-glycolic acid)

PLGA is a recognized,mature,biodegradable and biocompatible PLA-based modified copolymer with excellent physical and mechanical properties,which has been approved by the Food and drug Administration of the United States for a wide range of biomedical applications,such as Drug loading,surgical sutures,tissue anti-adhesion barriers and other in vivo implants[43][44][45]。 Of course,it is also often used to prepare wound dressings,but it usually needs to be modified to improve its hydrophilicity or tissue adhesion[46][47]。 Among them,blending with natural polymer materials is a common method[48]。
Liu Shirong,Taiwan,China,found many years ago that the electrospun nanofiber membrane of PLGA/collagen(COL)blend could promote the healing of open wounds in rats[49]。 the PLGA hydrogel dressing loaded with platelet lysate prepared by Ganem-Rondero et al.in Mexico through the double emulsion solvent evaporation method can provide a semi-closed moist environment In the mouse skin defect model test,which makes the wound disappear significantly from the 7th day,and no mice show significant weight loss or infection[8]。
Gelatin(GEL)can be used to improve the swelling,hydrophilicity and degradability of PLGA.For example,Castell-Rodriguez et al.in Mexico prepared electrospun wound dressings with PLGA:GEL ratios of 9:1,7:3,and 5:5,and observed that cells on the 7:3 dressing had the most significant proliferation rate and could be completely degraded and disappeared by the eighth week of the animal In vivo experiment[50]; Huang Yubin,Changchun Yinghua Institute,Chinese Academy of Sciences,used PLGA/GEL electrospun fibers loaded with cisplatin as the skeleton,put them into the acetic acid GEL solution of CS/GEL blend,and addedβ-disodium glycerophosphate to adjust the pH value of the GEL solution to neutral.CaCl2was added to improve the hemostatic effect,and then genipin was used as a crosslinking agent to crosslink the fiber skeleton with the gel solution,and finally the sandwich sponge/fiber/sponge composite(CFSC)was prepared by freeze-drying[51]。 the sponge structure of CFSC can not only achieve rapid hemostasis of surgical wounds,but also absorb the spread of tumor cells during the operation to prevent the risk of distant metastasis caused by tumor cells entering the blood.Its fibrous skeleton can maintain the strength of the material and continuously release cisplatin to kill tumor cells,which can be used as a hemostatic and chemotherapeutic synergistic scheme for tumor resection。
Israel Zilberman et al.loaded GS on the composite material of porous PLGA surface layer and spongy COL bottom layer,and irradiated it with different doses of gamma rays,and found that the irradiation dose of 10 or 25 kGy at room temperature did not bring significant changes to the drug release,water absorption,air permeability and mechanical properties of the composite material.the results showed that it was feasible to use PLGA as wound dressing withγ-ray sterilization,which could promote the application of PLGA in the field of wound care,especially in the field of burn wound care[52]。
Soleimani et al.In Iran prepared a core-shell fibrous membrane coated with epidermal growth factor(EGF)on the core of PLGA/GEL,and found that the mechanical properties of this fibrous membrane were similar to those of human skin,compared with commercial wound dressings.It not only has more excellent blood coagulation and platelet adhesion functions,but also has the ability to encapsulate and release EGF,and has higher COL expression ability,which is an ideal material for skin tissue engineering scaffolds and wound dressings[53]。
There are also reports about the application of PLGA blended with synthetic polymers or inorganic materials.For example,Han Zhichao et al.,Institute of Chemistry,Chinese Academy of Sciences,made a hemostatic material by coating a sponge layer of carboxymethyl chitosan(CMC)containing glycerol on a fibrous membrane made of PLGA and PLA-PEG blends,and found that the material could easily adhere to the wound surface and had good hemostatic ability[54]。 the intestinal tissue adhesion was reduced from 93%in the blank control group to 17%in the rat model of intestinal wall defect 10 days after operation,which indicated that the hemostatic material had good anti-adhesion effect。
Jia Weitao of Shanghai Jiaotong University prepared a new type of organic/inorganic composite dressing by loading Cu2+and vitamin E(VE)on PLGA/borate cotton-like composite fibers[55]。 The results of in vitro test showed that the dressing could release Cu2+and VE in a controlled manner.The results of wound healing test of full-thickness skin defect in mice showed that the dressing could significantly enhance the secretion of vascular endothelial growth factor,the expression of angiogenesis genes,the formation of venous endothelial cells and the growth of skin epithelial cells,and was a promising wound dressing.Similarly,Zhang Hongbo et al.Of East China University of Science and Technology loaded andrographolide on PLGA/nano-mesoporous silica composite fibers,and the mechanical properties and hydrophilicity of the composite dressing were better than those of pure PLGA.And in a mouse back full-thickness skin defect model test,obviously shows better antibacterial,re-epithelialization promoting and wound healing functions than a blank control group[56]。
There are also related research reports on the application of PLGA after chemical modification.For example,Feng Yakai of Tianjin University developed a fiber fragment(PLGA-HA FFS)by grafting hyaluronic acid(HA)on the surface of PLGA,and found that the loading rate of azithromycin(AZ)on PLGA-HA FFS could reach 83%,and it could be released continuously in 21 days of in vitro drug release test[57]。 AZ-loaded PLGA-HA FFS had a hemostatic time of(28±2)s in a mouse liver injury hemostatic model test,compared with(50±7)s or more for a commercial hemostatic agent.at the same time,its hemolysis rate is less than 2%,which is lower than the generally accepted 5%hemolysis rate.It can also promote the growth of L929 cells,bring no obvious toxicity to RAW264.7 cells,promote the secretion of anti-inflammatory cytokine IL-10 and inhibit the secretion of proinflammatory cytokine TNFα.Therefore,this scheme can achieve multiple functions such as effective hemostasis,anti-infection and immune regulation At the same time。

2.4 Other modified polylactic acid

In addition to the common PLA-PEG and PLGA materials,scientists also use a variety of substances to modify PLA to prepare wound dressings.Among them,ester compounds are often used to blend with PLA to prepare medical dressings because they contain a large number of ester groups and have good compatibility with PLA[58]。 Polycaprolactone(PCL)is one of the most commonly used PLA modified polymers,because it not only has the advantages of biocompatibility and biodegradability,but also has good elastic and mechanical properties,especially suitable For improving the brittleness of PLA.In order to solve the antibacterial problem of PLA/PCL blend dressings,antibacterial agents can be added.for example,Chen Xiaoming of Guangzhou Medical University used PLA/PCL blended nanofibers loaded with silver ions to make dressings that not only have good hydrophilicity,water absorption,moisture retention and air permeability,but also can effectively kill SA and Escherichia coli(EC)[59]。 Khan et al.In Pakistan prepared a biomimetic extracellular matrix bilayer dressing with PLA on one side and PCL on the other side,and both sides were loaded with VE acetate[60]。 They found that the addition of VE acetate increased the degradation rate of PLA and PCL,but did not affect the ability of the dressing to absorb water.the results of chicken fertilized egg development test showed that the double-layer dressing containing VE acetate could promote the growth of blood vessels.Edirisinghe et al mixed hydrophilic bacterial cellulose(BC)into the mixture of PLA and PCL with a mass ratio of 70%:30%,and made the PLA/PCL/BC ternary mixture into a tubular nonwoven fiber wound dressing.They found that when the content of BC was as high as 30 wt%,the dressing still had good physical strength[61]。 However,in the binary blend of PLA/BC,the strength of the material decreases significantly when the BC content is more than 10 wt%,which proves that PCL contributes to the expansion of the application of PLA materials。
There have also been reports of the use of other ester polymers with PLA to prepare wound dressings.for example,Chen Haiyun et al.of Yunnan University For Nationalities mixed PLA and poly(trimethylene carbonate)at a mass ratio of 70%:30%to make a film dressing[62]。 They found that the dressing had good breathability and comfort(elongation and deformation properties).in vivo experiments in mice showed that the dressing not only had a positive effect on wound hemostasis and infection prevention,but also promoted the growth of L6 cells,fibroblasts and epidermal stem cells in the wound.the test results of 11 indexes such as immunoglobulin,transaminase and creatinine in the blood of mice showed that the dressing was harmless to the liver and kidney of mice,and showed good biodegradability and biocompatibility。
Most of the polyhydroxy compounds have good hydrophilicity and can also be used to improve the properties of PLA medical materials.Among them,natural cellulose and its modified substances can be used to modify PLA to prepare wound dressings with good performance[63]。 For example,Lin Jiahong of Tianjin University of Technology mixed PLA fiber,natural cotton fiber and natural Tencel fiber to make non-woven fabric,and then coated CS/nano-silver antibacterial coating on the surface of non-woven fabric to make antibacterial hemostatic dressing[64]。 the hemostatic time of the dressing in the rat femoral artery injury model test was about 180 s,which was significantly shorter than 380 s of cotton cloth,and it could resist bacteria continuously。
El-Sherbiny et al.,Egypt,added 3 wt%hydrophobic thymoquinone(TQ)antibacterial agent to a solution of PLA and cellulose acetate(CA)with a mass ratio of 70%:30%to prepare a nanofiber membrane dressing[65]。 Due to the good hydrophilicity of CA,the In vitro release rate of TQ in the dressing could reach 55%within 24 H,and the inhibitory zone on the formation of SA and EC could be clearly observed in the disc diffusion antibacterial test.in the wound healing test on the back of mice,the dressing could increase the cell proliferation rate to 60%at 7 days,increase the re-epithelialization of tissues and the formation of granulation tissue,and significantly promote wound healing。
Hydrophilicβ-cyclodextrin(β-CD)derived from the hydrolysis Of starch can also modify PLA-based dressings.Liu Yaowen et al.of Sichuan Agricultural University prepared PLA/CI/β-CD composite dressing by embedding organic antibacterial agent cinnamaldehyde(CI)withβ-CD and then blending it with PLA[66]。 the results showed that the water contact angle of the dressing was about 19.2°(the water contact angle of PLA was about 100°under the same test conditions),and the dressing had appropriate hydrophilicity,so that the release rate of CI in 20 H was controlled at about 60%,and the cytotoxicity of less than 3%cell mortality was achieved while the sterilization rate was more than 80%。
In addition to the natural source polyols described above,synthetic polyols can also be used to modify PLA wound dressings[67]。 For example,an asymmetric hydrophobic/hydrophilic fibrous membrane dressing with PLA on one side and polyvinyl alcohol(PVA)on the other side prepared by Goyanes et al.In Argentina has a water contact angle of 122°on the PLA side and a water contact angle as low as 44°on the PVA side,enabling the dressing to achieve both wound exudate absorption and water loss control[25]。 In addition,the dressing has a O2permeability of up to 65%and low cytotoxicity,which contributes to wound healing 。
Doble et al.In India added 10 wt%curcumin(Cur)to a solution of PLA and hyperbranched polyglycerol(HPG)at a mass ratio of 80%:20%to prepare a nanofiber membrane dressing[68]。 the water contact angle of the dressing is 68°,which is obviously lower than 108°of PLA under the same condition,and the dressing has better hydrophilicity;the 12 H release concentration of Cur can reach 25μg/mL,which can eliminate wound inflammation and promote wound cell adhesion,survival and proliferation,so it has potential advantages as a wound dressing for the treatment of acute/chronic diabetic patients。
Zhou Changren et al.Of Jinan University prepared nanofibers by blending octa-(3-hydroxypropyl)-polyhedral oligomeric silsesquioxane(POSS)functional nanoparticles with PLLA[22]。 They found that POSS not only enhanced the strength and toughness of PLLA,but also helped to form porous fibers.the PLLA/POSS dressings were tested in a full-thickness skin injury model in mice,and the results showed that PLLA/POSS dressings contributed to the growth of blood vessels,showing their potential applications in wound healing and regenerative medicine。
Many amine compounds have biological activity,which can be used to prepare dressings with PLA to obtain more biological properties.For example,GEL is a product of natural collagen after partial hydrolysis and contains a variety of amino acid units.Zhang Xinqiong of Anhui Medical University and others have confirmed in clinical trials that the blending bionic nanofiber membrane with a mass ratio of PLA to GEL of 70%:30%can promote the re-epithelialization of varicose ulcer wounds of lower limbs,accelerate the scab formation of wounds,significantly shorten the healing time of wounds and reduce the number of dressing changes[69]。
As a bio-based polymer,polydopamine(PDA)was deposited on the surface Of PLLA-poly(citric acid-siloxane)fibers loaded with Cur by Leibo et al.of Xi'an Jiaotong University,and then elastic dressings were prepared[70]。 The water contact angle of the dressing was about 72°,which could provide suitable cell adhesion.The maximum tensile strength of the dressing was(3.41±0.05)MPa,which was equivalent to that of normal skin.In the whole blood coagulation test,the blood coagulation index(BCI,the lower the value,the better the coagulation effect)was significantly lower than that of gauze.In the model test of full-thickness skin defect on the back of mice,the wound could be completely healed within 11 days,while the commercial 3M TegadermTMgroup needed 16 days.Moreover,the results of histological examination showed that it had no toxicity in vivo to key organs such as liver,spleen,kidney,heart and lung in mice.More importantly,in the photothermal chemotherapy test,the temperature of the dressing can be rapidly increased and stabilized at about 48 deg C,the viability of A375 melanin tumor cells can be reduced to 12.8%,the free radical clearance rate can reach 93.9%,and the skin tissue damage is little,which indicates that the dressing can be used as a multifunctional bioactive wound dressing in the treatment of wounds caused by skin tumors and bacterial infections 。
Bulgaria Rashkov et al.polymerized N,N-dimethylamino-2-ethyl methacrylate(DMAEMA)and then reacted with PLLA(or poly-D-lactic acid)to prepare two diblock copolymers(the basic structural formula is shown in Figure 2a)[71]。 Due to the existence of a large number of N,N-dimethylamino groups in the polymer,the electrospun fibers made of these copolymers have hemostatic and antibacterial properties。
Recently,our group used tranexamic acid(TA)and aminomethylbenzoic acid(ABA),which are clinically mature small molecular hemostatic drugs,as comonomers of lactic acid monomer(LA),respectively,through a direct melt polycondensation method.A series of polylactic acid-based hemostatic particles with molar ratios of n(LA)/n(TA or ABA)of 95/5,90/10,80/20,70/30,60/40 and 50/50 were prepared,and the products were confirmed to be copolymers P(LA-co-TA)or P(LA-co-ABA)of LA and TA or ABA by infrared spectroscopy and nuclear magnetic resonance(NMR)[14,72]。 these particles have a diameter of about 8 to 30μm,an irregular shape,and a moderate pore structure.in the whole blood clotting time test,the hemostatic time of some hemostatic particles is equivalent to that of TA or ABA monomers,showing good hemostatic performance.In the porcine model of liver incision bleeding,some hemostatic particles can quickly absorb wound exudate and achieve hemostasis,and form a layer of blood scab wound protective film with good adhesion within 5 minutes.In addition,These materials showed good degradation properties In PBS buffer solution at 37℃and pH=7.4,and could release TA or ABA hemostatic monomers continuously,thus providing long-term hemostatic function。
Jia Qingxiu of Beijing Institute of Fashion Technology first synthesized bio-based polyamide(BDI)with itaconic acid,decanediamine and butanediamine by direct melt polycondensation,and then made PLA/BDI/PLA three-layer fibrous membrane medical dressing with silver ions together with PLA[73]。 the dressing has no toxicity in the cytotoxicity test,the relative cell growth rate can reach the level of grade 1(75%to 99%),and the dressing can obviously inhibit the growth of fusobacterium nucleatum for a long time。

3 Polysaccharide

3.1 Chitosan

Chitosan(CS),as a kind of biomass resource,can be obtained by deacetylation of chitin or extraction from fungi,and has a wide range of uses,especially in food,medicine and other fields[74][75][76][77][78]。 Among them,the wound dressing made from CS has the advantages of hemostasis,biodegradability,biocompatibility and antibiosis[79]。 For example,Abacioglu et al.in Turkey tested the rat femoral artery bleeding model and found that within the first 4 minutes of the experiment,the hemostatic rate of the pure CS group was 90%,while that of the blank control group and the commercial hemostatic agent Ankaferd group was 40%and 100%,respectively[80]。
Chitosan with a degree of deacetylation of 11.69%±0.14%was extracted from dung beetles by Ma Jiahua et al.of Southwest University of Science and Technology.the hemostatic time in The mouse liver bleeding model was(37.60±4.39)s,while that of medical gauze was(152.80±12.83)s[81]。 Hu Zhang of Guangdong Ocean University used plasma recalcification analysis to compare the coagulation effects of various CS,and found that CS with high molecular weight(105~106g·mol-1)and narrow distribution of medium deacetylation degree and its acid salt had strong procoagulant effect[82]。 in conclusion,the hemostatic mechanism of CS is independent of the patient's own coagulation pathway and function,which makes this natural material have great potential for development In hemostatic applications[78]。
in addition,pure CS itself can also be used For blood coagulation after loading drugs,so that the material is multifunctional.for example,He Xiuxia of Changchun University of Science and Technology made porous xerogel by loading rosemary extract on pure CS with different molecular weights,and found that all samples had obvious bacteriostatic effects on SA,EC and Salmonella,and there was little difference In bacteriostatic effect between low molecular weight CS and high molecular weight CS[83]。 At the same time,the BCI of high molecular weight CS is about 20%lower than that of low molecular weight CS,and it has better coagulation effect,which is consistent with the results of Hu Zhang et al[82]。
Moreover,the modification of CS with different substances can also make the material obtain more functions,which shows a good application prospect in reducing wound infection and accelerating wound healing,and is a current research hotspot.For example,King et al.in the United States introduced an N-octadecylbenzene side chain with a substitution degree of 2.5%to the CS main chain through 4-octadecylbenzaldehyde,and the resulting modified CS powder showed rapid hemostasis,reduced blood loss,and increased survival rate in a mouse model of severe liver injury and bleeding[84]。 Although alkylation of CS can improve its hemostatic activity,long alkyl chains can reduce the hydrophilicity of CS。
Hydroxylation of CS with hydroxyl compounds can not only improve its hemostatic activity,but also maintain its hydrophilicity[85]。 Among them,the reaction of phenolic acid compounds(such as gallic acid)with free amino groups of CS is one of the chemical modification methods to introduce phenolic hydroxyl groups into CS to achieve hydroxylation[11]。 For example,Lee et al.In Korea prepared hydrogel dressings with good hemostatic properties by introducing catechol hydroxyl groups to the CS backbone through hydrogenated caffeic acid[86]。 However,the modified CS with high positive charge content can cause uncontrolled adsorption of immune proteins,which can lead to inflammatory immune response in vivo,and should be overcome in clinical application.Therefore,Lee et al.Introduced a large number of ethylene glycol side groups to the CS backbone,which effectively reduced the immune response of the tissue while maintaining the hemostatic efficacy[87]。 This is because ethylene glycol units can form a surface hydration layer tightly through hydrogen bonding,which prevents the non-specific adsorption of immune proteins and bacteria。
It has also been reported that natural polyhydroxy polymers can be used to modify CS to maintain its hemostatic activity and improve its hydrophilicity.Among them,the common modification method is blending[88]。 For example,Wang Lianyong of Nankai University prepared a hydrophilic hydrogel dressing by blending N-dodecyl CS with oxidized dextran,which showed good hemostatic activity in vivo in the rat liver injury bleeding model test.it also showed good tissue adhesion,cell compatibility,granulation growth and collagen deposition in the model test and tissue section examination of rat infected full-thickness skin defect,and the killing rate of SA and Pseudomonas aeruginosa reached 95.0%and 96.4%,respectively,so It had the application potential of hemostasis and wound infection prevention[89]。 Elsabahy et al.Made a hydrogel dressing by blendingβ-CD polyester with CS.The hemostatic time of the dressing in rat,rabbit and pig wounds was about 30,150 and 30 s,respectively,while that of the corresponding commercial wound dressing Surgicel®was as high as 90,260 and 95 s,respectively[90]。
Poly(vinyl alcohol)is a kind of non-toxic and water-soluble polymer,which is widely used in vacuum suction dressings,implantable medical devices and other fields.It can also be used to modify CS,especially to obtain hemostatic materials by blending method[91][92]。 For example,Indian Datta et al.Made a fibrous hemostatic material from a mixed solution of CS,PVA and TA.TA was dispersed in the fiber in solid form,and its release rate could reach 90%in 10 H[93]。 In the whole blood clotting time test,the clotting time of the sample group was only(167±6)s,while that of the blank control group was(253±6)s.Zhao Xiaoli et al.,Chinese Academy of Sciences,used sodium tripolyphosphate as a crosslinking agent to prepare hemostatic microspheres with diameters of 0.4~1.1 mm after chemical crosslinking modification with PVA and CS[94]。 in the whole blood clotting time in vitro and rat liver bleeding model test,the clotting time of the sample group was 38%and 37%shorter than that of the gauze control group,respectively.In the rat femoral artery bleeding model test,the formation of thromboembolism in the sample group was also significantly less than that in the pure CS group,indicating that PVA crosslinking helps to improve the swelling degree of CS and improve its hemostatic performance。
Amine compounds,especially some natural basic amino acids,can provide raw materials For tissue growth and help wound healing,and can be used to modify CS wound dressings.for example,Jing Miaolei of Tianjin University of Technology introduced arginine into the amino group of CS through amide bond,which improved the antibacterial and tissue adhesion of CS,and reduced the coagulation time of rabbit whole blood from 201 s in the blank control group to 145 s in the sample group[95]。 Taheri et al.in Iran attached arginine to the surface of CS by electrostatic interaction and prepared a modified CS nanofiber dressing with an average fiber diameter of 100-150 nm.the dressing is easy to apply to the wound site,sustainably releases arginine,and in vivo experiments and histological examinations in rats,the ability of the sample group to re-epithelialize,deposit collagen,and generate blood vessels is significantly enhanced compared to the blank control group[96]。
Moreover,natural amine polymers,especially amino acid-based peptides and proteins,can be used to modify CS to prepare blood coagulation materials[3]。 For example,Li Chengpeng et al.Of Guangdong Ocean University mixed CS microspheres encapsulated with tilapia peptide(TP)with pure CS solution and freeze-dried them to make spongy wound dressings[97]。 Because TP is a substance with good hemostatic and tissue repair activity,the dressing has good water absorption and platelet adhesion properties,can promote the formation of fibrin,and has no cytotoxicity.in the rabbit femoral artery bleeding model test,the hemostatic time of the dressing was significantly shorter than that of CS,and the amount of bleeding was also significantly reduced.Chinese Academy of Medical Sciences Wang Hong et al added silk fibroin,which can regulate the release of growth factors,to CS by solution method,and the hemostatic time of the composite material was as low as(48±7)s In the hemostatic test of rat superficial thoracic and abdominal vein model,while that of pure CS was as long as(132±17)s[98]。
Similarly,biobased polymeric amine PDAs are a good source of CS-modifying materials.Li Jiwei of Qingdao University and others first dropped the mixed solution of CS and pentasodium tripolyphosphate into CaCl2solution to prepare hybrid micro-flowers(CS-CaP),then immersed CS-CaP into PDA solution and freeze-dried to prepare flower-like hemostatic materials[99]。 the clotting time of the material was only about 85 s In the rat model of tail-cut hemorrhage,which was significantly shorter than that of the blank control group(430 s).the results of morphological tests show that blood cells and platelets can be easily induced to aggregate on the surface of the material due to the synergistic effect of chemical activation,high hydrophilicity and special structure of the material,thus showing excellent hemostatic properties.in the fibroblast culture test,the material has no cytotoxicity and shows good biocompatibility。
Some synthetic functional amine polymers can also be used to modify CS.For example,Guo Baolin et al of Xi'an Jiaotong University first grafted(2,3-epoxypropyl)trimethyl ammonium chloride and polyaniline onto CS(the preparation route is shown in Figure 3A,and the product is named as QCSP),and then crosslinked with benzaldehyde functionalized polyethylene glycol-poly(sebacate-glycerol)ester(the preparation route is shown in Figure 3B,and the product is named as PEGS-FA)to prepare a self-healing hydrogel dressing[12]。 the rapid self-healing property of the hydrogel is derived from the dynamic covalent Schiff base network between the amine group of QCSP and the benzaldehyde group of PEGS-FA.Due to the intrinsic kinetic equilibrium,the Schiff base can be considered as a quasi-covalent bond,so that the cleavage and regeneration of the imine bond always occur in the hydrogel network.the CS-modified dressing can achieve rapid hemostasis,up-regulate the expression of various genes and promote wound healing,and also has a bactericidal rate of up to 99%,a free radical clearance rate of 84%and a biomimetic level of physical strength。
In addition,Guo Baolin et al.Also introduced glycidyl trimethyl ammonium chloride and glycidyl methacrylate into the CS molecular chain through a one-pot method,and used carbon nanotubes to reinforce the material to prepare an injectable conductive low-temperature gel[100]。 the gel has the characteristics of good mechanical property,quick blood triggering shape recovery,quick blood absorption speed,good near infrared response and the like,has better hemostatic effect than commercial hemostatic materials in a plurality of hemostatic test models,and proves that the gel has great potential in the aspects of hemostasis of fatal non-compressive bleeding and wound healing in vivo。
Other types of polymers containing amine groups have also been reported to modify CS.For example,Zhao Xuanhe et al.in the United States prepared a dry double-sided tape tissue adhesive dressing by mixing cross-linked polyacrylic acid and CS grafted with N-succinimide ester with functional additives such asα-ketoglutaric acid through solution,forming In a glass mold,and then irradiating and drying with ultraviolet light[101]。 In vivo animal experiments show that the dressing can achieve strong adhesion to a variety of wet tissues within 5 s,because it can remove the interfacial water on the tissue surface,produce rapid temporary cross-linking with the surface,and then covalently cross-link with the amine groups on the tissue surface,further improving the adhesion stability and strength。

3.2 Alginate

Alginate(ALG)is also a common natural polysaccharide.as a bio-based polymer material,ALG has good biocompatibility and a series of unique biological activities,which can provide a variety of physical and chemical protective functions such As hemostasis,bacteriostasis,wound healing and so on.Clinical trials have confirmed that even dressings made of pure ALG can significantly reduce the amount of bleeding during tumor surgery[96]。 the hemostatic time of pure ALG was(55.3±5.1)s(shorter than that of gauze(101±14.7)s),and The bleeding volume was 2.4±0.2 s(less than that of gauze(3.9±0.2)s)[103]。 These results provide a basis for ALG to be further developed into various hemostatic materials,so it is widely used in hemostatic materials,but usually needs to be modified for application[104][105]。
Because pure ALG has poor water solubility and mechanical strength,it needs to be modified to expand its application[106]。 the mechanical properties of ALG and the drug loading properties of its aqueous solution or hydrogel can be improved by the reaction and crosslinking of the hydroxyl groups on the polyhydroxy polymer with the carboxyl groups on ALG.Based on this chemical modification principle,Italian Catanzano et al.used gluconolactone to crosslink ALG and HA,loaded TA on the ALG/HA crosslink,and prepared macroporous ALG/HA/TA sponge dressing by freeze-drying method.the whole blood clotting time test confirmed that the dressing not only contributed to drug loading and release,but also significantly accelerated the coagulation process[107]。
Collagen(COL)is a natural macromolecular amine compound,which can also be used to improve the performance of ALG hemostatic materials[108]。 Jin Jia of Zhejiang University of Science and Technology found that the addition of 1 wt%COL could significantly improve the platelet aggregation,adhesion and activation ability of ALG/CMC composite to achieve rapid hemostasis,and could be degraded in vivo without causing immune response and inflammation in rat experiments[109,110]。 Furthermore,Wu Hao et al.of Shanghai Jiaotong University studied the effects Of various components in the composite material,and found that when the COL content was reduced to 0.5 wt%in 99 wt%ALG,the ALG/CMC/COL hemostatic powder prepared by emulsification/crosslinking method was typical spherical with narrow size distribution,had good water absorption,could be rapidly degraded in vitro and in vivo,and had no toxicity to human skin fibroblasts[111]。 Its BCI was 37.2%,which was significantly lower than that of pure ALG(91.7%).the blood loss was(0.15±0.04)mL and(0.34±0.09)mL in rat liver and tail-cut bleeding model,respectively,which was lower than that of The blank group(1.15±0.13)mL and(4.71±0.91)mL,so it was a hemostatic material with good comprehensive performance。
the lone pair electrons on the N atom of small molecular amine compounds can combine with the carboxylate ions on the ALG molecular chain to form a quaternary ammonium structure with bactericidal function.Based on this,Daemi et al.in Iran prepared ALG wound dressings modified with tributylamine,which exhibited good killing properties against SA and EC and healing promoting properties for full-thickness skin wounds In mice[112]。
Aldehydes can also crosslink with the hydroxyl groups of ALG to improve the water solubility of ALG.For example,Liu Lin of Zhejiang University of Science and Technology made fibers from ALG,CaCl2and sulfonamide mixed solution by wet spinning method,and then crosslinked the fibers with glutaraldehyde at 50℃for 4 H,and dried them to make gel fiber dressings[113]。 the test results showed that the mechanical properties of aldehyde crosslinked ALG were improved,the drug release time was longer,the cell adhesion and proliferation performance was better,and it was more suitable for wound dressing than pure ALG。

3.3 Hyaluronic acid

hyaluronic acid(HA),also known as Hyaluronic acid,is a linear anionic natural polysaccharide widely found in the lubricating fluid around articular cartilage,eyes and skin of human and animals,which can control the assembly of immune cells,release inflammatory cytokines and balance hemostasis,and can be used to prepare wound dressings,which can be easily absorbed by human body after degradation in vivo[114][115][15]。
However,due to the rapid decomposition of pure HA by HA enzyme in vivo,the half-life of pure HA in tissues is very short,which limits the wide application of pure HA in the field of medicine,so HA-based hemostatic materials are often modified.For example,Yang Li et al of Chongqing University made nanofibers from the blend of HA and polyester PCL,and loaded EGF to make wound dressings,which showed the function of accelerating skin regeneration in the rat full-thickness skin defect model test[116]。 If HA is modified by blending poloxamer with polyether polymer,it can not only promote the healing of skin wounds,but also improve the moisture retention and air permeability of dressings[117]。 Li Faxue et al of Donghua University mixed methacrylic acid-terminated PEG with HA grafted with aminoethyl methacrylate,and then loaded chlorhexidine acetate(CHX)to prepare a hydrogel,which not only had a BCI as low as 32%,but also could accelerate the wound healing on the back of mice,and could release CHX continuously within 10 days to exert antibacterial properties[118]。
Various natural starches or other polysaccharides can also be used to modify HA to obtain hemostatic materials.For example,Yang Wenzhi et al.of Hebei University grafted HA onto pullulan(Pu)to make a layered sheet porous membrane dressing with good liquid absorption,which shortened the clotting time of rabbit blood by 27.4%compared with the blank group.It did not cause erythema and edema on the skin of mice after 48 hours,and the healing degree in the rat full-thickness skin defect model test was significantly better than that in the blank group[119]。
Similarly,GELs derived from the degradation of natural collagen,which contain a variety of amino acid units,can also be used to modify HA-based hemostatic materials.For example,Sun Yulong et al.of the Chinese Academy of Sciences prepared an injectable hydrogel dressing by in-situ chemical crosslinking with HA,and found that the dressing could be degraded by trypsin and had good tissue sealing ability.It can effectively stop bleeding in 30 seconds in the rat liver bleeding model,which is significantly shorter than the 90 seconds of the blank group,and can be used as a tissue sealant or surgical hemostatic agent in clinic[120]。

3.4 Cellulose

as a kind of polysaccharide,cellulose has a wide range of sources,low price,hemostatic function and good biological safety.Therefore,Brooks et al.in Canada have done a lot of useful exploration In the use of phosphorylcholine(CP)modified cellulose As hemostatic materials[121]。 For example,after modifying the surface of cellulose membrane(CM)with CP,they prepared a CM-based hemostatic dressing with brush-like molecular structure.the CP group on the dressing can make red blood cells adhere and aggregate on the CM more effectively,which helps to form thrombus and promote the hemostasis process,as confirmed by the obvious shape change of red blood cells in SEM photos[5]。
CS can also be coated directly on the surface of CM to enhance the hemostatic properties of CM.For example,the CS coated CM wound dressing prepared by Luo Xiaogang of Wuhan University of Engineering not only has mechanical flexibility,high wettability,hydrophilicity,air permeability and sterilization,but also shows good wound healing effect in mouse wound healing model[122]。
If natural cellulose is oxidized and modified,it can not only improve its hemostatic ability,but also endow it with the function of promoting wound healing[123]。 of course,the hemostatic material can also be prepared by further modifying the oxidized cellulose with a wider variety Of substances.For example,Sezer et al.In Turkey prepared a blood coagulation microparticle material by crosslinking oxidized cellulose and GEL with glutaraldehyde[124]。 the material can not only shorten the clotting time of human whole blood from 9 minutes of the blank group to 2 minutes,but also effectively activate platelets,and has no toxicity to human umbilical vein endothelial cells。
Yan Yonggang of Sichuan University also reported the study of using inorganic mesoporous bioglass microspheres(mBN)to modify CM,and found that the CM-mBN hemostatic material had the synergistic effect of the two.Especially,it effectively combines the advantages of mBN,such as Ca2+procoagulant effect,bioabsorbability,and strong adsorption performance due to strong electronegativity and large specific surface area,so as to ultimately enhance the blood coagulation activity of the material[125]。

4 Proteins/peptides

Many proteins are active hemostats. For example, fibrin (FIB) is an insoluble polymer protein produced by fibrinogen under specific conditions, which has certain elasticity and viscosity, and is essential for hemostasis and thrombosis[126]. It can also act as a reservoir of many growth factors and stimulate angiogenesis, so it is an ideal material for hemostatic materials and wound dressings[2]. At present, FIB sealant has been confirmed by clinical trials to have a hemostatic rate of more than 76% for non-emergency open peripheral arterial moderate bleeding[127]. The recombinant FIB patch was confirmed to achieve 100% hemostasis in rabbit liver, caudal vena cava and abdominal aorta[128].
However, FIB itself is difficult to agglutinate into a gel, and it is not easy to adhere firmly to the wound when the amount of bleeding is large. In order to improve the effectiveness and applicability of FIB-based dressings, they can be modified. For example, adding native protein thrombin to FIB, or cross-linking with native protein hydrolysate polypeptides, can improve its adhesion and maintain hemostatic effect[129][130].
Of course, gel dressings can also be made by blending natural polysaccharides with modified FIB[131]. For example, chitin, which contains a large number of hydroxyl and amide groups, was blended with FIB by Jayakumar et al. In India, and then loaded with tigecycline (TI) antibacterial drug to make a gel dressing. Its adhesion strength on the surface of pig skin exceeded 12 kPa, reaching the level of clinical tissue sealant[132]. Coagulation time was only (53 ± 4) s, which was significantly shorter than 520 s in the blank group. It can release TI for 21 days to kill SA (including methicillin-resistant SA) and EC.
Collagen (COL) is the main component of animal connective tissue, and is also the most abundant and widely distributed functional protein in mammals. It has good biocompatibility, biodegradability, tissue adhesion and low immunogenicity, and has hemostatic function, so it can be used as hemostatic materials and wound dressings. However, its mechanical strength is poor, and its hemostatic effect needs to be improved, so it generally needs to be modified before use. For example, Hou Dengyong et al. Of Shanghai Ocean University added about 5 wt% CS to COL and electrospun it on ALG non-woven fabric substrate to make a wound dressing. The BCI of the dressing was about 36.9%, which was significantly less than 79.9% of medical gauze, and it had a healing effect on rabbit back wounds[133]. On the basis of adding CS to COL, Czech Abdel-Mohsen et al continued to add aloe extract, and the fibrous dressing prepared showed better hydrolysis, swelling, hemostasis and biocompatibility than natural COL[134].
Cross-linking of COL with dialdehyde compounds is a common means to produce hemostatic materials. For example, Li Bafang of Ocean University of China and his colleagues prepared a porous composite hemostatic dressing by crosslinking cod skin COL and ALG with glutaraldehyde, which had good hemostatic performance, tensile strength and elongation at break, and could be completely degraded after 8 weeks of implantation in rats without causing serious inflammation[135]. Recently, 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide was also used to cross-link the COL of tilapia skin, and the resulting spongy hemostatic dressing not only has strong water absorption and rapid blood clotting ability, but also shows good biological safety in acute systemic toxicity, skin irritation, intradermal reaction, sensitization and cytotoxicity tests in mice[136].
Keratin and certain vegetable proteins also have hemostatic properties[137]. For example, Swamy et al in India extracted a cysteine protease from Bermudagrass latex, which could reduce the clotting time of whole blood from 248 s in the blank group to 39 s at a concentration of 40 μg/mL, which is consistent with the hemostatic application of Bermudagrass plants in folk medicine[138]. The hemostatic time of the hydrogel dressing prepared by Wang Bochu et al. Of Chongqing University loaded insulin on human hair keratin in rat liver hemorrhage model was about 40 s, while that of the blank group was as high as 560 s[139]. It has been proved by in vivo experiments that it can up-regulate the expression of transforming growth factor TGF-β1 and hydroxyproline, thereby promoting cell growth and angiogenesis.
As an intermediate product of protein hydrolysis, polypeptide also has hemostatic effect. For example, Wang Qigang of Tongji University made a hemostatic hydrogel with guanidine-containing oligopeptide, and its hemostatic time in the mouse liver bleeding model was 110 s, which was shorter than 195 s in the blank group[140]. Recently, there are also research reports on the preparation of hemostatic materials by synthesizing peptides from amino acids. For example, Ludai et al. Of Northwest Normal University synthesized a series of triblock copolymers using L-arginine, L-cysteine and L-lysine as monomers and Planik L-31 as initiator[141]. The blood loss of these peptides in the rat liver blood model was as low as (0.36 ± 0.13) G, which was significantly less than that of the blank group (1.72 ± 0.63) G. The adhesive strength on pig skin and pig bone can be as high as 106 kPa, showing good tissue adhesion.

5 Polyphosphate

In addition to the above materials, attempts have been made to prepare hemostatic materials using more types of bio-based polymers. Among them, some natural inorganic polymers, such as polyphosphate (PolyP), can also be used to prepare hemostatic materials. Studies have shown that when the hemostatic function of human platelets is activated, they secrete PolyP with a degree of polymerization of 60-100 to activate coagulation factors yinzi and FXI and inhibit fibrinolysis[142]. PolyP can stay on the surface of platelets, and its long molecular chain can complex with divalent metal ions to enhance the activation of coagulation factor yinzi[143]. PolyP extracted from human platelets was chelated with EDTA to prepare nanoparticles, or the degree of polymerization of PolyP was increased to 1110 ~ 1540, which could accelerate the procoagulant process of PolyP[144][145].
Therefore, it is feasible to use PolyP to prepare hemostatic materials based on blending. For example, Filiaggi et al. In Canada added different amounts of Ca2+ to various PolyP with a degree of polymerization of 20 to 10,000 to make them coagulate and prepare hemostatic materials[146]. It was found that the hemostatic function of the material was improved with the increase of polymerization degree and aggregation degree of the aggregated PolyP, and the clotting time of the material was shortened from 432 s to 164 s in the blank group. At the same time, it has good platelet aggregation and rapid degradation, and the degradation rate of high degree of polymerization aggregated PolyP is not significantly slower than that of low degree of polymerization aggregated PolyP.
Although PolyP is an inorganic polymer, it also has good compatibility with some organic polymers, and new properties can be obtained after blending. For example, recently, Huang Junren et al. In Taiwan, China blended poly (trimethylaminoethyl methacrylate chloride-sulfobetaine methacrylate) with PolyP to make a gel hemostatic dressing[147]. The bleeding amount of the dressing in the rat tail cutting bleeding test was 2. 6 G, which was lower than that of the blank group (4. 1 G).The dressing had antibacterial properties on EC, was non-toxic to L929 cells, and could be repeatedly adhered and removed on the skin.

6 Conclusion and prospect

Biobased polymer materials have good application prospects in the field of biomedical materials due to their diverse types, abundant resources, biodegradable, bioabsorbable and adjustable properties. Among them, bio-based polymers such as polylactic acid, chitosan, protein, sodium alginate, hyaluronic acid and polyphosphate have been widely studied, and their applications in hemostatic materials and wound dressings have been studied from the perspectives of blending modification, chemical modification, preparation process and application properties.
Compared with the development status at home and abroad, although the research level in the development of substrate types, the selection of modified substances and loaded drugs, the multi-functionality of materials, and animal experiments is relatively close, there is still a certain gap in the deeper research content of material structure design, preparation process, and pharmacological/mechanism analysis. In contrast, researchers in some developed countries have more material preparation methods and evaluation methods, and their reports are more comprehensive and in-depth, which are worthy of our reference and improvement.
Looking ahead, although the wound care performance of these materials has been confirmed by many experimental results, there is still a lot of research work to be done before they can be widely used in clinical practice. For example, the broadening of the variety and source routes of raw materials containing multiple functional groups, the combination of immediate hemostatic properties and long-term hemostatic properties, the loading of more functional drugs (especially medicinal plant extracts), the mechanical properties and physiological functions closer to the skin that can simulate the natural healing of wounds,As well as further clinical research, will be the future research focus of bio-based polymer materials in this frontier field.

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Funding

the National Natural Science Foundation of China(20772035)

the Guangdong Provincial Science and Technology Project(2017A010103016)

the Natural Science Foundation of Guangdong Province(2021A1515012342)

the Open Fund of the Key Laboratory of Functional Molecular Engineering of Guangdong Province in SCUT(2017kf01)

and the Science and Technology Program of Guangzhou(202002030362)

and the Science and Technology Program of Guangzhou(201607010301)

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