polyvinyl alcohol nanofibers with enhanced skin healing properties by improving fibrinogen adsorption

Journal Pre-proof Konjac glucomannan/polyvinyl alcohol nanofibers with enhanced skin healing properties by improving fibrinogen adsorption

Bo Yang, Yushan Chen, Zhiqiang Li, Pengfei Tang, Youhong Tang, Yaping Zhang, Xiaoqing Nie, Cheng Fang, Xiaodong Li, Hongping Zhang PII:

S0928-4931(19)33619-7

DOI:

https://doi.org/10.1016/j.msec.2020.110718

Reference:

MSC 110718

To appear in:

Materials Science & Engineering C

Received date:

29 September 2019

Revised date:

13 January 2020

Accepted date:

2 February 2020

Please cite this article as: B. Yang, Y. Chen, Z. Li, et al., Konjac glucomannan/polyvinyl alcohol nanofibers with enhanced skin healing properties by improving fibrinogen adsorption, Materials Science & Engineering C (2020), https://doi.org/10.1016/ j.msec.2020.110718

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© 2020 Published by Elsevier.

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Konjac glucomannan / Polyvinyl Alcohol nanofibers with enhanced skin healing properties by improving fibrinogen adsorption Bo Yang a, Yushan Chen a, Zhiqiang Li b, Pengfei Tang a, Youhong Tang c, Yaping Zhanga, Xiaoqing Nie d, Cheng Fang e, Xiaodong Li f, *, Hongping Zhang a, * State Key Laboratory of Environmental Friendly Energy Materials, Engineering Research

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a

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Center of Biomass Materials, Ministry of Education, School of Materials Science and Engineering, Southwest University of Science and Technology, Sichuan 621010, China Department of Orthopedics, General Hospital of Western Theater Command, Chengdu,

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Institute for NanoScale Science and Technology and College of Science and Engineering,

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c

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610038, China

Flinders University, South Australia 5042, Australia Fundamental Science on Nuclear Wastes and Environmental Safety Laboratory, Southwest

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University of Science and Technology, Mianyang 621010, China Global Centre for Environmental Remediation, University of Newcastle, Callaghan, NSW,

2308, Australia f

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Institute of Chemical Materials, China Academy of Engineering Physics (CAEP), Mianyang

621900, China

___________________________________________________________________________ *Corresponding author. Tel: +86-816- 6089009, Fax: +86-816-6089009, E-mail: [email protected] (H. P. Zhang) and Tel(Fax): +86-816-2481795; E-mail: [email protected]. 1

Journal Pre-proof Abstracts: Skin tissue engineering aims to develop the effective healing strategy to repair the wound by optimizing skin scaffold materials. During the skin wound healing process, fibrin plays an important role due to the specific blood coagulation effect. In this study, the outstanding fibrin capability of konjac glucomannan (KGM) is demonstrated by the molecular dynamics simulation and confirmed by the protein adsorption experiments. A series of konjac glucomannan / polyvinyl alcohol (KGM/PVA) composites with different ratio are fabricated

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and their role in enhancing the skin repair are tested by in vitro cell culture and in vivo study. The Eads (adsorption energy) between fibrin and KGM is about 30% larger than that between

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fibrin and PVA. The fibrinogen adsorption rates of PVA and KGM/PVA (5:5) composites can

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reach about 20% and 60%, respectively. The results show the blood adsorption capacity of

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KGM/PVA (5:5) composite can reach about 13 g/g. After 7 days of cell culture, the optical density values of 3T3 fibroblasts on KGM/PVA (5:5) composite could reach 0.8. The

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mechanical properties of the composites are also verified to meet the practical needs. Thus, we propose a potential wound dressing material strategy based on the materials design and

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the intrinsic properties of KGM.

healing

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Key words: Konjac glucomannan; Nanofibers; Fibrin adsorption; Materials design; skin

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Journal Pre-proof 1. INTRODUCTION Skin tissue plays an important role in human health as a natural barrier to the outside world [1]. The defection of skin, which could be caused by various factors, leads to the invasion of external physical and chemical stimuli and causes additional damage to the human body [2-3]. The skin tissue healing process can be roughly divided as four stages, including hemostasis, inflammation, proliferation and maturation [4-5]. During these stages, fibrin and its precursor fibrinogen (would generated after the skin tissue damage) are confirmed to be the important

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glycoproteins, which are greatly related to the blood coagulation process and further scar formation [6-8]. Furthermore, fibrin can provide the platform for the cell migration and

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biological behaviors as a provisional extracellular matrix [9, 10]. To speed up the healing

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process of the skin wounds, an effective biocompatible material has been developed as wound

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healing dressing [11]. Thus, for the wound dressing besides biocompatibility and biodegradability, the outstanding adsorption behavior of fibrin and fibrinogen can be an

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important property. Eldin et al developed a chitosan-based wound dressing film [12]. The excellent properties including the protein adsorption capacity, coagulation and blood

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compatibility were confirmed by bovine serum albumin (BSA) adsorption experiments. A fibrous silk fibroin/polydopamine (SF/PDA) membrane with excellent protein adsorption

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ability, as well as the cell spreading and proliferation was explored by Zhang et al [13]. The good wound healing effect of the membrane was confirmed due to its promoting effect on the generation of hydroxyproline, which is helpful for wound healing. Singh et al designed bio-mimetic moxifloxacin loaded hydrogels with good wound fluid adsorption and protein adsorption behavior [14]. The wound fluid absorption studies indicate the excellent wound fluid adsorption capacity (about 7.2 g/g). The albumin adsorption capacities of the hydrogel can reach 0.19 ± 0.02 mg cm-2. The free radical scavenging ability of hydrogels was demonstrated by the anti-oxidation experiments. Along this research direction, recently, Zhang et al proposed a multilayered structured chitosan/polydopamine (CS/PVA) sponge with excellent coagulation ability due to its adhesion to the blood cells [15]. Their multilayered 4

Journal Pre-proof structures provide adequate platforms for platelets aggregation with the huge specific surface area. It was demonstrated to be a key process for wound healing. Research further demonstrated that the layered nanofiber structure can also promote the regeneration of functional dermis in the early repair stage. Consequently, the nanofiber-layered sponge receives increasing attention. As a water-soluble polymer, polyvinyl alcohol (PVA) has been widely used in the biomedical field due to its non-toxic, biocompatible and biodegradable characteristics [16]. However, the

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limitation on the biological function of the pure PVA material hindered its applications in wound dressing. In other words, due to lack of active functional groups on the chain, the

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biocompatibility and biodegradability of PVA needs to be improved [17-19]. Blending PVA

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with other natural polymers that have specific biological functions can be an effective way to

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improve repair effect of the PVA-based wound dressing materials [20-22]. Konjac glucomannan (KGM), one of the most important natural polysaccharides, exhibits

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significant potentials in biomedical application for its abundant hydroxyl groups and outstanding liquid adsorption capacity [23]. KGM have already been used as the raw material

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to prepare hydrogel, membrane or even injectable gel to serve as the wound dressing or other biomedical applications [24-28]. Furthermore, KGM can be blended with other materials, such

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as silk fibroin, chitosan, human hair proteins and polyvinylpyrrolidone, to fabricate wound dressings with strong water-absorption capacity, high swelling ratio and good biocompatibility in order to accelerate the tissue regeneration [29-34]. After wound, lots of bloods and body fluids leakage are the issues that need to be firstly dealt with. Then, several anti-inflammatory cytokines would be released due to the human’s self-defensive. Thus, the wound dressing materials are required to own excellent both water and protein absorbency [35].Nevertheless, while current wound repair materials focus on the increase in biocompatibility, we should pay more attention on the biomedical behavior of the materials in the whole wound regeneration micro-environments (hemostasis, water retention, breathability). In this study, PVA is blended with KGM by an electrospinning method in order to explore a 5

Journal Pre-proof skin repair material. The priority of KGM on the capability and compatibility of fibrin’s adsorption to PVA are systematically studied by both molecular dynamics simulations and the adsorption experiments. The interaction strength and the secondary structures variation of fibrin during the adsorption process on KGM or PVA are studied. The unique 3 dimensional (3D) structures of KGM/PVA composites can enhance the ventilation, moisturizing ability and hemostatic properties. This study provides an insight to develop an efficient wound dressing

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by considering enhancing the fibrin adsorption.

2. EXPERIMENTAL SECTION

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2.1 Materials

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Polyvinyl alcohol (PVA) (Average polymerization degree =1750, Tianjin Fuchen Chemical

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Reagent Factory, China), Konjac glucomannan (KGM) (Molecular weight =800 kDa, Wuhan Yuancheng Co-founded Polytron Technologies Inc. China), Glacial acetic acid (Chengdu

Aladdin

Industrial

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Kelong Chemical Reagent Co. Ltd. China). Fetal bovine serum (FBS) was obtained from Corporation

(China).

Penicillin-Streptomycin,

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3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and dimethyl sulfoxide

reagent grade.

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(DMSO) were purchased from Sigma-Aldrich (USA). All chemicals and solvents were of

2.2 Preparation of KGM/PVA nanofiber materials PVA was first dissolved in acetic acid (60 wt%) at the concentration of 12% (W/V) and stored in a water bath at 45℃, stirred until PVA was completely dissolved. Then, the KGM was dissolved in acetic acid at the concentration of 10% (W/V) at 45℃ and stirred until KGM was completely dissolved. After that, a series of KGM/PVA blend solutions (KGM solution/PVA solution = 0/100, 30/70, 40/60, 50/50, V/V%) were prepared by mixing the two solutions. The blend solutions were placed in a 5 mL syringe mounted on the microinjection pump respectively. The voltage was set to 15 kV, a collector was set 15 cm from the injector nozzle, 6

Journal Pre-proof the polymer solutions were pumped out at a rate of 5.5 mL h-l. The fibrous materials can be formed on the aluminum sheet collector after the power supply was switched on, and a certain thickness of fibrous material can be obtained by collecting fibers over and over again. Then, the fibrous materials were dried at room temperature (See Figure S1.) The collected materials were used for studying the wound dressing.

2.3 Characterization

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Microstructure and FTIR analyses of nanofibers The microstructure of PVA and KGM/PVA nanofibers was analysed by scanning electron

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microscope (SEM, UItra55, Germany) at 20 kV. Before the analysis, the samples were cut into

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the certain size (about 5 mm × 5 mm) and coated with gold to increase the conductivity

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(Cressington 208HR, British).

Fourier transform infrared (FTIR) spectra were measured using an IR spectrometer (380 FT-IR,

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Thermo Scientific Nicolet). The samples were ground into powder, mixed with KBr powder and compressed into wafer for FTIR test.

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Mechanical property measurement

The mechanical properties of the PVA and KGM/PVA composites were evaluated by a tensile

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testing instrument (Instron 5567, USA), followed by ASTM D882-75. Tensile strength was computed according to the load-strain curve and the film dimensions. For tensile strength testing, these nanofibers had a cuboid shape that 6 cm in height, 2 cm in width and 0.3 cm in thickness. Each sample was stretched to fracture and the tensile force was recorded. As parallel experiments, six measurements were taken for each sample, then the average was calculated. Measurement of water absorption The water absorption of PVA and KGM/PVA nanofibers was determined. Nanofibers（1 cm×1 cm）were immersed in deionized water for 30 mins to ensure that the amount of adsorption reached saturation. Before weighing the nanofibers, the excess water was removed with filter paper. The water absorption (WB) was calculated according to the follows: 7

Journal Pre-proof WB= (W-W0)/W0

(1)

Where W0 and W are the weight of the samples before and after immersion in ultrapure water, respectively. Stability of composites Weight variation of PVA and KGM/PVA composites were monitored by immersing the samples in deionized water at room temperature. The samples were removed from deionized water on the 7th day, the 14th day and the 21th day, respectively. Samples (1 cm×1 cm）were

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infiltrated 5 mins in alcohol, then taken them out and placed for 24 hours to be dried naturally. There are three parallel samples in each group. Finally, the change of weight was recorded.

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The micromorphology of PVA and KGM/PVA composites after 21 days of immersion were

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observed. FTIR spectra of KGM/PVA composites before and after immersion were measured.

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Differential Thermogravimetry (DTG) data of composites were recorded using thermal

2.4 In vitro cell culture

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analyser (TGAQ500, USA) at a scan rate of 5℃ /min under air atmosphere.

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The KGM/PVA nanofibers possessed excellent cell affinity and favoured cell adhesion and attachment. 3T3 fibroblasts（Stem Cell Bank, Chinese Academy of Sciences, SCSP）the typical

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cell type that primarily responsible for wound repair, were cultured on various samples to investigate the biological property [36]. In brief, 4×104 of cells were seeded on PVA and KGM/PVA nanofibers (diameter:1 cm) and incubate in a carbon dioxde cell incubator. Before culture, the nanofibers were immersed in PBS solution for 3 days to remove impurities. The purified nanofibers were treated in 75% ethanol for 24 hours for sterilization. Then, nanofibers were immersed in the medium (DMEM). The cell adhesion and proliferation in the different

groups

were

characterized

by

laser

confocal

microscopy

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3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) after 3 and 7 days in the culture, respectively. Before test, the original medium was replaced with DMEM containing MTT (0.5 mg/mL) and incubated at 37℃ for 4 hours. Then, the MTT solution was removed, 8

Journal Pre-proof 400 ul of dimethyl sulfoxide (DMSO) was added, and cultured in incubator for 15 minutes. Finally, the optical density of the nanofibers was measured at 570 nm by ELISA (MQX200, BioTEK, USA).

2.5 Blood adsorption capacity of composites The blood adsorption performance of PVA and KGM/PVA nanofibers was determined follow the previous study [37]. All the samples (about 1 cm×2 cm) were immersed in fresh blood of a

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Sprague Dawley (SD) rat for 30 mins to ensure that the amount of adsorption reached saturation. The adsorption process was carried out at 36℃.The blood content (BC) was

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calculated according to the follows:

(2)

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BC= (W-W0)/W0

2.6 In vivo wound healing

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respectively.

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Where W0 and W are the weight of the samples before and after immersion in fresh blood,

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A full-thickness skin defect model was used to characterize the accelerated wound regeneration performance of the nanofibers, according to our previous study [38-39]. Above all, a defect of 8 mm in diameter was created on the back of a Sprague Dawley (SD) rat, then the nanofibers (PVA, KGM/PVA=5:5) were implanted into the defect. The same wound was also treated with no dressing was implanted as a control. Adult male Sprague Dawley (SD) rats (140-180 g) were used in the present study. The animals were anesthetized with an intraperitoneal injection of pentobarbitone sodium (30 mg/kg). Animals recovered from anesthesia were housed individually in properly disinfected cages and rats were divided into three different groups 9

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consisting of six animals each. Out of them, first group was treated with no dressing, the second group with PVA and the third group treated with KGM/PVA. After the nanofibers were implanted in the defects, we took pictures to observe the closure area per week to evaluate the wound healing. 3 days after the operation, rats were subcutaneously injected with penicillin daily to reduce the risk of infection. The status of wound healing was recorded on the 7th

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day ,14th and 21th. After 21 days of post-implantation, the SD rats were sacrificed and the skin

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defect was collected. The wound tissue regeneration was analyzed by hematoxylin and eosin

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(H&E) staining and visualized by an optical microscope [40]. This study was carried out in

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strict accordance with animal laboratory care and guidelines.

2.7 Molecular dynamics simulation

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In order to investigate the role of the KGM/PVA composite during the initial stage of the hemostasis, molecular dynamics simulation was carried out the explore the interactions

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between fibrin and KGM or PVA at atomistic scale [41]. All the MD calculations were carried out with an open source code NAMD [42]. The VMD software was used to do the and post-processing analysis [43]. CHARMM36 force fields were used to define the interactions of the study systems [44]. The amorphous models of KGM and PVA were built first. Then, the gamma chain of fibrin was selected and the relative atomic mass of the two models was kept the same (240,000) [45]. The fibrin/KGM or fibrin/PVA interaction systems were first equilibrated by the following processes: Energy Minimization, 1 ns MD simulation under NVT ensemble, 5 ns MD simulation under NVT ensemble. The steepest descent minimization was utilized as the integrator for the EM process. The MD under NVT ensemble (T = 300 K) was performed for 5 ns with a time-step of 2 fs, respectively. 10

Journal Pre-proof 2.8 The fibrinogen adsorption experiment To further demonstrate the fibrin capability of KGM and PVA, the fibrinogen adsorption experiment was carried. First, the fibrinogen solution with the concentration of 1 mg/mL was prepared by dissolved certain fibrinogen powders into PBS solutions (0.01 M, pH=7.4) [46]. KGM/PVA fibril composites were immersed into the fibrinogen solution and shaking for 2 hours at 37℃. Then, the specimens were treated (washed off) with PBS and DI water to remove the unabsorbed proteins. Then the Bicinchoninic acid (BCA) Protein Assays were used

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3. Results and discussion

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3.1 Binding energy between fibrin and KGM or PVA

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In order to explore the fibrin capability of KGM and PVA, the interactions between fibrin and KGM or PVA are studied by the Eads (adsorption energy) calculations (See Figure S2).

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According to the Figure 1, the Eads between fibrin and KGM is about 30% larger than that

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between fibrin and PVA. Two different interaction manners are considered here. Fibrin interacts with KGM or PVA in vacuum or in the water exhibit the similar phenomenon. It indicates that the fibrin capability of KGM is significantly stronger than PVA. Figure 1e shows the secondary structure analysis of fibrin before and after interacts with KGM or PVA in water environments. It is known that the secondary structural of protein can be divided into three groups, they are alpha helix (H), beta strands (E) and coil (C). It can be seen that three amino acids domains (150-155, 178-182, and 240-242) of fibrin change from alpha helix to uncoiling configurations when them are adsorbed onto PVA. Nevertheless, comparing with PVA, KGM exhibits better ability to sustain the secondary structures of the fibrin. It is indicated that KGM should own a better biocompatibility. Figure 2 shows the fibrinogen adsorption rates of the different KGM/PVA electrospun 11

Journal Pre-proof composites, the fibrinogen adsorption rate of PVA is only about 20%. With the increase of KGM content, the fibrinogen adsorption rates of KGM/PVA composites can reach 35%, 50% and 60% respectively, it is indicated that the fibrinogen capability of PVA can be significantly

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improved by the addition of KGM.

Fig. 1. Atomistic model for fibrin adsorbed onto PVA and KGM in vacuum or in water, and the 12

Journal Pre-proof secondary structure analysis of fibrins. (a) KGM/fibrin in vacuum, (b) PVA/fibrin in vacuum, (c) KGM/fibrin in water, (d) PVA/fibrin in water. (e) the comparison of the variation of the

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secondary structures of fibrins interact with KGM or PVA.

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Fig. 2. Fibrinogen adsorption rates of the PVA and different KGM/PVA composites.

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3.2 Micromorphology and FTIR of KGM/PVA composites Electrospinning KGM/PVA composites have unique fibrous structures. In Fig. 3, the diameter

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of the pure PVA fiber is about 800 ±50 nm. With the addition of KGM, the diameters of the fibers decrease to 600 50, 500 50, 40050 nm with the KGM content of 30%, 40% and 50%,

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respectively. This might be due to the hydrogen bonds formed between KGM and PVA molecules which make the molecular chains intertwine closely. The fibers with smaller diameters have larger gap, which can be more favorable for gas diffusion. In addition, the fibrous networks can also endow the PVA/KGM fibers with good liquid adsorption capacity. Thus, the porous fibrous networks of the PVA/KGM fibers could provide a suitable microenvironment for wound regeneration.

Fourier transform infrared spectroscopy (FTIR) analysis was carried out to investigate surface group of the materials. The standard spectra of KGM, PVA and KGM/PVA are presented. For KGM, the broad peak at about 3400 cm-1 results from the stretching vibration of O-H group. 13

Journal Pre-proof The peaks at about 2900 cm-1,1400 cm-1 and 1100 cm-1 are assigned to -CH2- stretching vibration and two C-H bending modes, respectively. The peak at about 850 cm-1 are usually attributed as C-O-C stretching modes. For PVA, the peak at around 1000 cm-1 is unique and different from KGM. In the KGM/PVA composite, the characteristic peaks of KGM appear at about 850 cm-1, 1100 cm-1, 1400 cm-1, along with the peak at 1000 cm-1 of PVA, indicating

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that KGM has been successfully added into PVA matrix (See Fig. 3f.).

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Fig. 3. Micromorphology and FTIR of the PVA and different KGM/PVA composites.

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Micromorphology of (a) the PVA, (b)KGM/PVA=3:7, (c) KGM/PVA=4:6, (d)KGM/PVA=5:5. (e) Statistical diagram of diameter for different samples. (f) FTIR of KGM, PVA and

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KGM/PVA composite.

3.3 Mechanical, water absorption and stability of KGM/PVA composites An excellent wound dressing should own certain strength, good blood adsorption and biodegradability. Figure 4 shows the related characterization results. It is indicated that the addition of KGM do not have the significant effects on the tensile strength of the PVA. The tensile strength of KGM/PVA composites are about 2.5 MPa (See Fig. 4a). Thus, KGM/PVA composites have good mechanical properties, which will help to prevent external mechanical stimulation during the wound repair. In order to evaluate the adsorption effects of the body fluids, the water adsorption experiments are carried out. The water adsorption behavior of PVA 14

Journal Pre-proof is about 10.5 g/g. With the addition of KGM, the water adsorption behavior of the KGM/PVA composites increase to 11 g/g,11.8 g/g and 12 g/g with the KGM content of 30%, 40% and 50%, respectively. It is shown that KGM can improve the water adsorption behavior of PVA (See Fig. 4b). Fig. 4c. and Fig. 4d show the mass loss behavior of KGM/PVA films. KGM has apparent advantages in mass loss than PVA according to the mass loss rates and the variation of micromorphology. The mass loss of the sample is obvious in the initial stage, and the mass loss rate decreases gradually with time, and tends to be stable after 21 days. The mass loss

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amount of pristine PVA is only 25% after 21 days. After modified by 30%, 40% and 50% KGM, the mass loss can reach 30%, 32% and 35% respectively. Thus, the incorporation of

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KGM can accelerate the mass loss of the PVA matrix.

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From the FTIR results in Figure 4e, the characteristic peak of KGM, including 850 cm-1, 1100 cm-1 and 1400 cm-1, trends to stabilize, suggesting the existence of KGM. The

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broadened peak over 3000 cm-1 after 14 days is assigned to the extra adsorption of water.

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In Figure 4f, the KGM/PVA composite is apparent more thermo-stable than KGM and PVA

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alone. The main peak of the KGM/PVA composite appears at ~380℃, compared to 250C of PVA and ~320C of KGM. In terms of the water adsorption, the KGM/PVA composite in the

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first 7 days trends to be slow in the following days, this can be explained that the KGM will be degraded first. The mass loss can be explained by the dominant contribution of the KGM degradation. At 7 days of immersion, two main peaks of KGM/PVA composites appear at about 300℃ and 350℃, and the peak at ~300℃ is gradually decreased with the time of immersion of 10 day and 14 day. This may mean that the PVA in the KGM/PVA composites is also starting to degrade slightly. After 7 days, KGM/PVA composite trends to be stable in the water, particularly when focusing the marked peaks at ~300℃.

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Fig. 4. Mechanical, water absorption and mass loss properties of PVA and different KGM/PVA composites. (a)The tensile strength, (b) the water adsorption behavior, (c) the mass loss behavior, (d) the micromorphology after immersing testing, (e) the FTIR before and after immersing in the water and (f) the differential thermogravimetry (DTG).

3.4 In Vitro Cell Culture KGM/PVA composite has better cell affinity and biocompatibility, and is more conducive to the adhesion and proliferation of 3T3 fibroblasts. As is shown in Fig. 5 (a-d), the cells 16

Journal Pre-proof aggregation together on the PVA. Fortunately, after modified by 30%, 40% and 50% KGM, 3T3 cells spread evenly on the composite, and the pseudopod structure can be clearly observed. In addition, the optical density values of cells cultured for 3 days and 7 days are shown in Fig. 5e. The optical density of cells on each fibrous sample was only about 0.2 after 3 days. The fibroblasts proliferated actively, and a large number of cells can be seen on the samples (See Figure a-d). The more content of KGM, the more obvious cell proliferation can be seen. The optical density values of cells on PVA and KGM/PVA (5:5) composite could reach 0.6 and 0.8

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respectively. The optical density shows the concentration of cells in solution. Higher optical density in KGM/PVA groups demonstrates that nanofibers have good bioactivity which can

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promote cell adhesion and proliferation [32, 48].Thus, cell proliferation can be effectively

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promoted with the addition of KGM. This is mainly due to KGM has a large amount of active

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functional groups which have good cell affinity. KGM molecular chain contains a large number of hydroxyl groups, which can bind to certain proteins in the cell, thereby promoting cell

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adhesion and proliferation [31, 49].

Fig. 5. Adhesion and proliferation of 3T3 fibroblasts on PVA and different KGM/PVA composites. (a) the PVA, (b) KGM/PVA=3:7, (c) KGM/PVA=4:6, (d) KGM/PVA=5:5. (e) the optical density values of cells cultured for different KGM/PVA composites at 3 days and 7 days.

3.5 Measurement of blood adsorption capacity performance 17

Journal Pre-proof The blood absorption performance of KGM/PVA composites was investigated by the blood absorption model. As shown in Figure 6, both PVA and KGM/PVA with different ratio of KGM/PVA exhibit good blood adsorption ability. To further comparing the difference, the blood adsorption capacity was summarized and shown in Figure 6b. The blood adsorption capacity of the control sample (PVA) is about 9.5 g/g. While there are significant improvements for the KGM/PVA composites. It can reach the maximum of 13 ± 0.2g /g for

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KGM/PVA with 50% KGM.

Fig. 6. Blood adsorption capacity performance of PVA and different KGM/PVA composites.

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(a) Real figure of films before and after blood adsorption capacity. (b) Quantitative analysis of

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the blood absorption for different samples.

3.6 In vivo wound regeneration

The healing performance of PVA is significantly improved with the incorporation of KGM. Figure 7 (a) shows the wound regeneration model, it indicates the wound healing effect on the 7th day. Although, the phenomenon of scab can be seen in all samples, the larger wound closure area can be seen in KGM/PVA group. The wounds have been healed completely in each group after 21 days. Comparing to the blank group and PVA group, the degree of healing for the KGM/PVA group is better than the other two groups. Change in the area of trauma demonstrates the higher healing efficiency of KGM/PVA group. After 14 days, the healing ratios of the KGM / PVA group and the PVA group are 85% and 78%, respectively. The healing ratio of the control group is only 66%. After 21 days, the healing ratio of the 18

Journal Pre-proof blank group, PVA group and KGM/PVA group reach 86%, 92% and 98%, respectively. Therefore, the addition of KGM can significantly accelerate the wound healing efficiency.

In addition, histological staining indicates that the incorporation of KGM apparently promote the formation of new skin tissues (Fig. 7c). The distance between the new growing tissue and the mature tissue is about 1950 μm for the blank sample. It decreases to 980 μm and 600 μm for PVA and KGM/PVA respectively. The enlarge view revealed there were some samples in

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the PVA group. Moreover, collagen fibers were observed in KGM/PVA group, which further

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confirmed the maturation of regenerated tissues.

Fig. 7. Wound healing with the treatment of different samples. (a) digital images of the wound defects with different samples on days 0,7, and 21, (b) healing ratio of different groups, (c) representative images of H&E stained histological sections after 21days. 19

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Above all, the excellent wound repair effect of KGM/PVA composite is mainly due to: (1) good hemostasis can significantly improve the healing process of skin defects. For example, hemostatic antimicrobial oxidative electroactive hydrogel is used for skin wound healing [50-52] .(2) KGM exhibits the outstanding ability to adsorb the fibrin which can speed the wound healing process [26, 53-54]. (3) The good permeability and water retention of the fibrous structure can improve the excretion of wound exudates [55-56].

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Conclusion In this study, we successfully developed an electrospun KGM/PVA fibrous wound dressing

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with high specific surface area, good air permeability and moisture retention. Besides, the

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fibrin adsorption ability of PVA can be significantly improved with the addition of KGM. The

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molecular dynamics study demonstrates the better adsorption ability of KGM on fibrin than PVA. The secondary structural analysis of fibrin before and after adsorption on PVA or

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PVA/KGM composites demonstrates that the biological functions of fibrin exhibit no obvious variation. Further, the fibrin protein adsorption experiment demonstrates the phenomenon

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again. With the help of KGM functionalization, the mechanical strength, water absorption, blood absorption properties and the blood coagulation of the PVA nanofibers were also

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demonstrated to be apparently improved. Compared with other composites, KGM/PVA (5:5) composite has the highest fibrin adsorption rate and the best water absorption and blood absorption performance. In Vitro cell experiments have also confirmed that it has the best cellular affinity and biocompatibility. Thus, the addition of KGM into PVA in this study provides a facile and effective strategy to enhance the hemostasis and inflammation during the wound healing process. The electrospun fibrous composites with fibrin adsorption can be a potential wound healing dressing.

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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (H. P. Zhang) ORCID

Notes

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The authors declare no competing financial interest.

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Hongping Zhang: 0000-0002-6534-1952

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ACKNOWLEDGEMENTS

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H. Zhang is grateful to the National Natural Science Foundation of China (NSFC, Grant No. 31300793) and Longshan Academic Talent Research Supporting Program of SWUST (Grant

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No. 17LZX411&18LZX447) for supporting this research. Xiaoqing Nie is grateful to the

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Konjac glucomannan / polyvinyl alcohol nanofiber membranes with enhanced skin healing properties by improving fibrinogen adsorption Bo Yang, Yushan Chen, Zhiqiang Li, Pengfei Tang, Youhong Tang, Yaping Zhang, Xiaoqin Nie,

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Cheng Fang, Xiaodong Li, Hongping Zhang

Interaction between fibrin and KGM or PVA was explored by molecular dynamic

specific protein. 

KGM/PVA films with excellent skin repair effect were successfully fabricated by electrospinning.

The study explores a strategy to develop the excellent wound dressing based on the

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

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Fibrinogen adsorption experiment demonstrated superiority of KGM capturing the

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

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simulation at the atomistic scale.

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

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Highlights

molecular design.

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