阅读说明：本技术 一种用于加速伤口愈合的热激活力电协同敷料及制备方法 (Heat-activation-electricity cooperative dressing for accelerating wound healing and preparation method thereof ) 是由 姚光 尹晨晖 莫小艺 娄文豪 黄思荣 毛琳娜 潘泰松 高敏 林媛 于 2021-09-15 设计创作，主要内容包括：本发明提供一种用于加速伤口愈合的热激活力电协同敷料及制备方法,属于生物材料技术领域。该敷料选用相变温度低于人体体表温度的形状记忆合金超结构作为敷料骨架,同时与静电驻极体相结合,通过力电协同多场刺激,可有效促进纤维细胞生长因子、转化生长因子、血管内皮生长因子等相关典型生长因子的分泌,同时静电驻极体提供的静电场可以杀菌,从而调节创面微环境,促进创面闭合、代谢,抑制结痂形成,实现了体温下力电协同加速伤口愈合的功能。(The invention provides a thermal-activation electric synergistic dressing for accelerating wound healing and a preparation method thereof, belonging to the technical field of biological materials. The dressing adopts a shape memory alloy superstructure with the phase transition temperature lower than the body surface temperature of a human body as a dressing framework, is combined with the electrostatic electret, can effectively promote the secretion of relevant typical growth factors such as fibroblast growth factors, transforming growth factors, vascular endothelial growth factors and the like through the force-electricity synergistic multi-field stimulation, and can sterilize by the electrostatic field provided by the electrostatic electret, thereby regulating the microenvironment of the wound surface, promoting the closure and metabolism of the wound surface, inhibiting the formation of scabs, and realizing the function of accelerating the healing of the wound under the body temperature through the force-electricity synergistic action.)

1. A thermal-activation-force electric cooperative dressing for accelerating wound healing is characterized by comprising a flexible material, a mechanical superstructure grid skeleton layer and an electrostatic electret film;

the mechanical superstructure grid framework layer comprises a pattern area and a blank area positioned in the center of the pattern area, wherein the pattern area is formed by periodically tiling unit structures and is used for providing a force field, and the unit structures are closed, symmetrical and hollowed-out graphs with negative Poisson's ratio;

the flexible material is attached to the mechanical superstructure grid framework and the blank area and used for avoiding allergy caused by direct contact of the shape superstructure grid framework and human skin; meanwhile, no flexible material is arranged in a hollow area of the mechanical superstructure grid skeleton graph, and the flexible material is used for skin ventilation;

the electrostatic electret film is arranged on the surface of the flexible material in the blank area and comprises a positive electrode and a negative electrode which are separated from each other, the positive electrode is a circular ring, the negative electrode is arranged at the center of the circular ring of the positive electrode, and the area between the positive electrode and the negative electrode completely covers the area of a wound area and is used for providing electric stimulation to the wound.

2. The thermally-activated electro-cooperative dressing of claim 1, wherein the mechanical superstructure mesh framework material is a shape memory alloy having a phase transition temperature lower than a body surface temperature; the flexible material is Ecof lex, PDMS or hydrogel; the material of the electrostatic electret film is polytetrafluoroethylene.

3. The thermally-activated electro-cooperative dressing of claim 1, wherein the mechanical superstructure grid framework has a thickness of 100 μ ι η; the shape memory alloy is preferably a nickel titanium alloy.

4. The thermally-activated electro-cooperative dressing of claim 1, wherein the pattern of unit structures is axisymmetric or rotationally symmetric.

5. The thermally-activated electro-cooperative dressing of claim 4, wherein the axisymmetric unit structure is obtained by connecting two openings in the transverse direction M; the rotationally symmetric unit structure is an annular structure obtained by connecting basic graphs end to end, the basic graphs are S-like and are formed by alternately connecting three sections of straight lines and arcs at two ends, and the straight lines are tangent to the arcs.

6. A thermally activated electro-cooperative dressing as claimed in claim 1, wherein the size of the negative pole region is equal to 1/2 of the size of the wound so that a sufficient electric field can be generated.

7. A method of making a thermally-activated electro-cooperative dressing for accelerating wound healing, comprising the steps of:

step 1, preparing a mechanical superstructure grid framework by cutting a shape memory alloy by laser;

step 2, cutting the electrostatic electret film by adopting laser to obtain a circular anode and a cathode positioned in the center of the anode, wherein the electrostatic electret film is obtained by high-voltage polarization treatment;

step 3, preparing a flexible material solution;

step 4, soaking the mechanical superstructure grid skeleton obtained in the step 1 in the flexible material solution obtained in the step 3 for a period of time, and then taking out and drying;

step 5, repeatedly carrying out the soaking and drying of the step 4 for many times until the mechanical superstructure grid framework is completely coated by the flexible material;

and 6, coating a layer of flexible film on the central blank area of the mechanical superstructure grid skeleton prepared in the step 5, and then attaching the positive electrode and the negative electrode of the electrostatic electret film obtained in the step 2 to the surface of the flexible film on the central blank area to obtain the required thermal-activation electro-synergetic dressing.

8. A thermally-activated electro-cooperative dressing as claimed in any of claims 1 to 6 when applied, the dressing is first stretched at room temperature, the dressing exhibiting an opening following stretching; when the dressing is attached to a wound, the dressing shows that the original shape is gradually recovered, a force field effect is generated on the edge of the wound, and meanwhile the electrostatic electret film generates electric stimulation on the wound.

Technical Field

The invention belongs to the technical field of biological materials, and particularly relates to a thermal-activation electric synergistic dressing for accelerating wound healing and a preparation method thereof.

Background

Skin wounds are the result of the disruption of tissue integrity by extreme external factors and have become a significant public health problem. With the great progress of modern biomedical technology, drug-based (inflammation inhibitory drugs, growth factor-mediated, etc.) and non-pharmacological wound treatment strategies (e.g., wound dressings, compression bandages, negative pressure therapy, electrical stimulation therapy, etc.) have been rapidly developed. At present, the mainstream wound healing scheme is mainly pharmacological treatment and adopts a smearing mode for treatment, but the pharmacological treatment mode has the problems of rapid degradation of the medicine and easy loss of the activity. For non-pharmacological wound treatment strategies, although most non-invasive physical intervention treatment strategies such as compression bandages, negative pressure therapy, electrical stimulation therapy and the like are attractive treatment means in wound care, the complexity of equipment operation and stimulation implementation thereof greatly limits clinical application. The wound dressing is a common mode for treating wounds at present due to the convenience in use.

In the aspect of non-invasive physical therapy based on electro-mechanical intervention, researches show that electrical stimulation can simulate the natural wound healing mechanism of an endogenous electric field so as to promote skin growth, and mechanical pressurization regulation can regulate the wound healing direction and promote angiogenesis. Such as: long et al prepared an electric field stimulation bandage powered by kinetic energy, and the electric stimulation could simulate an endogenous electric field and promote migration, proliferation and differentiation of fibroblasts, thereby promoting healing of the skin wound of rats^[1]. Zhu et al prepared a motion-driven wearable device based on piezoelectric PVDF material, electricityStimulation can promote and enhance the expression of key growth factors, thereby effectively promoting the deposition of collagen, angiogenesis and epithelial regeneration in vivo^[2]. Research work of Boeno et al shows that low-frequency physical electrical stimulation can promote the increase of collagen fibers at a wound part and accelerate the healing of injury of the achilles tendon of a rat^[3,4]. Willett et al demonstrated accelerated vascularization by loading the extracellular matrix with mechanical pressure^[5]. Mooney et al prepared an adhesive self-shrinking wound-active dressing to exert sufficient contractile force to promote the growth of granulation tissue and achieve active closure of the wound^[5]. However, the prior art adopts single physical therapy of force intervention or electric intervention, and does not have a scheme of promoting wound healing by the force-electricity cooperative stimulation.

Therefore, how to design a dressing for orderly and efficiently healing wounds through the force-electricity cooperation and multi-field stimulation becomes an urgent problem to be solved.

[1]Y.Long,H.Wei,J.Li,et al.Effective wound healing enabled by discrete alternative electric fields from wearable nanogenerators.ACS Nano,2018,12,12533-40.

[2]S.Du,N.Zhou,Y.Gao,et al.Bioinspired hybrid patches with self-adhesive hydrogel and piezoelectric nanogenerator for promoting skin wound healing.Nano Research,2020,13,2525-2533.

[3]X,Xu,H.Zhang,Y.Yan,et al.Effects of electrical stimulation on skin surface.Acta Mech.Sin,2021,1-29.

[4]M.A.Ruehle,E.A.Eastburn,S.A.Labelle,et al.Extracellular matrix compression temporally regulates microvascular angiogenesis.Sci.Adv.,2020,6,eabb6351.

[5]S.O.Blacklow,J.Li,B.Freedman,et al.Bioinspired mechanically active adhesive dressings to accelerate wound closure.Sci.Adv.,2019,5,eaaw3963.

Disclosure of Invention

In view of the problems of the background art, the invention aims to provide a thermally-activated electrically-cooperative dressing for accelerating wound healing and a preparation method thereof. The dressing adopts a shape memory alloy superstructure with the phase transition temperature lower than the body surface temperature of a human body as a dressing skeleton, and is combined with an electrostatic electret, so that the power and electricity synergistic stimulation generated at the body temperature is realized, and the wound healing is accelerated.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a thermally-activated electro-cooperative dressing for accelerating wound healing comprises a flexible material, a mechanical superstructure grid skeleton layer and an electrostatic electret film;

the mechanical superstructure grid framework layer comprises a pattern area and a blank area positioned in the center of the pattern area, wherein the pattern area is formed by periodically tiling unit structures and is used for providing a force field, and the unit structures are closed, symmetrical and hollowed-out graphs with negative Poisson's ratio;

the flexible material is attached to the mechanical superstructure grid framework and the blank area and used for avoiding allergy caused by direct contact of the shape superstructure grid framework and human skin; meanwhile, no flexible material is arranged in a hollow area of the mechanical superstructure grid skeleton graph, and the flexible material is used for skin ventilation;

the electrostatic electret film is arranged on the surface of the flexible material in the blank area and comprises a positive electrode and a negative electrode which are separated from each other, the positive electrode is a circular ring, the negative electrode is arranged at the center of the circular ring of the positive electrode, and the area between the positive electrode and the negative electrode completely covers the area of a wound area and is used for providing electric stimulation to the wound.

Further, the mechanical superstructure grid framework material is a shape memory alloy, and the phase transition temperature of the shape memory alloy is lower than the body surface temperature of a human body; the flexible material is an Ecoflex material, PDMS or hydrogel; the material of the electrostatic electret film is preferably polytetrafluoroethylene.

Further, the thickness of the mechanical superstructure grid framework is 100 μm; the shape memory alloy is preferably a nickel titanium alloy.

Further, the pattern of the unit structures comprises an axial symmetry or a rotational symmetry.

Further, the axisymmetric unit structure is obtained by connecting two horizontal M openings; the rotationally symmetric unit structure is an annular structure obtained by connecting basic graphs end to end, the basic graphs are S-like and are formed by alternately connecting three sections of straight lines and arcs at two ends, and the straight lines are tangent to the arcs.

Further, the size of the negative pole area should be equal to 1/2 of the size of the wound so that a sufficient electric field can be generated.

A method of making a thermally-activated electro-cooperative dressing for accelerating wound healing, comprising the steps of:

step 1, preparing a mechanical superstructure grid framework by cutting a shape memory alloy by laser;

step 2, cutting the electrostatic electret film by adopting laser to obtain a circular anode and a cathode positioned in the center of the anode, wherein the electrostatic electret film is obtained by high-voltage polarization treatment;

step 3, preparing a flexible material solution;

step 4, soaking the mechanical superstructure grid skeleton obtained in the step 1 in the flexible material solution obtained in the step 3 for a period of time, and then taking out and drying;

step 5, repeatedly carrying out the soaking and drying of the step 4 for many times until the mechanical superstructure grid framework is completely coated by the flexible material;

and 6, coating a layer of flexible film on the central blank area of the mechanical superstructure grid skeleton prepared in the step 5, and then attaching the positive electrode and the negative electrode of the electrostatic electret film obtained in the step 2 to the surface of the flexible film on the central blank area to obtain the required thermal-activation electro-synergetic dressing.

When the thermal activation force electricity is applied to the dressing, the dressing is stretched at room temperature, and the dressing is stretched along with the stretching; when the dressing is attached to a wound, the dressing shows that the original shape is gradually recovered, a force field effect is generated on the edge of the wound, and meanwhile the electrostatic electret film generates electric stimulation on the wound.

In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:

1. when the force field direction is perpendicular to the wound edge direction, the force field has the best effect on wound healing acceleration, and is distributed with different force fields required for linear wounds and circular wounds. The force-electricity cooperative dressing adopts the memory alloy to be processed into the memory alloy framework, and because the shape memory alloy can recover the original shape under the condition that the temperature is higher than the phase change temperature, the shape memory alloy can be contracted when being attached to the surface of the skin after being stretched, so that the dressing can realize the control of the uniaxial or multiaxial strain under the body temperature; meanwhile, the electrostatic electret film is designed into a separated positive electrode area and a separated negative electrode area, so that the direction of the electric field of the permanent electric electret is controllable, and the healing process is promoted by enhancing the endogenous electric field.

2. The force-electricity synergistic multi-field stimulation integrated dressing provided by the invention can effectively promote secretion of related typical growth factors such as fibroblast growth factor, transforming growth factor, vascular endothelial growth factor and the like, and an electrostatic field provided by the electrostatic electret can sterilize so as to adjust wound microenvironment, promote wound closure and metabolism and inhibit scab formation.

Drawings

Fig. 1 is a schematic structural diagram of the power-electricity cooperative dressing of the invention.

Fig. 2 is a schematic diagram of the basic unit structure of the mechanical superstructure grid framework of the mechanical-electrical cooperative dressing and the mechanical superstructure grid framework under different parameter conditions.

Fig. 3 is a structural diagram and an installation schematic diagram of an electrostatic electret film of the power and power cooperative dressing of the invention.

FIG. 4 is a drawing diagram of SMA-L in two XY directions at different temperatures and different stretching distances, when α is taken at 50 °, 60 °, and 70 °, respectively.

FIG. 5 is a drawing diagram of the SMA-C generated in the XY directions at different temperatures and different stretching distances when β is taken at 110 °, 120 ° and 130 °, respectively.

FIG. 6 is a force diagram of the contraction of SMA-L in both XY directions at 35 ℃ when α is taken at 50 °, 60 °, and 70 °, respectively.

FIG. 7 is a force diagram of the contraction of SMA-C in both XY directions at 35 ℃ when β is taken at 110 °, 120 °, and 130 °, respectively.

FIG. 8 is a finite element electric field distribution plot of an electrostatic electret film of the invention.

Fig. 9 is a graph of the results of four sets of experiments with different dressings for linear wounds.

Fig. 10 is a graph of the results of four sets of experiments with different dressings for a circular wound.

Figure 11 dressing intervention day 8, round wound healing control experiment wound skin H & E stained section control.

Figure 12 dressing intervention day 8, round wound healing control experiment wound skin key growth factor distribution.

Figure 13 dressing intervention day 8, round wound healing control experiment wound skin Integrated Optical Density (IOD) curve analysis.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the following embodiments and accompanying drawings.

A thermal-activation electric cooperative dressing for accelerating wound healing is shown in figure 1, and comprises a flexible material, a mechanical superstructure grid skeleton layer and an electrostatic electret film;

the mechanical superstructure grid framework layer comprises a pattern area and a blank area positioned in the center of the pattern area, wherein the pattern area is formed by periodically tiling unit structures and is used for providing a force field, and the unit structures are closed, symmetrical and hollowed-out graphs with negative Poisson's ratio; the mechanical superstructure grid framework material is a shape memory alloy, and the phase transition temperature of the shape memory alloy is lower than the body surface temperature of a human body;

the flexible material is attached to the mechanical superstructure grid framework and the blank area and used for avoiding allergy caused by direct contact of the shape superstructure grid framework and human skin; meanwhile, no flexible material is arranged in a hollow area of the mechanical superstructure grid skeleton graph, and the flexible material is used for skin ventilation;

the electrostatic electret film is arranged on the surface of the flexible material in the blank area and comprises a positive electrode and a negative electrode which are separated from each other, the positive electrode is a circular ring, the negative electrode is arranged at the center of the circular ring of the positive electrode, and the area between the positive electrode and the negative electrode completely covers the area of a wound area and is used for providing electric stimulation to the wound.

Example 1

Taking the application of the power and electricity cooperative dressing to linear wounds as an example, the Ecoflex material is selected as the flexible material.

The unit structure of the mechanical superstructure grid framework pattern area of the power and electricity cooperative dressing is shown in the right picture of fig. 2(a), the unit structure is an up-down and left-right axisymmetric pattern, specifically is obtained by connecting two transverse M openings and is named as a shape memory alloy grid L-shaped (SMA-L). When the bottom side length is 1.8mm and the line width is 0.18mm, the unit structure can be adjusted by adjusting the angle alpha between the bottom side length and the bevel edge and the height l between the upper bottom edge and the lower bottom edge.

The structural schematic diagram of the electrostatic electret film of the force-electricity cooperative dressing is shown in fig. 3(a), the positive electrode area separated by the electrostatic electret film is a concentric rectangular ring, the negative electrode area is a rectangle, and the finite element electric field distribution diagram is shown in fig. 8 (a).

When the angles alpha between the side length of the part and the oblique side are respectively 50 degrees, 60 degrees and 70 degrees, and l corresponds to 1.4332mm, 2.0749mm and 3.3559mm, the schematic diagram of the constructed mechanical superstructure grid framework is shown in the left diagram of fig. 2 (a).

The electro-mechanical cooperative dressing with the mechanical superstructure grid framework has different stretching distances at different temperatures, and the tensile force generated by the SMA-L in two directions is shown in figure 4.

Example 2

Take the example that the power and electricity cooperated dressing is suitable for a round wound.

The unit structure of the mechanical superstructure grid framework pattern area of the force-electricity cooperative dressing is shown in the right diagram of fig. 2(b), the unit structure is a rotational axis symmetric graph and is an annular structure obtained by connecting basic graphs end to end, the basic graphs are S-like and are formed by alternately connecting three sections of straight lines and two sections of circular arcs and named as shape memory alloy grid C type (SMA-C). When the width and radius of the circular arc are 0.12mm and 0.41mm, respectively, and the width and length of the straight line are 0.24mm and 1.18mm, the circular arc correspondence angle β may be adjusted to adjust the unit structure.

The structural schematic diagram of the electrostatic electret film of the force-electricity cooperative dressing is shown in fig. 3(b), the positive electrode area separated by the electrostatic electret film is a concentric ring, the negative electrode area is a circle, and the finite element electric field distribution diagram is shown in fig. 8 (b).

When the beta is 110 degrees, 120 degrees and 130 degrees respectively, the schematic diagram of the constructed mechanical superstructure grid framework is shown in the left diagram of fig. 2 (b).

The electro-mechanical cooperative dressing with the mechanical superstructure grid framework has different stretching distances at different temperatures, and the tensile force generated by the SMA-L in two directions is shown in figure 5.

FIG. 4 is a drawing diagram of SMA-L in two XY directions at different temperatures and different stretching distances, when α is taken at 50 °, 60 °, and 70 °, respectively. As can be seen from the figure, when α is taken as 50 °, 60 ° and 70 °, respectively, the stretching is performed at a speed of 0.02mm/s at 20, 25, 30, 35, 40, 45 and 50 ℃, and the lattice stretching exhibits anisotropy during the biaxial stretching in the XY two directions at different stretching distances. When the grid length is lengthened by 4mm along the x-axis, the length of the y-axis is increased by only 0.3 mm. The characteristic shows the anisotropy of the grid in tensile property, and can effectively deal with the wound shape which only needs unidirectional stress adjustment, such as linear wound.

FIG. 5 is a drawing diagram of the SMA-C generated in the XY directions at different temperatures and different stretching distances when β is taken at 110 °, 120 ° and 130 °, respectively. It can be seen from the figure that when β is 110 °, 120 ° and 130 °, the tension of the mesh to the x and y axes is substantially the same at different temperatures and different stretching distances, thereby showing the isotropy of the mesh, and effectively coping with the shape of a wound requiring stress adjustment in the same direction and magnitude, such as a circular wound.

FIG. 6 is a force diagram of the contraction of SMA-L in both XY directions at 35 ℃ when α is taken at 50 °, 60 °, and 70 °, respectively. As can be seen from the figure, the tension of the dressing of the invention at body temperature is in the same order of magnitude as the skin tension, and the dressing can effectively modulate the wound stress.

FIG. 7 is a force diagram of the contraction of SMA-C in both XY directions at 35 ℃ when β is taken at 110 °, 120 °, and 130 °, respectively. As can be seen from the figure, the tension of the dressing of the invention at body temperature is in the same order of magnitude as the skin tension, and the dressing can effectively modulate the wound stress.

FIG. 8 is a finite element electric field distribution plot of an electrostatic electret film of the invention. From the finite element electric field distribution, it can be known that the direction of the electric field at the wound edge is approximately perpendicular to the wound edge and directed to the inside of the wound, so that the efficiency of the distributed electric field for accelerating wound healing is highest.

Fig. 9 is a graph of the results of four groups of experiments with different dressings for linear wounds, where EMSD-L group indicates the use of a force-electricity cooperative dressing of the present invention, MD-L group indicates the use of only a dressing with a mechanical superstructure grid skeleton of the present invention, ED-L group indicates the use of only an electrostatic electret film, and BC-L group indicates the use of no stimulation. As can be seen, the wounds in the EMSD-L group produced significant healing effects the following day; meanwhile, the comparison of the EMSD-L group and the rest three groups of experimental results shows that the wound healing process of the EMSD-L is obviously faster, and the effect of accelerating the wound healing by the cooperation of power and electricity is more obvious.

Fig. 10 is a graph of the results of four groups of experiments with different dressings treated for a circular wound, where EMSD-C group indicates the use of a force-electricity cooperative dressing of the present invention, MD-C group indicates the use of only a dressing with a mechanical superstructure grid skeleton of the present invention, ED-C group indicates the use of only an electrostatic electret film, and BC-C group indicates the use of no stimulation. Compared with the wound healing condition of the B-CC group, the wound healing condition of the ED-C group and the MD-C group has obvious acceleration effect on the healing process of the wound. It is demonstrated that both force and electric fields can have an effective effect on wound healing. The comparison of the EMSD-C group and the rest three groups of experimental results shows that the wound healing process of the EMSD-C is obviously faster, and the effect of accelerating the wound healing by the cooperation of power and electricity is more obvious. The rightmost column in the figure is the 6 th day of dressing intervention, and the circular wound healing control experiment wound skin hematoxylin and eosin (H & E) stained section is also shown in the figure, and the power and electricity synergistic dressing can effectively promote wound healing.

On day 8 of the control test, the skin was H & E stained at different incisions of the round wound and examined histologically, and the results are shown in fig. 11. Histological analysis showed that the EMSD-C group re-epithelialization of wound and granulation tissue formation was in the remodeling stage, while the MD-C, ED-C and BC-C groups were delayed in healing. The center of the EMSD-C treated wound had formed an epidermis and the sectioning results showed that the intact new epidermis was tightly associated with the underlying granulation tissue. The regenerated epidermis and granulation tissue of the MD-C group and the ED-C group are loosely connected, the healing is poorer than that of the EMSD-C group, and the epidermis of the BC-C group is completely lost.

Figure 12 dressing intervention day 8, round wound healing control experiment wound skin key growth factor distribution. As shown in fig. 12, IHC staining images show the overall expression profile of various growth factors, with black portions being the stained growth factors. The immunohistochemistry results show that the secretion of the EMSD-C constitutive fibroblast growth factor (EGF), transforming growth factor-beta (TGF-beta) and Vascular Endothelial Growth Factor (VEGF) is obviously increased compared with the control group. In addition, as shown in FIG. 13, the average absorbances of EMSD-C group Epidermal Growth Factor (EGF), transforming growth factor (TGF-. beta.), and Vascular Endothelial Growth Factor (VEGF) were 0.24, 0.23, and 0.20, respectively, higher than those of MD-C group (0.21, and 0.19), ED-C group (0.22, and 0.18), and BC-C group (0.19, 0.20, and 0.17), respectively, by Integrating Optical Density (IOD) curve analysis to quantify the expression intensity of growth factors. Compared with the BC-C group, the expression of EGF, TGF-beta and VEGF in the EMSD-C group is obviously enhanced. EGF expression in MD-C and ED-C groups was higher than that in CC group, indicating that both force field and electric field stimulation could promote keratinocyte proliferation and phenotypic expression. Furthermore, the expression of VEGF and EGF was elevated in MD-C and ED-L groups, respectively, compared to BC-C, suggesting that force and electric field stimulation play an important role in angiogenesis and tissue remodeling, respectively. The above experimental results again demonstrate the synergistic effect of the force and electric fields in promoting wound healing.

While the invention has been described with reference to specific embodiments, any feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise; all of the disclosed features, or all of the method or process steps, may be combined in any combination, except mutually exclusive features and/or steps.