- Open Access
Nano-silver-incorporated biomimetic polydopamine coating on a thermoplastic polyurethane porous nanocomposite as an efficient antibacterial wound dressing
© The Author(s) 2018
- Received: 12 August 2018
- Accepted: 26 October 2018
- Published: 12 November 2018
Developing an ideal wound dressing that meets the multiple demands of good biocompatibility, an appropriate porous structure, superior mechanical property and excellent antibacterial activity against drug-resistant bacteria is highly desirable for clinical wound care. Biocompatible thermoplastic polyurethane (TPU) membranes are promising candidates as a scaffold; however, their lack of a suitable porous structure and antibacterial activity has limited their application. Antibiotics are generally used for preventing bacterial infections, but the global emergence of drug-resistant bacteria continues to cause social concerns.
Consequently, we prepared a flexible dressing based on a TPU membrane with a specific porous structure and then modified it with a biomimetic polydopamine coating to prepare in situ a nano-silver (NS)-based composite via a facile and eco-friendly approach. SEM images showed that the TPU/NS membranes were characterized by an ideal porous structure (pore size: ~ 85 μm, porosity: ~ 65%) that was decorated with nano-silver particles. ATR-FITR and XRD spectroscopy further confirmed the stepwise deposition of polydopamine and nano-silver. Water contact angle measurement indicated improved surface hydrophilicity after coating with polydopamine. Tensile testing demonstrated that the TPU/NS membranes had an acceptable mechanical strength and excellent flexibility. Subsequently, bacterial suspension assay, plate counting methods and Live/Dead staining assays demonstrated that the optimized TPU/NS2.5 membranes possessed excellent antibacterial activity against P. aeruginosa, E. coli, S. aureus and MRSA bacteria, while CCK8 testing, SEM observations and cell apoptosis assays demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, a steady and safe silver-releasing profile recorded by ICP-MS confirmed these results. Finally, by using a bacteria-infected (MRSA or P. aeruginosa) murine wound model, we found that TPU/NS2.5 membranes could prevent in vivo bacterial infections and promote wound healing via accelerating the re-epithelialization process, and these membranes had no obvious toxicity toward normal tissues.
Based on these results, the TPU/NS2.5 nanocomposite has great potential for the management of wounds, particularly for wounds caused by drug-resistant bacteria.
- Thermoplastic polyurethane
- Porous structure
- Biomimetic polydopamine
- Methicillin-resistant staphylococcus aureus
- Wound dressing
Wound dressings play a critical role in the management of cutaneous wounds because they can protect the wounds and promote the regeneration of dermal and epidermal tissues [1, 2]. Due to an increasing number of people suffering from burns, diabetic ulcers, venous ulcers etc., the demand for better dressings is growing dramatically [3, 4]. Generally, an ideal dressing should possess non-toxicity, biocompatibility, robust mechanical properties and suitable permeability for gas and water exchange [5, 6]. As natural biomaterials, collagen, gelatin, alginate and chitosan have been extensively used to prepare various types of dressings (e.g., hydrogels, films and foams) due to their biocompatibility and biodegradability [1, 7]. However, their poor mechanical properties make it difficult for them to meet rigorous clinical requirements [5, 8].
Thermoplastic polyurethane (TPU) is a biocompatible and biodegradable elastomer that has been approved by the FDA, and has been widely applied in biomedical science [9, 10]. It has been reported that TPU can be used for catheters, vascular grafts and drug delivery carriers [11–13]. Moreover, TPU also exhibits remarkable chemical stability and good mechanical properties [10, 12]. These superior performances indicate that TPU is a promising candidate for wound dressings. However, lacking antibacterial activity would limit its application in wound care, as bacterial infections always pose a severe threat to the wound bed .
A feasible way to solve this problem is to incorporate antibiotics such as amoxicillin, vancomycin or gentamicin into wound dressings [15–17]. Nevertheless, the emergence of drug-resistance worldwide due to the overuse of antibiotics continues to threaten public health . Thus, alternative antibacterial agents are urgently needed. Nano-silver (NS) as an excellent antibacterial agent with robust and broad-spectrum bactericidal activity against both Gram-positive and Gram-negative bacteria, including multi-drug-resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA) [19, 20]. More importantly, it has been proposed that nano-silver destroys bacteria through various mechanisms (cell membrane disruption, DNA replication interference, respiratory function inhibition) without causing drug-resistance [21, 22]. However, the toxicity of nano-silver towards mammalian cells is a concern. Recent studies have demonstrated that the toxic effects of nano-silver occur only at high concentrations, and the incorporation of nano-silver into materials mitigates the toxicity [23, 24]. Consequently, nano-silver is considered as an ideal antibacterial agent for inclusion in biomaterials.
Although several methods have been employed to synthesize nano-silver, the complicated methods of preparation and the formation of hazardous by-products that occur during the synthetic process renders them undesirable [25–27]. Recently, biomimetic polydopamine (PD) has attracted much interest in tissue engineering due to its versatile surface modification and reducing properties [28, 29]. Inspired by the phenomenon of mussel-adhesion, researchers have discovered that dopamine (DA) undergoes self-polymerization to form a polydopamine layer under alkaline conditions. A layer of polydopamine can be coated onto any type of biomaterials, and being enriched with amines and catechols enables the in situ formation and integration of metal nanoparticles on the materials’ surface via a redox reaction. Furthermore, polydopamine is nontoxic, and no harmful by-products are produced during the mild formation process [30–32].
Materials and animals
Thermoplastic polyurethane (TPU) was obtained from Lubrizol (USA). N,N-dimethylformamide (DMF) was purchased from Sigma-Aldrich (MO, USA). Silver nitrate (AgNO3, 99%), dopamine and sodium citrate (Na-citrate) were purchased from Sangon (Shanghai, China). BALB/c mice (male, ~ 25 g) were obtained from the Experimental Animal Department of Third Military Medical University (TMMU). All animal experimental methods were approved by the ethical committee of the TMMU, and all animal experiments were performed in accordance with the guidelines of the TMMU.
Preparation of a TPU porous membrane
A TPU porous membrane was prepared using the combined methods of immersion precipitation and particle leaching. Briefly, 12.5 g of TPU granules, 100 mL of DMF and 25 g of Na-citrate powder (particle size: 75–150 μm) were blended thoroughly to form a homogeneous TPU/DMF/Na-citrate mixture. Next, the mixture was placed in a vacuum oven for 2 h at 50 °C to remove air bubbles, and then was uniformly cast in a polytetrafluoroethylene mould, followed by immersion into ethanol. After solidification, the TPU membrane was washed with deionized water for 2 days to extract the Na-citrate particles. Finally, the membrane was dried at 45 °C for 4 h, and a microporous TPU membrane was obtained.
Synthesis of a TPU/NS nanocomposite
To prepare a TPU/NS nanocomposite, the TPU membrane was first immersed into a dopamine (DA) solution (2 mg/mL in 10 mM Tris–HCl, pH 8.5) for 20 h at 25 °C. During this time the colour of the membrane evolved from pale white to dark brown. Subsequently, the DA-coated membrane was placed into a AgNO3 solution at different concentrations (1, 2.5 and 5 mM) for 6 h at 25 °C protected from light. Finally, the samples were washed with deionized water twice to remove the residual silver ions and dried at 45 °C for 4 h. The DA-coated and AgNO3-treated membranes were labelled as TPU/DA, TPU/NS1, TPU/NS2.5 and TPU/NS5, respectively.
Characterization of the TPU/NS nanocomposite
The morphologies of the pristine TPU and TPU/NS membranes were observed using scanning electron microscopy (SEM, Crossbeam 340, Zeiss, Germany), and the compositional analysis was conducted by energy-dispersive X-ray spectrometry (EDS). Based on the SEM images, the average pore size, porosity and diameters of the nano-silver particles were measured using Image J software and was read by two independent investigators. X-ray diffraction (XRD) spectra of the TPU and TPU/NS membranes were obtained with a 2θ range between 10° and 80° using an X-ray diffractometer (X’Pert Power, Panalytical B.V., Netherlands). The attenuated total reflectance Fourier transform-infrared (ATR-FTIR) spectra of the samples were obtained using an ATR-FTIR spectrometer (Nicolet 460, USA). The water contact angles of the samples were measured using a contact angle analyser (Theta Lite 101, Biolin Scientific, Sweden).
Mechanical properties measurements
The mechanical properties of as-prepared membranes were measured using a tensile test as previously described . Briefly, the dumbbell-shaped specimens were gripped and oriented vertically with metallic clamps. Then, the specimens were stretched to failure at a constant speed of 20 mm/min using an MTS industrial testing system (Exceed 44, Germany) at room temperature. Three specimens were used for each group.
The antibacterial activity of TPU/NS nanocomposites towards Pseudomonas aeruginosa (P. aeruginosa, ATCC 27853), Escherichia coli (E. coli, ATCC 25922), Staphylococcus aureus (S. aureus, ATCC 25923), and MRSA (ATCC 43300) was determined using a bacterial suspension assay . Briefly, a bacterial colony was incubated in 4 mL of Luria–Bertani (LB) medium with shaking at 37 °C overnight to obtain a log-phase bacterial suspension. After diluting with LB medium to the starting concentration (optical density at 600 nm; OD600 = 0.07), 500 μL of the bacterial suspension were added to each well of a 24-well plate. Next, a sterilized test membrane (10 × 10 mm) was immersed into the bacterial suspension. The plate was placed in a shaker and incubated at 37 °C for 24 h at 50 rpm. Finally, 100 μL of bacterial suspension from each well was transferred into a 96-well plate, and the OD600 was recorded using an enzyme-linked immunosorbent assay reader. To quantify the number of bacteria, the bacterial suspension was serially diluted with saline to obtain a 2500-fold dilution for P. aeruginosa and E. coli, or a 10000-fold dilution for S. aureus and MRSA, and 25 μL of the diluted bacterial solution was uniformly spread on agar plate. After incubating at 37 °C for 18 h, the bacterial colonies were photographed and the number of bacterial colonies was counted. In this assay, a bacterial solution without any treatment served as a control group.
In addition, the antibacterial activity of samples against P. aeruginosa and MRSA was further evaluated qualitatively using a Live/Dead™ Baclight™ Bacterial Viability Kit (Invitrogen, USA). The green-fluorescing SYTO9 and red-fluorescing propidium iodide (PI) in the kit can label live and dead bacteria, respectively [35, 36]. Briefly, the bacterial suspension after 24 h of co-incubation was harvested and washed with phosphate-buffered saline (PBS) twice, then 5 μL of SYTO9 and 5 μL of PI dye were added to 1 mL of bacterial solutions and incubated at room temperature for 15 min in the dark. Finally, the stained bacteria were washed two times with PBS and then visualized using a fluorescence microscope (Olympus, Japan). To determine the long-term antibacterial activity of the TPU/NS, samples were incubated with bacterial suspensions for 14 days at 37 °C and then stained using the Live/Dead™ Baclight™ Bacterial Viability Kit as described above.
In vitro evaluation of cytotoxicity
The cytotoxicity of as-prepared membranes against HaCaT cells and NIH3T3 fibroblasts was investigated according to ISO 10993-5. First, the leach liquor was obtained as follows: sterilized specimens (1.4-cm diameter) were immersed into 1 mL of RPMI1640 or DMEM medium at 37 °C for 24 h. The medium was then sterilized by filtration using an aseptic filter (pore size: 0.22 μm). The leach liquor in RPMI1640 medium was used to treat HaCaT cells, while that in DMEM medium was used to treat NIH3T3 fibroblasts. Next, 3000 HaCaT cells or NIH3T3 fibroblasts were inoculated into each well of a 96-well plate and incubated for 24 h at 37 °C. The medium was then replaced with 500 μL of leach liquor or pristine medium containing 10% foetal bovine serum (Gibco, USA). Cells inoculated with pristine medium were used as a control group. After 24 and 48 h, the medium was replaced with 100 μL of pristine medium containing 10 μL of CCK8 solution (Dojindo Laboratories, Kumamoto, Japan) and then incubated at 37 °C for 2 h. Finally, the optical density at 450 nm was measured using an enzyme-linked immunosorbent assay reader, and the cell viability was calculated.
Additionally, the cytotoxicity of samples at 48 h was determined further using SEM observations and cell apoptosis assays. For SEM observations, the cells that were treated for 48 h as described above were dehydrated with an ethanol solution and sputter-coated with gold. For cell apoptosis assays, all adherent and suspended cells were carefully harvested, and the test was performed using an Annexin V-Propidium iodide (PI) apoptosis detection kit according to the manufacturer’s protocol. Finally, the percentage of apoptotic and necrotic cells were detected using a fluorescence-activated cell sorting (FACS) sorter by an Attune Acoustic Focusing Cytometer (Life Technologies, USA), and the data were analysed using FlowJo software (Tree Star Incorporation, USA).
Release of silver ions (Ag+) into PBS
To investigate the amount of Ag+ released from the TPU/NS2.5 membrane, a section of sterilized sample (10 × 10 mm) was immersed into 6 mL of phosphate-buffered saline (PBS) at 37 °C for different times (1, 3, 5, 7, 10 and 20 days). Subsequently, the total supernatant was collected at each determined time point and analysed by inductively coupled plasma mass spectrometry (ICP-MS, 7700× Agilent, USA). In addition, the total silver content of the membrane was determined by sampling (n = 3) in 4% nitric acid.
In vivo animal study
Furthermore, the wound tissues (6 × 6 mm) on post-surgery day 7 in each group were harvested and homogenized in 5 mL of physiological saline, and the number of bacteria was counted using the colony counting method as described above.
In addition, five additional mice were observed in each group until the wounds were completely healed to determine the average number of days for complete wound closure.
At day 7 post-surgery, the wound samples including the entire wound with adjacent normal skin (10 × 10 mm) were collected and fixed in 4% paraformaldehyde. After 24 h, the samples were sectioned and stained with hematoxylin and eosin (H&E) for histological analysis. Based on these H&E stained sections, the number of inflammatory cells infiltrated in the wound edge, and the length of the newly regenerated epidermis, which was defined as the distance from the border between normal skin and the wound region to the anterior edges of the newly regenerated epidermis , were measured using Image J software by two independent pathologists.
In addition, to investigate the in vivo toxicity of TPU/NS2.5, another five mice (without bacterial treatment) in each group were sacrificed at day 7, and the major organs, including heart, liver, spleen, lung and kidney, were harvested for H&E staining.
The experimental data were expressed as the means ± standard deviations (SD) and statistically compared using one-way ANOVA. The statistical significance was set as p < 0.05 (“*”) and p < 0.01 (“**”), and ns indicates no significant differences.
Morphology and characterization of TPU/NS nanocomposites
The average pore size, porosity and pore density of TPU, TPU/DA, TPU/NS1, TPU/NS2.5 and TPU/NS5 membranes
Pore size (μm)
Pore density (pores/mm2)
84.1 ± 12.3
69.5 ± 3.6
88.9 ± 7.2
82.3 ± 11.9
67.0 ± 6.6
89.8 ± 12.2
85.5 ± 18.4
65.4 ± 5.2
83.3 ± 6.9
85.0 ± 16.9
65.4 ± 5.6
84.3 ± 9.5
83.3 ± 10.6
64.8 ± 5.0
85.2 ± 6.4
The chemical structures of the prepared membranes were determined using ATR-FTIR analysis. As shown in Fig. 1j, characteristic absorption peaks of TPU were observed at 3324 cm−1, attributed to the N–H group, and 2934 and 2856 cm−1, attributed to the –CH2 group . The spectrum of TPU/DA was similar to that of TPU, but the peak at approximately 3324 cm−1 became stronger after coating with polydopamine, which was attributed to the stretching vibration band of the –OH group . Compared with TPU/DA, the TPU/NS spectra showed intense absorption peaks at 1596 and 3324 cm−1, which might be attributed to the existence of nano-silver in the composite . The XRD results further verified the in situ formation of nano-silver. As shown in Fig. 1k, compared with TPU and TPU/DA membranes, two characteristic peaks at 2θ = 38.1° and 44.4° were obviously present in the diffractogram of TPU/NS membranes, and these corresponded to the (111) and (200) planes of silver nanoparticles, respectively (JCPDS No. 65-2871) .
Surface wettability is an important parameter that can influence the biological behaviour of biomaterials, therefore, the water contact angles of TPU, TPU/DA, TPU/NS1, TPU/NS2.5 and TPU/NS5 were measured. Figure 1l showed the water contact angle of pristine TPU to be 106.9°, indicating the intrinsic hydrophobic nature of TPU. After coating with polydopamine, the water contact angles of TPU/DA, TPU/NS1, TPU/NS2.5 and TPU/NS5 were dramatically decreased to 43.9°, 60.6°, 62.5° and 70.8°, respectively, which was consistent with previous studies that indicated that polydopamine coatings yielded hydrophilic surfaces . The improvement of hydrophilicity on the membrane surface is helpful for promoting cell adhesion . It should be noted that the water contact angles of TPU/NS membranes were higher than that of TPU/DA membranes, and this was probably attributed to the increased surface roughness after deposition of nano-silver . Taken together, the SEM, EDS, ATR-FTIR, XRD and water contact angle results confirmed the successful preparation of TPU/NS nanocomposites.
Mechanical properties of TPU/NS nanocomposites
Antibacterial activity of TPU/NS nanocomposites
Cytotoxicity of TPU/NS nanocomposites
To further evaluate the cytotoxicity of TPU/NS membranes, a flow cytometry apoptosis assay was employed and the results were shown in Fig. 5d–h. The Annexin V+ quadrants (both for the PI+ and PI−) represent apoptotic cells, while the PI+ and Annexin V− quadrant represent necrotic cells . For HaCaT cells (Fig. 5e, f), the percentages of apoptotic and necrotic cells in the control, TPU, TPU/DA, TPU/NS1 and TPU/NS2.5 groups were all below 9.0% and 0.7%, respectively, and no significant differences were observed among these groups, confirming that TPU/NS1 and TPU/NS2.5 were biocompatible with mammalian cells. Nevertheless, the corresponding ratios in the TPU/NS5 group were increased significantly to 56.4% and 2.1%, respectively. Similarly, the percentages of apoptotic (32.0%) and necrotic cells (0.4%) in TPU/NS5-treated NIH3T3 fibroblasts were also obviously higher than in the other groups (apoptotic cells: < 4.0%, necrotic cells: < 0.2%, Fig. 5g, h). These data are in agreement with the CCK8 results and the SEM observations, indicating that TPU/NS5 exhibited cytotoxicity towards HaCaT cells and NIH3T3 fibroblasts, which could be attributed to the high dose of nano-silver that induced excessive production of reactive oxygen species and caused DNA damage, leading to cell apoptosis and necrosis .
Based on the antibacterial activity results and the cytotoxicity evaluations, the TPU/NS2.5 membrane was selected as the optimal sample for use in subsequent experiments due to its excellent antibacterial activity and good biocompatibility.
Ag+ release into PBS
In vivo effect of TPU/NS2.5 on healing of infected wounds
Taken together, these results demonstrate that TPU/NS2.5 membranes can efficiently eliminate MRSA and P. aeruginosa infections in vivo, and maintain a non-septic and normal wound microenvironment for tissue regeneration, leading to rapid re-epithelialization and wound closure, while causing no measurable damage to normal tissues. Therefore, TPU/NS2.5 is a promising candidate for application in the management of infected wounds.
In summary, we prepared a biocompatible, flexible and antibacterial wound dressing by incorporating nano-silver onto a porous TPU membrane using biomimetic polydopamine. The entire preparation process was facile, mild and eco-friendly. The TPU/NS2.5 dressing possessed strong mechanical strength and excellent flexibility, and exhibited acceptable antibacterial activity against P. aeruginosa, E. coli, S. aureus and MRSA while exhibiting no obvious toxicity to mammalian cells. Furthermore, by employing a bacteria-infected (MRSA or P. aeruginosa) wound model, we found the dressing could effectively prevent bacterial infection in vivo and promote wound healing by accelerating re-epithelialization. Therefore, the constructed TPU/NS2.5 membrane has great potential for biomedical applications such as wound management.
MLL carried out experiments, analyzed data and wrote the paper. JW and GXL designed the study and supervised the project. TFL, XWC and JCY assisted in the data analysis and discussion. JD, WFH, XRZ, XHH and QL drew the figures and assisted in the preparation and characterizations of the nanocomposite. All authors read and approved the final manuscript.
We thank the assistance from Miss Danfeng He (Institute of Burn Research, Southwest Hospital, Army Medical University, China) for the instruction of XRD spectra analysis.
All authors declare that they have no competing interests.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
Consent for publication
Ethics approval and consent to participate
All animal experiments were performed in accordance with the guidelines and the ethical standards of the Institutional Animal Care and Use Committee of the Third Military Medical University.
This work was supported by the State Key Laboratory Funding (SKLZZ201221) and National Special Scientific Projects of Public Welfare Industry Funding of China (No. 201502015).
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