R H I N O L O G Y
Effects of polymer-based, silver nanoparticle-coated silicone
splints on the nasal mucosa of rats
Sultan S¸evik Elic¸ora1•Duygu Erdem1•Aykut Erdem Dinc¸1•O¨ zlem Altunordu Kalaycı2•
Baki Hazer3• Gamze Yurdakan4•Canan Ku¨lah5
Received: 28 September 2016 / Accepted: 15 November 2016 / Published online: 18 November 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Infection is a serious complication after nasal packing that otolaryngologists seek to avoid. The aim of this study is to investigate the use of silver (Ag) nanopar-ticle, which serves as antimicrobial agents, with nasal tampons. The study design is an experimental animal model and the setting is tertiary referral center. Twenty-four rats were randomized into the following Twenty-four groups: (1) control group (n = 6); (2) silicone nasal splint (SNS) group (n = 6); (3) polypropylene-grafted polyethylene glycol (PP-g-PEG) amphiphilic graft copolymer-coated SNS group (n = 6); and (4) Ag nanoparticle-embedded PP-g-PEG (Ag-PP-g-PEG) amphiphilic graft copolymer-coated SNS group (n = 6). These tampons were applied to rats for 48 h, after which they were removed in a sterile manner, and the rats were sacrificed. The nasal septa of the rats were excised, and assessments of tissue changes in the nasal mucosa were compared among the groups. The removed tampons were microbiologically examined, and quantitative analyses were made. When the groups were compared microbiologically, there were no significant differences in bacterial colonization rates of
coagulase-negative Staphylococcus spp. among the three groups (p = 0.519), but there was a statistically significant dif-ference among bacterial colonization rates of Heamophilus parainfluenzae and Corynebacterium spp. (p = 0.018, p = 0.004). We found that H. parainfluenzae grew less robustly in the Ag-PP-g-PEG than the PP-g-PEG group (p = 0.017). However, we found no significant difference between the Ag-PP-g-PEG and SNS groups, or between the SNS and PP-g-PEG groups. The growth of Corynebac-terium spp. did not differ significantly between the Ag-PP-g-PEG and SNS groups (p = 1.000). When Group 4 was compared with Group 2, the former showed less inflam-mation. Compared with other tampons, Ag-PP-g-PEG amphiphilic graft copolymer-coated silicone nasal tampons caused less microbiological colonization and inflammation. Therefore, the use of these tampons may prevent secondary infections and reduce the risk of developing complications by minimizing tissue damage.
Keywords Polyethylene glycol Ag nanoparticle Nasal tampon Nasal splint
Introduction
Septoplasty is one of the most common surgeries in otorhinolaryngology practices. Although many suture techniques have been prescribed after septoplasty, nasal tampon application is still a common technique [1,2]. An ideal tampon has certain characteristics: it should exert pressure but not harm the mucosa; it should not cause infection; it should not bother the patient while being removed; it should be able to be easily applied and removed; and it should not delay the healing process. Many materials have been used as tampons, such as calcium & Sultan S¸evik Elic¸ora
drsultan@mynet.com
1 Department of Otorhinolaryngology, Faculty of Medicine,
Bu¨lent Ecevit University, Zonguldak, Turkey
2 Department of Physics, Faculty of Arts and Science,
Bu¨lent Ecevit University, Zonguldak, Turkey
3 Department of Chemistry, Engineering of Nanotechnology,
Bu¨lent Ecevit University, Zonguldak, Turkey
4 Department of Pathology, Faculty of Medicine,
Bu¨lent Ecevit University, Zonguldak, Turkey
5 Department of Microbiology, Faculty of Medicine,
Bu¨lent Ecevit University, Zonguldak, Turkey DOI 10.1007/s00405-016-4394-6
alginate nasal packing (Algoste´ril), polyvinyl acetal (Me-rocel), sterile gauze, sterilized silicone splints, gel tampons, and biodegradable synthetic polyurethane foam. Presently, sterilized silicone splint tampons are the most commonly used; however, although they possess most of the charac-teristics of an ideal tampon [3], in the long term, they may cause perforation [4] and increase the risk of infection.
Infections caused by tampons delay the healing process. Tampons may also cause sinus infections [5] and tubal dysfunction [6, 7], significantly affecting the patient’s postoperative comfort. When these infections progress, sepsis may occur and the life of the patient could even be threatened [8, 9]. Thus, these infections need to be pre-vented. In this study, we investigated the use of silver (Ag) ions which serve as antimicrobial agents [10], with poly-mer-coated nasal tampons.
Materials and methods
Care of animals and treatmentThis study was performed in the experimental research laboratory of the Faculty of Medicine. It was approved by the University Ethics Committee (No: 2015-24-04/11) and complied with the Guidelines for the Care and Use of Experimental Animals. Twenty-four male Wistar albino rats, each weighing between 200 and 250 g, were used in this study. They were maintained according to standard guidelines.
Nasal splint preparation
A Breathe-Easy (Invotec International; Jacksonville, FL, USA) silicone internal nasal splint (INS) was cut into the size of 1 mm 9 2 mm 9 10 mm. A total of 18 nasal tampons were prepared.
Chlorinated polypropylene (PP-Cl; Mw = 150,000 Da) with 1 Cl per three repeating units where is the Cl relative to CH3 polyethylene glycols (PEGs) with Mn = 4000 Da, and silver nitrate (AgNO3) were obtained from
Sigma-Aldrich (St. Louis, MO, USA). Tetrahydrofuran (THF) was also supplied by Sigma and was distilled over sodium before use. Polypropylene-g-PEG (PP-g-PEG) graft copolymers were synthesized by the reaction of PP-Cl with, respectively, according to the procedure described by Balci et al. [11].
Synthesis of Ag embedded into PP-g-PEG comb-type amphiphilic graft copolymers
Silver nanoparticle-embedded PP-g-PEG (Ag-PP-g-PEG) amphiphilic graft copolymers were prepared according to a
previously reported procedure by Kalayci et al. [12]. A total of 0.0858 g AgNO3 were dissolved in 10 mL THF.
Next, 0.074 g NaBH4was dissolved in 1.7 g distilled H2O
to prepare a fresh solution. Meanwhile, 0.01 mL metal salt solution was added to a polymer solution containing 0.2 g PP-g-PEG (4000) in 10 mL THF, after which the mixture was vigorously stirred at room temperature and NaBH4
solution (0.01 mL) was added. The solution was stirred for 1 h, poured into a Petri dish, and allowed to evaporate. The solvent cast nanocomposite film was washed with methanol and dried under vacuum for 24 h. The dry nanocomposite film was dissolved in 10 mL toluene for optical characterization.
Coating of silicone tube with Ag-PP-g-PEG amphiphilic graft copolymers
PP-g-PEG film and Ag-embedded PP-g-PEG nanocom-posite film were dissolved in 15 mL toluene, 0.100, 0.084 g, respectively. A silicon tube (diameter: 10 mm 9 1 mm 9 2 mm) was inserted into Ag-PP-g-PEG solution in toluene, after which it was removed to allow evaporation of the solvent, and left to air dry. This proce-dure was repeated 15 times until an Ag-PP-g-PEG film formed on the silicone tube.
All of the tampons were sterilized by ethylene oxide. Nasal splint application
The 24 rats were randomized (using random number tables) into the following four groups: (1) control group (n = 6); (2) silicone nasal splint (SNS) group (n = 6); (3) PP-g-PEG amphiphilic graft copolymer-coated SNS group (n = 6); and (4) Ag-PP-g-PEG amphiphilic graft copolymer-coated SNS group (n = 6). Each rat was anesthetized via intramuscular injection of 90 mg/kg ketamine hydrochloride (KetalarÒ 10 mL vial; Pfizer) and 10 mg/kg xylazine hydrochloride (RompunÒ50 mL 2% vial; Bayer). In Groups 2, 3, and 4, the tampons were placed in the right nasal passages of the rats and sutured with a 4-0 silk suture (Fig.1).
Nasal splint removal
The rats in all of the groups were sacrificed after 48 h. The tampons were removed in a sterile manner and were put into sterilized containers. The nasal septum was excised for histopathological examination.
Microbiologic studies
After the incubation period, the nasal tampons were removed. Each nasal tampon was inoculated with 1 mL brain heart infusion broth (Merck), vortexed, and incubated
at 37°C for 2 h. Quantitative analysis of the cultures was performed according to previously described standard procedures [13]. Briefly, 10 and 100 lL of each sample were inoculated onto 5% sheep blood agar (Oxoid; Bas-ingstoke, UK), EMB agar (Oxoid), and chocolate agar (Oxoid). After a 24 h incubation period at 37°C, colonies with different morphology types were defined, and identi-fication of the bacteria was performed according to stan-dard microbiological techniques. The microbial growth number per mL for each bacterial species was determined by the arithmetic means of the 10 and 100 lL sample cultures.
Histopathological studies
For histopathological examination, the biopsy specimens were fixed in 10% formalin immediately after removal, dehydrated in graded concentrations of ethanol, cleared in xylene, embedded in paraffin, cut into 5 lM-thick sections, and then stained with hematoxylin and eosin. All of the specimens were subjected to histologic examination. A pathologist performed a blinded examination of the sec-tions under a light microscope. The surface of normal septal mucosa was lined by respiratory epithelium, with hyaline cartilage, which consists of vessels and connective tissue under the submucosa. The findings were compared with the normal mucosal pattern and were scored from 0 to 3, based on the presence and characteristics of inflamma-tion (acute or chronic inflammainflamma-tion), mucosal erosion, ulceration, and perforation. The severity of the inflamma-tion was scored by the number of inflammatory cells in a 4009 magnification area: no inflammatory cells, 0; less than 10 inflammatory cells, mild; 10–30 inflammatory cells, moderate; and over 30 inflammatory cells, severe. Histomorphological changes were scored as follows: nor-mal histology, limited only to the mucosa, involving the
submucosa, and mucosal ulcerations and/or perforations [4].
Statistical analysis
Statistical analysis was performed with the SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as frequencies and percents. The Chi-squared test was used to determine differences among the three groups for categorical vari-ables. Differences among the groups were analyzed by the Kruskal–Wallis test for continuous variables. Dual com-parisons among the groups with significant values were evaluated using the Dunn’s test after the Kruskal–Wallis test. A p value less than 0.05 was considered statistically significant.
Results
Microbiologic evaluation
Only Groups 2, 3, and 4 were microbiologically compared, because Group 1 did not undergo nasal packing. We found no significant difference between the three groups in terms of the colonization rate of Staphylococcus spp. (p = 0.519). However, significant between-group differ-ences in the colonization rates of H. parainfluenzae and Corynebacterium spp. were evident (p = 0.018 and p = 0.004, respectively).
In terms of H. parainfluenzae, the PP-g-PEG group exhibited the highest colonization rate, followed by the SNS group. No bacterial growth was evident in the Ag-PP-g-PEG group. When groups were evaluated by Dunn’s test which is a post-hoc analysis, a significant difference was apparent between the Ag-PP-g-PEG and PP-g-PEG groups (p = 0.017), but not between the Ag-PP-g-PEG and SNS groups. In terms of Corynebacterium spp., the PP-g-PEG group exhibited the highest colonization rate, followed by the SNS group; this difference was significant (p = 0.041), as was that between Ag-PP-g-PEG and PP-g-PEG groups (p = 0.005). No bacterial growth was evident in the Ag-PP-g-PEG group, and this level did not differ significantly from that in the SNS group (p = 1.000).
The numbers of bacteria for each group are shown in Table1.
Histopathological evaluation
Groups 1, 2, 3, and 4 were evaluated histopathologically. When evaluated in terms of inflammation, Ag-PP-g-PEG packing caused less inflammation than did any other Fig. 1 Suturation of the nasal tampons to the nasal septum
Table 1 Number of bacteria and its distribution for each group Coagulase-Negative Staphylococcus (CNS) spp., cfu/mL Heamophilus parainfluenzae, cfu/mL Corynebacterium spp., cfu/mL Group 1a Group 2 (SNS), N = 6 1 400 15,000 0 2 10,000 0 0 3 25,000 0 0 4 1600 2000 20,000 5 20,000 1200 0 6 20,000 1200 0 Group 3 (PP-g-PEG), N = 6 1 700 100 2500 2 20,000 6000 2400 3 5000 25,000 20,000 4 20,000 0 5000 5 5000 2500 3000 6 100 3000 2500 Group 4 (Ag-PP-g-PEG), N = 6 1 10,000 0 0 2 10,000 0 0 3 7000 0 0 4 20,000 0 0 5 15,000 0 0 6 7000 0 0
SNS silicone nasal splint group, PP-g-PEG polypropylene-grafted polyethylene glycol (PP-g-PEG) amphiphilic graft copolymer-coated SNS group, Ag-PP-g-PEG-Ag nanoparticle-embedded PP-g-PEG (Ag-PP-g-PEG) amphiphilic graft copolymer-coated SNS group
a Because no tampons were used in Group 1, microbiological examination was not performed
Fig. 2 aControl groups, normal mucosa (910
magnification, H&E). b Ag-PP-g-PEG group, mucosal lymphoplasmocyter inflammatory cells, mild inflammation (940
magnification, H&E). c PP-g-PEG groups, submucosal lymphoplasmocyter inflammatory cells, severe inflammation (940
magnification, H&E). d SNS groups, submucosal lymphoplasmocyter inflammatory cells, severe inflammation (940 magnification, H&E)
material (p = 0.024), followed by the PP-g-PEG material. The SNS group experienced the most intense inflamma-tion; this observation was statistically significant (p = 0.030). The inflammation scores differed significantly only between the Ag-PP-g-PEG and SNS groups (Table3). With respect to inflammation localization, there was also no difference between the groups (p = 0.132). In 80% of Ag-PP-g-PEG, inflammation was limited in mucosa. In 83% of the SNS group, inflammation advanced to the submucosa (Fig.2). Inflammation and inflammation localization for each group are shown in Table2.
Dual comparisons between different nasal packing groups are shown in Table3.
Discussion
PP is a material that can be used in various biomedical practices, and is usually used in non-absorbable sutures, vascular grafts, abdominal wall healings, and urogenital area surgeries [14–17]. Because of its hydrophobic feature, PP makes adhesion difficult; however, it may also cause severe foreign body reactions. This feature provides an advantage of refreshing weak tissues, yet it limits other clinical practices. Thus, hydrophilic blocks were added to the structure of PP to change the hydrophilic structure, crystallinity, mechanical features, and biocompatibility of PP [18]. PEG has been used extensively for this purpose [19]. Studies have shown that PEG-grafted copolymers reduce platelet adhesion and bacteria repulsion [20]. Ag nanoparticles have been demonstrated to have antimicro-bial effects [21–24]. In subsequent studies, nanoparticles (esp. metals, such as Au and Ag) were added to these polymers, and the biocompatibility and antimicrobial effectiveness of the polymers increased [8].
In a study, the Ag nanoparticle was embedded into PP-g-PEG to preventing ventricular shunt catheter infec-tions [23]. In this study, tampons in which Ag nanoparti-cles were embedded into PP-g-PEG were used. No microorganisms other than Coagulase-Negative Staphylo-cocci (CNS) spp. were reproduced on these tampons. CNS spp. is the major component of nasal flora, and constitutes 68% of the nasal flora [25]. Although it was thought that tampons changed the nasal flora balance in favor of Sta-phylococcus, no infections were encountered in the rats. Histopathologically, low-grade inflammation was seen in the Ag-PP-g-PEG groups.
Lower inflammation is a factor that accelerates the healing process [4]. In this study, SNS, PP-g-PEG, and PEG were compared, and it was found that Ag-PP-g-PEG caused less inflammation than the others. Inflamma-tion was mostly restricted to mucosa and low-grade inflammation.
Another complication caused by nasal tampons is toxic shock syndrome, which is caused by Staphylococcus Aur-eus (SA). In our study, SA colonization was not observed in the SNS, PP-g-PEG, and Ag-PP-g-PEG groups. In a study conducted by Hazer et al. [26], titanium screws were used on the animals. PP-g-PEG-Ag-covered screws were used on methicillin-resistant, Staphylococcus aur-eus (MRSA)-inoculated animals. In these animals, bacte-rial colonization was relatively low, and in the same study, the Ag concentration of muscle and blood tissue was investigated, but no accumulation was encountered. Table 2 Distribution of inflammation and inflammation localization for each group
Inflammation Localization 0 1 2 3 N M MS P Group 1 (control) 1 1 1 2 1 1 3 1 1 4 1 1 5 1 1 6 1 1
Group 2 (sterile silicone splint), N = 6
1 1 1 2 1 1 3 1 1 4 1 1 5 1 1 6 1 1 Group 3 (PP-g-PEG), N = 6 1 1 1 2 1 1 3 1 1 4 1 1 5 1 1 6 1 1 Group 4 (Ag-PP-g-PEG), N = 6 1 1 1 2 1 1 3 1 1 4 1 1 5 1 1 6 1 1
SNS silicone nasal splint group, PP-g-PEG polypropylene-grafted polyethylene glycol (PP-g-PEG) amphiphilic graft copolymer-coated SNS group, Ag-PP-g-PEG-Ag nanoparticle-embedded PP-g-PEG (Ag-PP-g-PEG) amphiphilic graft copolymer-coated SNS group Inflammation: 0, no inflammation; 1, mild; 2, moderate; 3, severe Localization: N, normal; M, limited to the mucosa; MS, limited to the mucosa and the submucosa; P, perforation
Although the pathogenicity of H. parainfluenzae in the respiratory tract remains unclear, the bacterium is consid-ered to be closely related to non-typable H. influenzae [27], which causes paranasal sinus infections [28]. We found bacterial colonization in the PP-g-PEG and SNS groups, but not in the Ag-PP-PEG group.
Some studies have shown that Corynebacterium spp. is components of the normal flora of healthy subjects [29]. Other studies have claimed that these bacteria play roles in the etiology of nasal polyps and chronic rhinosinusitis [30,31]. We found no bacterial colonization in the Ag-PP-g-PEG group and colonization in only one rat of the SNS group. Thus, these bacteria are probably not components of the normal rat nasal flora.
Our study had certain limitations. First, our sample size was low. Second, the rats were not subject to surgery; we thus lack information on the outcomes of nasal packing after surgery. Third, we have no data on the long-term effects of packing; rats cannot endure prolonged nasal packing, because the septa are very thin and tend to develop perforations. Further controlled studies are needed. Such studies should have larger sample sizes and use tampons for long-term packing. In addition, there is a need
for additional research on Ag toxicity. We believe that our work is a useful preliminary report.
Conclusions
This study showed that Ag-PP-g-PEG-covered tampons have good anti-inflammatory and antimicrobial effects compared with SNS tampons. With further development, the use of these tampons may decrease the risk of complications and protect patients from secondary infections.
Acknowledgements We would to thank Assistant Professor Fu¨ru¨zan Ko¨ktu¨rk, from the Biostatistics department of Bu¨lent Ecevit Univer-sity Faculty of Medicine, for performing the statistical analyses in this study; and Nilu¨fer Ugur O¨ zlu¨k, from the Microbiology department of Bu¨lent Ecevit University Faculty of Medicine, for the microbiological analysis.
Compliance with ethical standards
Conflict of interest The authors report no conflicts of interest. Funding This study was not funded.
Table 3 Statistical analysis of the bacterial colonization numbers, inflammation scores, and post-hoc analysis of dual comparisons
Group Mean N Std. deviation p value (Kruskal–Wallis test) Post-hoc analysis p value (Dunn’s test) H. parainfluenzae spp. SNS 3233.33 6 5816.414 SNS/Ag-PP-g-PEG 0.169 PP-g-PEG 6100.00 6 9518.403 0.018 PP-g-PEG/Ag-PP-g-PEG 0.017 Ag-PP-g-PEG 0.00 6 0.000 SNS/PP-g-PEG 1.000 Total 3111.11 18 6570.512 CNS spp. SNS 12833.33 6 10388.006 PP-g-PEG 8466.67 6 9169.442 0.519 Ag-PP-g-PEG 11500.00 6 5089.204 Total 10933.33 18 8223.138 Corynebacterium spp. SNS 3333.33 6 8164.966 SNS/Ag-PP-g-PEG 1.000 PP-g-PEG 5900.00 6 6977.105 PP-g-PEG/Ag-PP-g-PEG 0.005 Ag-PP-g-PEG 0.00 6 0.000 0.004 SNS/PP-g-PEG 0.041 Total 3077.78 18 6332.693 Inflammation SNS 2.67 6 0.516 SNS/Ag-PP-g-PEG 0.024 PP-g-PEG 1.83 6 1.329 PP-g-PEG/Ag-PP-g-PEG 0.515 Ag-PP-g-PEG 1.00 6 0.632 0.030 SNS/PP-g-PEG 0.600 Total 1.83 18 1.098
SNS silicone nasal splint group, PP-g-PEG polypropylene-grafted polyethylene glycol (PP-g-PEG) amphiphilic graft copolymer-coated SNS group, Ag-PP-g-PEG-Ag nanoparticle-embedded PP-g-PEG (Ag-PP-g-PEG) amphiphilic graft copolymer-coated SNS group. The statistically significant values are shown as bold
Ethical approvalAll applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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