This cycle produced a single bilayer of positively and negatively charged polyelectrolytes. First, the thickness and frequency of material deposited in each layer was obtained by a QCM QCM, 5 MHz, Stanford Research Systems.

Apart from this, we used Hitachi S electron microscope Tokyo, Japan to examine the morphology of the multilayer films structure at an accelerating voltage of 10 kV. A sample of each multilayer films was previously sputtered with a gold—palladium mixture for five minutes under vacuum.

Finally, adjusted the image so that the multilayer films structure was clearly visible and took a photographic record. Finally, Zeta potential measurements were performed by a zeta potential analyzer ZS90, Malvern Instruments Ltd.

aureus at at 37 °C. At specific time intervals, we used spectroscopy Synergy 2, BioTek, Winooski, VT, USA to test CHX concentration at nm.

In this experiment, silicon wafers were selected as substrate material. aureus , ATCC for 3 days. All samples were taken at the same time and dried under nitrogen atmosphere.

Then the samples were sterilized under UV light at nm for 30 min placed 25 cm from the samples. Specifically, Luria—Bertani LB broth and LB agar 1.

After incubation, the ZOI was measured with a ruler and recorded in centimeter and taken as the marker for multilayer films antibacterial activity. Meanwhile, the thickness of all samples after incubation were followed by spectroscopic ellipsometry M DITM, J.

According to published standard methods [ 47 ], the continuing wavelength ranging from to nm and selected the angle of incidence of both 65ºand 70º for ellipsometry measurements.

The thickness of samples was determined through the Cauchy model. We set parameters An and Bn for the Cauchy layer at 1. Then, the thickness that fit the multilayer films was fabricated such that it can be automatically calculated.

The shake-flask culture method with S. First, all the samples were sterilized under UV light at nm for 30 min. aureus solution suspension in saline solution vehicle, 0.

The unmodified PDMS was set as control group. Afterward, these test tubes were incubated in a shaker incubator for 24 h at 37 °C. aureus were pipetted from the test tubes described above and used to prepare consecutive dilutions by taking 0.

Next, L S. aureus solution from the above solution was plated on solid agar and repeated five times for each group. Following incubation for 24 h, the viable number of S. In vitro grown S. aureus were spun down for 10 min at rpm at 4 °C, rinsed three times with normal saline, and diluted in normal saline to get OD values of 1.

The control group add unmodified PDMS sample. The above mixture was put in a shaking incubator rpm at 37 °C for 4 h. Put forty microliters 40 µL of supernatant into µL of working solution, and protein concentration was measured by the Pierce BCA Protein Assay Kit.

And the incubation was continued for an additional 30 min, the absorption of the above mixed solution was determined at nm wavelength in order to calculate the protein leakage concentrations. The improper use of antibiotics promotes the development of antibiotic-resistant bacteria.

And the emergence of resistant bacteria has developed into a world-wide public health concern. In this regard, researchers have done a lot of work [ 48 ]. In this study, we selected the MRSA ATCC The antibacterial activity of the membranes against MRSA was evaluated by inhibition zone. Primary rat osteoblasts were isolated through a method described previously [ 49 ].

Confluent cells were digested by 0. About 1. At 4 and 7 days, the CCK-8 reagent was added into each plate well and incubated for 2 h. The absorbance was determined at a wavelength of nm. Six repeats were performed at each time point.

Animal care, operation, treatment procedures, and animal welfare were executed in strict accordance with the National Institutions of Health Guide for the Care, with relevant study programs also approved by the Animal Care and Use Committee of Wenzhou Medical University.

After the rats had been adaptively fed for 14 days in room temperature adaptability conditions, the experiment was conducted.

More specifically, rats were randomly divided into three different groups 10 animals per group. All the Kirschner wires were sterilized under UV light at nm for 30 min, stored in a sterile, sealed storage box.

Then, the skin, subcutaneous tissue and joint capsule was cut, exposing the tibial plateau. It is worth noting that important nerves, muscle, blood vessels, ligamentous tissues and anatomical structural should be protected as much as possible. After the tibial plateau was fully exposed, under strictly sterile conditions, the medullary cavity was drilled vertically with a prepared 0.

The K-wire was placed in the borehole as quick and as accurate as possible. aureus suspension was inoculated in the above borehole unmodified group.

The third group was placed with unmodified Kirschner wires, and no injection of S. aureus suspension SHAM group. All boreholes were subsequently closed with bone wax and the wound were stitched with 3—0 interrupted nylon sutures.

Strictly followed the requirements of surgical aseptic operation throughout this operation. The successfully resuscitated rats were monitored for 1 h. All rats were raised under standard breeding conditions and monitored daily.

Blood was examined for total WBC counts, CRP levels, IL-1 and IL-8, they are strong important inflammatory indicators. Used the small-animal X-ray fluorescence tomography energy 45 kV, current mA, integration time ms, Carestream DRX to inspect and evaluate the metaphysis of tibial plateau.

After the rats were killed, the knees wound were examined carefully, and then collected respective tissue fluid for the bacteriological examination. The Kirschner wires were removed from the borehole, washed and stained according to the kit protocol.

In addition, Kirschner wires were sonicated in prepared sterile PBS solution for 40 min. The supernatant from the K-wires were serially diluted in sterile saline, plated onto agar plate media Thermo Fisher Scientific , and incubated at 37 °C for 24 h.

Lastly, S. aureus colonies were counted and normalized to K-wires mass. The specimens are fixed in paraformaldehyde for 12 h and then subjected to CT examination. The experimental equipment is a micro-CT system energy 70 kVp, μA, integration time ms, threshold , Skyscan ; Skyscan, Kontich, Belgium.

We use a ring with a surface radius of 0. The bone mineral density BMD , trabecular bone number Tb. Sp , trabecular thickness Tb. Th and connectivity density Conn. D within the VOI zone are analyzed, 3D and histograms are made according to the built-in software.

The tibia specimens were removed from the freezer before the test and thawed at room temperature. The tibia specimens were subjected to three-point bending by an ElectroForce computer-controlled testing machine Bose Corp.

Maximum load, Resilience and Resilience stiffness were obtained. After the tibia specimens bending test, the tibia bones were decalcified with EDTA decalcification solution for one month.

Subsequently, the tibia bones were embedded in paraffin. The other portion were then stained with Masson trichrome. Overall, the frequency shifts decreased and dissipation increased steadily as the deposition step increased.

Film thickness was calculated using Q-tools, as illustrated in Fig. B Film thickness versis layer pairs calculated by Qsoft. Half of the layers were deposited layers of MMT, and the whole number of layers were deposited layers of PLL-CHX.

Each assembled layer had an alternating positive and negative potential. The release profile in vitro exhibited a slow CHX release in PBS. Indicated the strong retention property of MMT against CHX release.

Interestingly, analogous phenomena occurred in S. aureus Fig. The amount of drug released increased with the increased of the concentration of Staphylococcus aureus. CHX release in A different concentration of CMS solution and B different concentration of S.

We used the zone of bacterial inhibition ZOI to observe the effectively release CHX depending on the changes in the microenvironment. The results were depicted in Figs. In more detail, after immersing for 3 days, the ZOI increased with the increase in concentrations of S.

And the statistical graph was presented Fig. The 0. aureus solution to 2. We also assessed the changes in thickness through spectroscopic ellipsometry Fig. The similar phenomena could also be found when we varied the concentration of CMS. The ZOI increased with the increase in concentrations of CMS Fig.

The thickness also reduced with the increase in concentrations of CMS. The above measurement of ZOI corresponded with the changes of thickness. D — E Changes of ZOI and thickness.

E — F Changes of ZOI and thickness. As defined in Fig. It is worth noting that the number of Staphylococcus aureus increased significantly in the first 2 h. And slowly decreased during the following 24 h at 37 °C.

Finally, We could still find a lot of live bacteria in the test tubes after 24 h. Apart from this, we also developed protein leakage experiment.

The presence of protein in the bacterial suspension indicates damage to the bacterial cell membranes. This experiment we used a BCA Protein Assay Kit to evaluate the amount of protein leakage. As shown in Fig.

However, a higher protein concentration This suggested that more leakage of S. aureus content had happened. The above mentioned experiments might be due to CMS released quickly when outside S. aureus strains rapidly. According to previous studies, CHX has strong bactericidal effects [ 51 ].

After incubation, produced obvious zone of inhibition Fig. In vitro antimicrobial assays. A Bacterial inhibition rate assays. B protein leakage experiment. We used the Cell Counting Kit-8 CCK-8 assay to assess the effect of above extracts on proliferation of osteoblasts cells.

Our experiments showed that cell proliferation was in a time-dependent manner. From the 1 day after modeling, all rats returned to their normal condition Fig.

The WBC, CRP, IL-1 and IL-8 for three groups were analyzed. They played an important role in the development of infections. Above infection indicators proved a distinguishing difference between the 3 groups. All infection indicators were increased in 3 groups on the next day after surgery, this may be due to the stress reaction as a result of the surgery.

Unmodified group exhibited highest WBC, CRP, IL-1 and IL-8 levels due to lack of CHX and foreign body reactions after 7 days of implantation. Ultimately, all infection indicators of rats in the unmodified group remained higher than normal level after 6 weeks of implantation.

This showed that the infection cannot be effectively controlled. Since no bacteria were injected in rats and performed aseptic operation during surgery, no infection occurred in the SHAM group, all inflammation indicators were at normal levels. We used the small-animal X-ray fluorescence tomography to inspect and evaluate the metaphysis of tibial plateau in all rats.

Because the infection could not be effectively controlled, there observed severe infection in the rat's knee joint of unmodified group. Specifically, the tibial plateau of the unmodified group was characterized by an irregular partially osteolytic lesion, more serious was that adjacent bone tissue is also infected and soft tissue becomes swollen, part of patella, femoral condyle and tibial plateau were translucent Fig.

This might be caused by the spread of bacteria. To quantify the extent of bone infection, we follow the bone infection radiological evaluation system proposed by Lucke et al. From the Fig. The higher the score, the more serious the infection.

J X-ray score with different group. K bacteria recovered from implanted K-wire. Fluorescent microscopy images of live staining of S.

In order to further explore the effects of films enzymatic degradation on antibacterial effect in vivo. We performed a detailed bacteriological examination of the samples. After 24 h of culture, we found a lot of bacterias in the tissue fluid of the unmodified group Fig.

SYTO9 can stain live bacteria with intact cell membranes to form green fluorescence. aureus cells individually distributed on unmodified Kirschner wires. aureus cells Fig. Since no bacteria were injected, there were still no bacteria here in SHAM group Fig.

Intraosseous implant infection can affect the composition of bone tissue. In order to get a more accurate conclusion of the changes of bone composition, we used a micro CT on bone specimens obtained 6 weeks after implantation.

Conversely, unmodified group with no new bone formation in Kirschner wires surface Fig. Moreover, quantitative evaluation of the trabecular bone within the region of interest ROI was showed.

Compared with the unmodified implant group, the bone mineral density BMD , trabecular bone number Tb. Conversely, trabecular separation Tb. A 6 weeks after modeling, micro-CT 3D images of the bone specimens.

New bone formation around the Kirschner wires. B Bone mineral density BMD. C Trabecular bone number Tb. E Connectivity density Conn.

F Trabecular thickness Tb. G Trabecular separation Tb. Infection could affect bone strength, so we used three-point bending experiment to test the integration strength of bone. As demonstrated in the experiments, the Maximum load with unmodified group was However, a higher value The Resilience with unmodified group was The Resilience stiffness with unmodified group was The tibia specimens bending test with different group.

A The Maximum load. B The Resilience. C The Resilience stiffness. We found that there were a large number of inflammatory cells in the bone trabecula of the unmodified group, which confirmed the occurrence of bone infection Fig.

The SHAM group also showed normal bone trabecula Fig. A similar phenomenon identified for Masson trichrome. In unmodified group, most areas was stained red due to fibrosis in the bone marrow cavity after infection Fig.

Furthermore, CHX depicted on-demand property which was triggered intelligently by CMS or bacterium solution. Furthermore, in vivo research demonstrates the potential to provide more robust evidence for the use of this biomaterial to mitigate infections associated with intraosseous implants.

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Chlorine long has been used as the disinfectant in water treatment. Water disinfection with monochloramine by municipal water-treatment plants substantially reduced the risk for healthcare—associated Legionnaires disease , Chlorine dioxide also has been used to control Legionella in a hospital water supply.

Thus, if a user wished to have a solution containing ppm of available chlorine at day 30, he or she should prepare a solution containing 1, ppm of chlorine at time 0.

Sodium hypochlorite solution does not decompose after 30 days when stored in a closed brown bottle The use of powders, composed of a mixture of a chlorine-releasing agent with highly absorbent resin, for disinfecting spills of body fluids has been evaluated by laboratory tests and hospital ward trials.

The inclusion of acrylic resin particles in formulations markedly increases the volume of fluid that can be soaked up because the resin can absorb — times its own weight of fluid, depending on the fluid consistency.

One problem with chlorine-releasing granules is that they can generate chlorine fumes when applied to urine Formaldehyde is used as a disinfectant and sterilant in both its liquid and gaseous states. Liquid formaldehyde will be considered briefly in this section, and the gaseous form is reviewed elsewhere The aqueous solution is a bactericide, tuberculocide, fungicide, virucide and sporicide 72, 82, OSHA indicated that formaldehyde should be handled in the workplace as a potential carcinogen and set an employee exposure standard for formaldehyde that limits an 8-hour time-weighted average exposure concentration of 0.

The standard includes a second permissible exposure limit in the form of a short-term exposure limit STEL of 2 ppm that is the maximum exposure allowed during a minute period Ingestion of formaldehyde can be fatal, and long-term exposure to low levels in the air or on the skin can cause asthma-like respiratory problems and skin irritation, such as dermatitis and itching.

For these reasons, employees should have limited direct contact with formaldehyde, and these considerations limit its role in sterilization and disinfection processes. Key provisions of the OSHA standard that protects workers from exposure to formaldehyde appear in Title 29 of the Code of Federal Regulations CFR Part Formaldehyde inactivates microorganisms by alkylating the amino and sulfhydral groups of proteins and ring nitrogen atoms of purine bases Varying concentrations of aqueous formaldehyde solutions destroy a wide range of microorganisms.

Four percent formaldehyde is a tuberculocidal agent, inactivating 10 4 M. tuberculosis in 2 minutes 82 , and 2. anthracis The formaldehyde solution required 2 hours of contact to achieve an inactivation factor of 10 4 , whereas glutaraldehyde required only 15 minutes. For these reasons and others—such as its role as a suspected human carcinogen linked to nasal cancer and lung cancer , this germicide is excluded from Table 1.

When it is used, , direct exposure to employees generally is limited; however, excessive exposures to formaldehyde have been documented for employees of renal transplant units , , and students in a gross anatomy laboratory Formaldehyde is used in the health-care setting to prepare viral vaccines e.

To minimize a potential health hazard to dialysis patients, the dialysis equipment must be thoroughly rinsed and tested for residual formaldehyde before use.

Paraformaldehyde, a solid polymer of formaldehyde, can be vaporized by heat for the gaseous decontamination of laminar flow biologic safety cabinets when maintenance work or filter changes require access to the sealed portion of the cabinet.

Glutaraldehyde is a saturated dialdehyde that has gained wide acceptance as a high-level disinfectant and chemical sterilant Aqueous solutions of glutaraldehyde are acidic and generally in this state are not sporicidal.

Once activated, these solutions have a shelf-life of minimally 14 days because of the polymerization of the glutaraldehyde molecules at alkaline pH levels.

This polymerization blocks the active sites aldehyde groups of the glutaraldehyde molecules that are responsible for its biocidal activity.

Novel glutaraldehyde formulations e. However, antimicrobial activity depends not only on age but also on use conditions, such as dilution and organic stress. However, two studies found no difference in the microbicidal activity of alkaline and acid glutaraldehydes 73, The biocidal activity of glutaraldehyde results from its alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups of microorganisms, which alters RNA, DNA, and protein synthesis.

The mechanism of action of glutaraldehydes are reviewed extensively elsewhere , The in vitro inactivation of microorganisms by glutaraldehydes has been extensively investigated and reviewed , Spores of C.

Microorganisms with substantial resistance to glutaraldehyde have been reported, including some mycobacteria M. chelonae , Mycobacterium avium-intracellulare, M.

xenopi , Methylobacterium mesophilicum , Trichosporon , fungal ascospores e. chelonae persisted in a 0. Two percent alkaline glutaraldehyde solution inactivated 10 5 M. tuberculosis cells on the surface of penicylinders within 5 minutes at 18°C However, subsequent studies 82 questioned the mycobactericidal prowess of glutaraldehydes.

tuberculosis and compares unfavorably with alcohols, formaldehydes, iodine, and phenol Suspensions of M. avium, M. intracellulare, and M. tuberculosis estimated time to complete inactivation ~25 minutes The rate of kill was directly proportional to the temperature, and a standardized suspension of M.

tuberculosis could not be sterilized within 10 minutes An FDA-cleared chemical sterilant containing 2. tuberculosis per membrane Several investigators 55, 57, 73, 76, 80, 81, 84, have demonstrated that glutaraldehyde solutions inactivate 2. tuberculosis in 10 minutes including multidrug-resistant M.

tuberculosis and 4. tuberculosis in 20 minutes. Glutaraldehyde is commonly diluted during use, and studies showed a glutaraldehyde concentration decline after a few days of use in an automatic endoscope washer , This emphasizes the need to ensure that semicritical equipment is disinfected with an acceptable concentration of glutaraldehyde.

Data suggest that 1. Chemical test strips or liquid chemical monitors , are available for determining whether an effective concentration of glutaraldehyde is present despite repeated use and dilution. The frequency of testing should be based on how frequently the solutions are used e.

The bottle of test strips should be dated when opened and used for the period of time indicated on the bottle e. The results of test strip monitoring should be documented. The glutaraldehyde test kits have been preliminarily evaluated for accuracy and range but the reliability has been questioned To ensure the presence of minimum effective concentration of the high-level disinfectant, manufacturers of some chemical test strips recommend the use of quality-control procedures to ensure the strips perform properly.

In December , EPA issued an order to stop the sale of all batches of this product because of efficacy data showing the product is not effective against spores and possibly other microorganisms or inanimate objects as claimed on the label Other FDA cleared glutaraldehyde sterilants that contain 2.

Glutaraldehyde is used most commonly as a high-level disinfectant for medical equipment such as endoscopes 69, , , spirometry tubing, dialyzers , transducers, anesthesia and respiratory therapy equipment , hemodialysis proportioning and dialysate delivery systems , , and reuse of laparoscopic disposable plastic trocars Glutaraldehyde is noncorrosive to metal and does not damage lensed instruments, rubber.

or plastics. Glutaraldehyde should not be used for cleaning noncritical surfaces because it is too toxic and expensive. Colitis believed caused by glutaraldehyde exposure from residual disinfecting solution in endoscope solution channels has been reported and is preventable by careful endoscope rinsing , Healthcare personnel can be exposed to elevated levels of glutaraldehyde vapor when equipment is processed in poorly ventilated rooms, when spills occur, when glutaraldehyde solutions are activated or changed, , or when open immersion baths are used.

Acute or chronic exposure can result in skin irritation or dermatitis, mucous membrane irritation eye, nose, mouth , or pulmonary symptoms , Epistaxis, allergic contact dermatitis, asthma, and rhinitis also have been reported in healthcare workers exposed to glutaraldehyde , Glutaraldehyde exposure should be monitored to ensure a safe work environment.

The silica gel tube and the DNPH-impregnated cassette are suitable for monitoring the 0. The passive badge, with a 0. ACGIH does not require a specific monitoring schedule for glutaraldehyde; however, a monitoring schedule is needed to ensure the level is less than the ceiling limit.

For example, monitoring should be done initially to determine glutaraldehyde levels, after procedural or equipment changes, and in response to worker complaints In the absence of an OSHA permissible exposure limit, if the glutaraldehyde level is higher than the ACGIH ceiling limit of 0.

Engineering and work-practice controls that can be used to resolve these problems include ducted exhaust hoods, air systems that provide 7—15 air exchanges per hour, ductless fume hoods with absorbents for the glutaraldehyde vapor, tight-fitting lids on immersion baths, personal protection e.

If engineering controls fail to maintain levels below the ceiling limit, institutions can consider the use of respirators e. In general, engineering controls are preferred over work-practice and administrative controls because they do not require active participation by the health-care worker.

Even though enforcement of the OSHA ceiling limit was suspended in by the U. Court of Appeals , limiting employee exposure to 0. If glutaraldehyde disposal through the sanitary sewer system is restricted, sodium bisulfate can be used to neutralize the glutaraldehyde and make it safe for disposal.

The literature contains several accounts of the properties, germicidal effectiveness, and potential uses for stabilized hydrogen peroxide in the health-care setting.

Published reports ascribe good germicidal activity to hydrogen peroxide and attest to its bactericidal, virucidal, sporicidal, and fungicidal properties Tables 4 and 5 The FDA website lists cleared liquid chemical sterilants and high-level disinfectants containing hydrogen peroxide and their cleared contact conditions.

Hydrogen peroxide works by producing destructive hydroxyl free radicals that can attack membrane lipids, DNA, and other essential cell components. Catalase, produced by aerobic organisms and facultative anaerobes that possess cytochrome systems, can protect cells from metabolically produced hydrogen peroxide by degrading hydrogen peroxide to water and oxygen.

This defense is overwhelmed by the concentrations used for disinfection , Hydrogen peroxide is active against a wide range of microorganisms, including bacteria, yeasts, fungi, viruses, and spores 78, Bactericidal effectiveness and stability of hydrogen peroxide in urine has been demonstrated against a variety of health-care—associated pathogens; organisms with high cellular catalase activity e.

aureus , S. marcescens , and Proteus mirabilis required 30—60 minutes of exposure to 0. Synergistic sporicidal effects were observed when spores were exposed to a combination of hydrogen peroxide 5.

Other studies demonstrated the antiviral activity of hydrogen peroxide against rhinovirus The product marketed as a sterilant is a premixed, ready-to-use chemical that contains 7. The mycobactericidal activity of 7. tuberculosis after a minute exposure When the effectiveness of 7. No complaints were received from the nursing or medical staff regarding odor or toxicity.

A new, rapid-acting Manufacturer data demonstrate that this solution sterilizes in 30 minutes and provides high-level disinfection in 5 minutes This product has not been used long enough to evaluate material compatibility to endoscopes and other semicritical devices, and further assessment by instrument manufacturers is needed.

Under normal conditions, hydrogen peroxide is extremely stable when properly stored e. Corneal damage from a hydrogen peroxide-soaked tonometer tip that was not properly rinsed has been reported Hydrogen peroxide also has been instilled into urinary drainage bags in an attempt to eliminate the bag as a source of bladder bacteriuria and environmental contamination Although the instillation of hydrogen peroxide into the bag reduced microbial contamination of the bag, this procedure did not reduce the incidence of catheter-associated bacteriuria As with other chemical sterilants, dilution of the hydrogen peroxide must be monitored by regularly testing the minimum effective concentration i.

Compatibility testing by Olympus America of the 7. Iodine solutions or tinctures long have been used by health professionals primarily as antiseptics on skin or tissue.

Iodophors, on the other hand, have been used both as antiseptics and disinfectants. FDA has not cleared any liquid chemical sterilant or high-level disinfectants with iodophors as the main active ingredient.

An iodophor is a combination of iodine and a solubilizing agent or carrier; the resulting complex provides a sustained-release reservoir of iodine and releases small amounts of free iodine in aqueous solution.

The best-known and most widely used iodophor is povidone-iodine, a compound of polyvinylpyrrolidone with iodine. This product and other iodophors retain the germicidal efficacy of iodine but unlike iodine generally are nonstaining and relatively free of toxicity and irritancy , Several reports that documented intrinsic microbial contamination of antiseptic formulations of povidone-iodine and poloxamer-iodine caused a reappraisal of the chemistry and use of iodophors The reason for the observation that dilution increases bactericidal activity is unclear, but dilution of povidone-iodine might weaken the iodine linkage to the carrier polymer with an accompanying increase of free iodine in solution Iodine can penetrate the cell wall of microorganisms quickly, and the lethal effects are believed to result from disruption of protein and nucleic acid structure and synthesis.

Published reports on the in vitro antimicrobial efficacy of iodophors demonstrate that iodophors are bactericidal, mycobactericidal, and virucidal but can require prolonged contact times to kill certain fungi and bacterial spores 14, , , Three brands of povidone-iodine solution have demonstrated more rapid kill seconds to minutes of S.

aureus and M. chelonae at a dilution than did the stock solution The virucidal activity of 75— ppm available iodine was demonstrated against seven viruses Other investigators have questioned the efficacy of iodophors against poliovirus in the presence of organic matter and rotavirus SA in distilled or tapwater Besides their use as an antiseptic, iodophors have been used for disinfecting blood culture bottles and medical equipment, such as hydrotherapy tanks, thermometers, and endoscopes.

Antiseptic iodophors are not suitable for use as hard-surface disinfectants because of concentration differences. Iodophors formulated as antiseptics contain less free iodine than do those formulated as disinfectants Iodine or iodine-based antiseptics should not be used on silicone catheters because they can adversely affect the silicone tubing Ortho-phthalaldehyde is a high-level disinfectant that received FDA clearance in October It contains 0.

OPA solution is a clear, pale-blue liquid with a pH of 7. Tables 4 and 5. Preliminary studies on the mode of action of OPA suggest that both OPA and glutaraldehyde interact with amino acids, proteins, and microorganisms.

However, OPA is a less potent cross-linking agent. This is compensated for by the lipophilic aromatic nature of OPA that is likely to assist its uptake through the outer layers of mycobacteria and gram-negative bacteria OPA appears to kill spores by blocking the spore germination process Studies have demonstrated excellent microbicidal activity in vitro 69, , , , For example, OPA has superior mycobactericidal activity 5-log 10 reduction in 5 minutes to glutaraldehyde.

The mean times required to produce a 6-log 10 reduction for M. bovis using 0. OPA showed good activity against the mycobacteria tested, including the glutaraldehyde-resistant strains, but 0. Increasing the pH from its unadjusted level about 6. The level of biocidal activity was directly related to the temperature.

A greater than 5-log 10 reduction of B. atrophaeus spores was observed in 3 hours at 35°C, than in 24 hours at 20°C. atrophaeus spores The influence of laboratory adaptation of test strains, such as P.

aeruginosa , to 0. Resistant and multiresistant strains increased substantially in susceptibility to OPA after laboratory adaptation log 10 reduction factors increased by 0. Other studies have found naturally occurring cells of P.

aeurginosa were more resistant to a variety of disinfectants than were subcultured cells OPA has several potential advantages over glutaraldehyde. It has excellent stability over a wide pH range pH 3—9 , is not a known irritant to the eyes and nasal passages , does not require exposure monitoring, has a barely perceptible odor, and requires no activation.

OPA, like glutaraldehyde, has excellent material compatibility. A potential disadvantage of OPA is that it stains proteins gray including unprotected skin and thus must be handled with caution Meticulous cleaning, using the correct OPA exposure time e.

Personal protective equipment should be worn when contaminated instruments, equipment, and chemicals are handled In April , the manufacturer of OPA disseminated information to users about patients who reportedly experienced an anaphylaxis-like reaction after cystoscopy where the scope had been reprocessed using OPA.

Of approximately 1 million urologic procedures performed using instruments reprocessed using OPA, 24 cases 17 cases in the United States, six in Japan, one in the United Kingdom of anaphylaxis-like reactions have been reported after repeated cystoscopy typically after four to nine treatments.

Preventive measures include removal of OPA residues by thorough rinsing and not using OPA for reprocessing urologic instrumentation used to treat patients with a history of bladder cancer Nevine Erian, personal communication, June 4, ; Product Notification, Advanced Sterilization Products, April 23, A few OPA clinical studies are available.

Furthermore, OPA was effective over a day use cycle Manufacturer data show that OPA will last longer in an automatic endoscope reprocessor before reaching its MEC limit MEC after 82 cycles than will glutaraldehyde MEC after 40 cycles High-pressure liquid chromatography confirmed that OPA levels are maintained above 0.

OPA must be disposed in accordance with local and state regulations. The high-level disinfectant label claims for OPA solution at 20°C vary worldwide e. These label claims differ worldwide because of differences in the test methodology and requirements for licensure.

In an automated endoscope reprocessor with an FDA-cleared capability to maintain solution temperatures at 25°C, the contact time for OPA is 5 minutes. Peracetic, or peroxyacetic, acid is characterized by rapid action against all microorganisms. Special advantages of peracetic acid are that it lacks harmful decomposition products i.

It remains effective in the presence of organic matter and is sporicidal even at low temperatures Tables 4 and 5. Peracetic acid can corrode copper, brass, bronze, plain steel, and galvanized iron but these effects can be reduced by additives and pH modifications.

Maximum load, Resilience and Resilience stiffness were obtained. After the tibia specimens bending test, the tibia bones were decalcified with EDTA decalcification solution for one month. Subsequently, the tibia bones were embedded in paraffin. The other portion were then stained with Masson trichrome.

Overall, the frequency shifts decreased and dissipation increased steadily as the deposition step increased. Film thickness was calculated using Q-tools, as illustrated in Fig. B Film thickness versis layer pairs calculated by Qsoft.

Half of the layers were deposited layers of MMT, and the whole number of layers were deposited layers of PLL-CHX.

Each assembled layer had an alternating positive and negative potential. The release profile in vitro exhibited a slow CHX release in PBS. Indicated the strong retention property of MMT against CHX release.

Interestingly, analogous phenomena occurred in S. aureus Fig. The amount of drug released increased with the increased of the concentration of Staphylococcus aureus. CHX release in A different concentration of CMS solution and B different concentration of S.

We used the zone of bacterial inhibition ZOI to observe the effectively release CHX depending on the changes in the microenvironment.

The results were depicted in Figs. In more detail, after immersing for 3 days, the ZOI increased with the increase in concentrations of S. And the statistical graph was presented Fig.

The 0. aureus solution to 2. We also assessed the changes in thickness through spectroscopic ellipsometry Fig. The similar phenomena could also be found when we varied the concentration of CMS.

The ZOI increased with the increase in concentrations of CMS Fig. The thickness also reduced with the increase in concentrations of CMS.

The above measurement of ZOI corresponded with the changes of thickness. D — E Changes of ZOI and thickness. E — F Changes of ZOI and thickness. As defined in Fig. It is worth noting that the number of Staphylococcus aureus increased significantly in the first 2 h.

And slowly decreased during the following 24 h at 37 °C. Finally, We could still find a lot of live bacteria in the test tubes after 24 h. Apart from this, we also developed protein leakage experiment.

The presence of protein in the bacterial suspension indicates damage to the bacterial cell membranes. This experiment we used a BCA Protein Assay Kit to evaluate the amount of protein leakage. As shown in Fig.

However, a higher protein concentration This suggested that more leakage of S. aureus content had happened. The above mentioned experiments might be due to CMS released quickly when outside S. aureus strains rapidly.

According to previous studies, CHX has strong bactericidal effects [ 51 ]. After incubation, produced obvious zone of inhibition Fig. In vitro antimicrobial assays. A Bacterial inhibition rate assays. B protein leakage experiment. We used the Cell Counting Kit-8 CCK-8 assay to assess the effect of above extracts on proliferation of osteoblasts cells.

Our experiments showed that cell proliferation was in a time-dependent manner. From the 1 day after modeling, all rats returned to their normal condition Fig. The WBC, CRP, IL-1 and IL-8 for three groups were analyzed. They played an important role in the development of infections.

Above infection indicators proved a distinguishing difference between the 3 groups. All infection indicators were increased in 3 groups on the next day after surgery, this may be due to the stress reaction as a result of the surgery.

Unmodified group exhibited highest WBC, CRP, IL-1 and IL-8 levels due to lack of CHX and foreign body reactions after 7 days of implantation. Ultimately, all infection indicators of rats in the unmodified group remained higher than normal level after 6 weeks of implantation. This showed that the infection cannot be effectively controlled.

Since no bacteria were injected in rats and performed aseptic operation during surgery, no infection occurred in the SHAM group, all inflammation indicators were at normal levels.

We used the small-animal X-ray fluorescence tomography to inspect and evaluate the metaphysis of tibial plateau in all rats. Because the infection could not be effectively controlled, there observed severe infection in the rat's knee joint of unmodified group.

Specifically, the tibial plateau of the unmodified group was characterized by an irregular partially osteolytic lesion, more serious was that adjacent bone tissue is also infected and soft tissue becomes swollen, part of patella, femoral condyle and tibial plateau were translucent Fig.

This might be caused by the spread of bacteria. To quantify the extent of bone infection, we follow the bone infection radiological evaluation system proposed by Lucke et al.

From the Fig. The higher the score, the more serious the infection. J X-ray score with different group. K bacteria recovered from implanted K-wire. Fluorescent microscopy images of live staining of S. In order to further explore the effects of films enzymatic degradation on antibacterial effect in vivo.

We performed a detailed bacteriological examination of the samples. After 24 h of culture, we found a lot of bacterias in the tissue fluid of the unmodified group Fig. SYTO9 can stain live bacteria with intact cell membranes to form green fluorescence.

aureus cells individually distributed on unmodified Kirschner wires. aureus cells Fig. Since no bacteria were injected, there were still no bacteria here in SHAM group Fig.

Intraosseous implant infection can affect the composition of bone tissue. In order to get a more accurate conclusion of the changes of bone composition, we used a micro CT on bone specimens obtained 6 weeks after implantation.

Conversely, unmodified group with no new bone formation in Kirschner wires surface Fig. Moreover, quantitative evaluation of the trabecular bone within the region of interest ROI was showed. Compared with the unmodified implant group, the bone mineral density BMD , trabecular bone number Tb.

Conversely, trabecular separation Tb. A 6 weeks after modeling, micro-CT 3D images of the bone specimens. New bone formation around the Kirschner wires. B Bone mineral density BMD. C Trabecular bone number Tb.

E Connectivity density Conn. F Trabecular thickness Tb. G Trabecular separation Tb. Infection could affect bone strength, so we used three-point bending experiment to test the integration strength of bone.

As demonstrated in the experiments, the Maximum load with unmodified group was However, a higher value The Resilience with unmodified group was The Resilience stiffness with unmodified group was The tibia specimens bending test with different group. A The Maximum load.

B The Resilience. C The Resilience stiffness. We found that there were a large number of inflammatory cells in the bone trabecula of the unmodified group, which confirmed the occurrence of bone infection Fig. The SHAM group also showed normal bone trabecula Fig.

A similar phenomenon identified for Masson trichrome. In unmodified group, most areas was stained red due to fibrosis in the bone marrow cavity after infection Fig. Furthermore, CHX depicted on-demand property which was triggered intelligently by CMS or bacterium solution.

Furthermore, in vivo research demonstrates the potential to provide more robust evidence for the use of this biomaterial to mitigate infections associated with intraosseous implants.

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The preferred catheter of the invention includes a polymer having both bulk distributed chlorhexidine and a chlorhexidine coating. This embodiment of the invention produces a dual anti-infective activity.

The surface coating provides a readily available and rapid release of chlorhexidine. The bulk distributed chlorhexidine, due to the hydrophilic nature of the polymer, migrates slowly to the surface when the catheter is in contact with a body fluid and produces anti-infective activity of long duration.

For some applications of the anti-infective article of the invention, it may be desirable to include an antithrombogenic agent. Thus, another preferred article has chlorhexidine bulk distributed in the polymer and an antithrombogenic agent, such as dextran sulfate or, preferably heparin, coated thereon.

A suitable method for ionically affixing heparin is that of Grode et al. Journal of Biomedical Materials Research Symposium, 3, 77 wherein a quaternary ammonium surface active agent such as, for example, tridodecylmethylammonium chloride, is permeated into the surface of the polymer and then reacted with sodium heparin.

Another suitable method is that of Solomon et al. Although the invention has heretofore been described in terms of the preferred chlorhexidine, the use of other anti-infective agents may confer desirable properties on the catheter of the invention.

For example, an article having bulk distributed chlorhexidine may be surface coated with an antibiotic. Preparation of such an article may be carried out by permeating the polymer with a quaternary ammonium salt, as described above, and reacting the salt thereby affixed to the polymer surface with the desired antibiotic.

Exemplary of antibiotics which are suitable for affixation to the article of the invention are penicillin, oxacillin, clindamycin, carbenicillin, cephalosporins, cefoxitin, cefazolin, dicloxacillin, cloxacillin and clavulanic acid and mixtures thereof.

The anti-infective catheter prepared by the method of the invention will now be described in more detail with the aid of the drawings. In the following discussion of the drawings, elements identical or substantially similar to previously described elements are given the same reference number with a letter suffix.

Chlorhexidine molecules 20 are bulk distributed throughout the polymer. Catheter 10b has an outside wall 12b, a lumen 14b and a lumen wall 16b. Permeated into the surfaces of walls 12b and 16b are chlorhexidine molecules 18b. Chlorhexidine molecules 20b are bulk distributed in the catheter.

Laminated anti-infective catheters in accordance with the invention are illustrated in FIGS. In FIGS. A polymeric laminating layer 30 having a surface 32 is coated onto base tubing Chlorhexidine molecules 20c are bulk distributed in layers 22 and 30 and chlorhexidine molecules 18c are permeated into the surface of layer A laminated catheter tubing illustrated in FIG.

The following examples are provided to further illustrate typical catheter preparations of the invention and both in vitro and in vivo procedures for determining their anti-infective properties.

In vitro antimicrobial activity of the anti-infective tubing of the invention was measured by a standard zone of inhibition test.

A broth of the test organism, such as S. aureus, was started from standard disks Bactrol in trypticase soy broth TSB and allowed to grow overnight. Medical tubings of the invention were cut into suitable lengths of 1. The plates were then cultured 16 hours overnight.

Plates were evaluated for the inhibition of bacterial growth visually by the unaided eye. Zones were measured in millimeters across the axis of the tubing, the measurement including the diameter of the medical article. Tubing prepared as described in Example I above demonstrated the following antimicrobial activity in vitro.

Permanency of the chlorhexidine was evaluated using a saline leach study. The tubings of Example I were exposed to 37° C. normal saline for various lengths of time. At the appropriate time interval, samples were retrieved from the saline and placed on a prepared agar plate as described above. Zone sizes were measured as above to determine retained antimicrobial activity.

The following results were obtained:. Polyurethane pellets were blended with either 4. The blended material was then extruded into tubing and evaluated for in vitro antimicrobial activity against S.

aureus using the zone of inhibition method described in Example II. The blended material was then extruded using standard tubing extrusion equipment at a temperature of approximately ° C. The finished tubing produced the following zone of inhibition results when evaluated according to Example II.

The antimicrobial containing tubings of Example I were evaluated for efficacy in vivo with a subcutaneous rabbit model. Sterile tubing samples were placed in a surgically created pocket on the shaved back of a rabbit which had been washed and cleaned with an antiseptic.

The tubing was sutured in place to prevent the rabbit from removing it. A b 1×10 3 inoculum of Staphylococcus aureus colony forming units CFU was injected into the subcutaneous pocket at the time of tubing insertion to initiate the test.

Tubing samples were then retrieved from the rabbit over a period of days. Recovered samples were then quantitatively analyzed for the amount of S. aureus present using the method of Solomon and Sherertz, J.

Controlled Release, 6 Non-treated tubing samples were run concurrently as controls. The antimicrobial containing resins were then coextruded into tubing using standard equipment.

The resulting tubing exhibited the following rates of release determined as in Example II of chlorhexidine from the internal and external tubing surfaces which are proportional to the resin's chlorhexidine content.

The antimicrobial containing resin was then coextruded along with a non antimicrobial containing resin such that the lumen surface of the tubing did not contain any antimicrobial. The outer tubing layer thus provided antimicrobial activity to prevent or reduce microbial migration through the catheter wound tunnel, while the inner lumen was chlorhexidine free, thereby eliminating potentially adverse reactions such as intravenous infusion drug -chlorhexidine interactions.

Bulk distributed antimicrobial tubing was then extruded into 16 gauge tubing using standard equipment. The tubing was then treated according to the method of Grode et al. supra using tridodecyl methylammonium chloride to provide an ionically bonded heparin coating to both the inner and outer tubing surfaces, thus yielding a catheter tube with both antimicrobial and antithrombogenic properties.

The tubing produced the following in vitro antimicrobial effects. The tubing also demonstrated antithrombogenic efficacy as shown by a partial thromboplastin time of reater than seconds extension when determined by the procedure of B.

Brown, Hematology Principles and Procedures, Third Edition, Lea and Fabiger, Co. The tubing was then treated to provide a covalently bonded layer of heparin to both the inner and outer lumen surfaces using the method of Solomon et al.

This tubing demonstrated both antimicrobial and antithrombogenic properties similar to the tubing of Example VIII. The tubing was then coated with ionically bonded dicloxicillin by the method of Solomon and Sherertz supra to both the inner and outer tubing surfaces.

The resulting tubing had a bulk distributed broad spectrum antimicrobial chlorhexidine and a narrow layer of antibiotic with specific activity on the tubing surface. Other antibiotics specifically targeted for specific organisms may be used.

Polyurethane tubing was prepared as described in Example VII with bulk distributed chlorhexidine in the outer tubing layer. Following tubing extrusion, the tubing was treated as described in Example X to provide an ionically bonded dicloxicillin coating to both the inner and outer tubing surfaces.

This produced a tubing which had specific and broad antimicrobial action but without the presence of chlorhexidine in direct contact with the infusion fluid path.

The melt was coextruded with resin containing no antimicrobial as described in Example VII, resulting in an inner layer with chlorhexidine, and an outer tubing layer with no chlorhexidine.

Following extrusion, the tubing was treated as described in Example X to provide an ionically bonded clindamycin coating to both the inner and outer tubing surfaces. The two compounded resins were then coextruded into tubing such that the inner layer contained bulk distributed chlorhexidine, and the outer layer contained bulk distributed silver sulfadiazine.

This tubing had one type of antimicrobial present on the outer surface, and a different antimicrobial present on the inner surface.

Polyurethane resins were prepared as in A and coextruded into tubing such that the inner layer contained bulk distributed silver sulfadiazine and the outer layer contained bulk distributed chlorhexidine. In accordance with the procedure of Zdrahala et al. Polyurethanes in Biomedical Engineering, II, H.

Planck et al. Amsterdam, , p , pieces of 16 guage polyurethane 65D and polypropylene tubing were tested for the effect of absorbed water on tubing stiffness on the Instron Model Universal Testing Machine.

Bending forces in grams were determined after 24 hours under ambient conditions of 23° C. A preferred method to prepare the article includes blending of the polymer and the salt by twin screw compounding and extruding at high temperature. What is claimed is: 1. A method for preparing a medical article, the method comprising: a preparing a blend of chlorhexidine and pellets of a base polymer having a water absorption of at least 0.

b heating said blend to a sufficient temperature within a range from about ° C. to about ° C. and for a sufficient time to form a homogeneous melt of said polymer having said chlorhexidine uniformly distributed therein; and. c extruding said melt through a die to form a medical article having said chlorhexidine bulk distributed throughout said polymer.

The method in accordance with claim 1 wherein said based polymer is selected from the group consisting of polyurethane, polyurethaneurea and siloxane-urethane block copolymer.

The method in accordance with claim 1 wherein said chlorhexidine is about 0. The method in accordance with claim 1 wherein said melt is formed by twin screw compounding and wherein said heating step is at said temperature range from about ° C.

The method in accordance with claim 1 further comprising wetting said pellets with a polyol prior to said preparing. The method in accordance with claim 1 wherein said chlorhexidine is selected from the group consisting of chlorhexidine base and a salt thereof.

The method in accordance with claim 6 wherein said salt of chlorhexidine is selected from the group consisting of the hydrochloride, acetate and gluconate. The method of claim 1 further comprising applying to a surface of said article a coating of an agent selected from the group consisting of chlorhexidine, a surface active agent and an antithrombogenic agent.

The method in accordance with claim 8 wherein said applying step is performed by steeping said article in a solution of said agent. The method in accordance with claim 8 further comprising ionically bonding an agent selected from the group consisting of an antibiotic and an antithrombogenic agent to said surface active agent.

The method of claim 1 further comprising coating the article having bulk distributed chlorhexidine with a layer of laminating polymer having a water absorption of at least 0.

The method of claim 11 wherein said coating step is performed by steeping the article in a solution of said laminating polymer and chlorhexidine. The method of claim 11 further comprising applying a surface active agent to the surface of said article and reacting the surface active agent with a reagent selected from the group consisting of an antibiotic and an antithrombogenic agent.

A method for preparing a medical article, the method comprising: a preparing a homogeneous melt of a polymer having a water absorption of at least 0. b extruding said melt at a temperature in a range from about ° C. through a die to form a medical article having said chlorhexidine bulk distributed throughout said polymer.

Anti-infective and antithrombogenic medical articles and method for their preparation. USA true USA en. USA en. Method and device for inhibiting HIV, hepatitis B and other viruses and germs when using a catheter in a medical environment. Dispenser for at least one liquid or pasty product comprising a closure system that allows no ingress of air, and preservation process using the said dispenser.

Method and device for inhibiting H. hepatitis B and other viruses and germs when using a needle, scalpel and other sharp instrument in a medical environment. Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent.

Method of shaping structures with an overcoat layer including female urinary catheter. USB1 en. The Trustees Of Columbia University In The City Of New York. USB2 en. Compositions and methods for delivery of agents for neuronal regeneration and survival. Implantable or insertable medical device resistant to microbial growth and biofilm formation.

Antimicrobial medical articles containing a synergistic combination of anti-infective compounds and octoxyglycerin. Medical device having a surface including a biologically active agent therein, and methods.

WOA1 en. Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix. Rochester Medical Corporation, a subsidiary of C.

Bard, Inc. EPA1 en. Methods of processing chlorhexidine-containing polymerizable compositions and antimicrobial articles formed thereby. Apparatus and method for protecting a port site opening in the wall of a body cavity.

ePTFE small caliber vascular grafts with significant patency enhancement via a surface coating which contains covalently bonded heparin. Polyurethanes grafted with polyethylene oxide chains containing covalently bonded heparin.

Process for preparing polymer coatings grafted with polyethylene oxide chains containing covalently bonded bio-active agents. Process for preparing covalently bound-heparin containing polyurethane-peo-heparin coating compositions. Photodynamic cellular and acellular organism eradication utilizing a photosensitive material and benzalkonium chloride.

Minimally invasive medical apparatus for dispensing a biologically active compound and an associated medical procedure for dispensing a biologically active compound. Fluid delivery trocar-cannula complex, fluid delivery accessory, and method for delivering fluids during minimally invasive surgery.

WOA2 en. Combinations of antiseptic and antibiotic agents that inhibit the development of resistant microorganisms. Methods and clinical devices for the inhibition or prevention of mammalian cell growth.

Body cavity access assembly and an associated medical procedure for dispensing a liquid. Trocar-cannula complex and method for supplying fluid during cannula and further minimally invasive surgery.

CAA1 en. Microbe-resistant medical device, microbe-resistant polymeric coating and methods for producing same. Method of sustaining plant growth in hazardous substrates, limiting the mobility of subsurface contaminants, and beneficiation of normal soils.

Trocar-cannula complex, cannula and method for delivering biologically active agents during minimally invasive surgery. Infection-resistant polyurethane foams, process for their preparation and use in antiseptic-treated wound dressings.

aureus differed as E. coli cell divides by elongation resulting in lethality induced by nanostructures to daughter cells. In contrast, S. aureus daughter cells cluster on the original cell and dodge the bactericidal effects of nanostructures Lin et al.

In experimental studies to develop a nanopillar surface of a medical device with improved broad-spectrum bactericidal effect, the metal-organic framework MOF was positively charged to attract negatively charged bacterial cell walls to its surface and rupture them Riduan and Zhang, However, the killing rate depends on the bacterial species and surface nanostructures under consideration.

For P. aeruginosa , time-lapsed AFM and CLSM studies have confirmed that cicada nanopillars and their silicon replicas kill their adsorbed bacteria within ~ minutes and release the debris within ~20 minutes of cell rupture to preserve its bactericidal properties Ivanova et al.

Surface topographies should be optimised for the intended bactericidal application. Generally, nanostructures must be sufficiently dense to prohibit bacteria from escaping by contacting cavities between nanostructures, experiencing less or no suspension force. The bactericidal activity of nanopillar revolves around the height, sharpness, width, and spacing between the array of pillars Kelleher et al.

Spacing is essential to avoid the mere resting of bacteria on nanostructures without suspending the bacterial membrane on the nanostructure array. There are no standard topographical parameters for established comprehensive bactericidal activity. However, most inspected bactericidal parameters range from nm in height, nm tip diameter, and interspacing distance of less than nm Modaresifar et al.

Figure 1 Cicada nanopillar topography augments the bactericidal action via. Figure 2 Nanostructures mechanism to prevent fouling. A cicada wing- Stretching B dragonfly wing- tearing C different pitches of pillars. Bottomnm-bacteria pattering D Top: ROS mediated.

Bottom: Penetration. Bactericidal nano-featured surfaces have been developed on various substrates, including Titanium Ti , Silicon Si , Aluminium Al , glass, and polymers, in support of the biophysical model. Anisotropic randomly oriented nanopillar surface was fabricated on Ti by etching process exhibited broad-spectrum bactericidal property and cytocompatibility.

The etched titanium appears black owing to the presence of nanostructures with dimensions of 1µm height and an average diameter of 80 nm.

This multi-biofunctional Ti surface ruptured gram-positive and gram-negative bacteria, including E. coli, P.

aeruginosa, S. aureus , and M. smegmatis with multi-fold efficiency compared to polished Ti surface. Moreover, it enhances the attachment and proliferation of human mesenchymal stem cells hMSCs and encourages differentiation to osteogenic lineage in the presence of relevant factors in vitro Hasan et al.

Bacterial cells being rigid compared to mammalian cells are lysed by nanostructures, while elastic mammalian cells adhere with the help of integrins and spread over the nanostructures, recognising them as anchorage points and proliferating.

Thus, an optimally modified implant surface allows tissue cells to win the race for the surface and effective implant integration without developing bacterial infections Modaresifar et al.

Microfluidic experiments demonstrated black silicon nano spiked substrate to be functional under fluid flow. Thus, nanostructured surfaces can be employed in the inner surface of urinary catheters Wang et al.

In addition to the biophysical model involving the rupture of bacterial cells, it has been proposed that Titanium dioxide TiO 2 nanopillars impede bacterial cell division and proliferation and induce reactive oxygen species ROS production.

Biomimetic TiO 2 nanopillars penetrated and deformed the bacterial membrane, altering the genetic expression in response to mechanical stress Figure 2D. The lack of expression of fimbria appendages by E.

coli and K. pneumoniae evidences this. ROS production within bacterial cell increase differential expression of oxidative stress and repair proteins such as superoxide dismutase and methionine sulfoxide reductase in S.

The generated ROS increased the susceptibility of membrane and cellular components to damage, culminating in the degradation and lysis of bacterial cells Jenkins et al. There is no consensus on a model explaining the comprehensive bactericidal effect of nanostructured surfaces.

It is also challenging to arrive at, owing to the complex interaction between viscoelastic bacterial membranes with appendages and surface nanostructures inspired by various biological examples. Further, the interaction is influenced by the in vivo local factors.

These also make it challenging to attribute specific interaction forces requisite for a bactericidal effect. Graphene and its derivatives as 2D nanomaterials have been extensively studied for broad-spectrum antimicrobial properties contributed by their multifunctional properties: increased stability and surface area, high biocompatibility, and uncomplicated surface modification Pandit et al.

Additionally, ROS generation and disturbance in the redox reaction by graphene affects the cellular metabolism, which, together with the other effects, results in broad-spectrum bacterial inactivation Krishnamoorthy et al. The loss of membrane potential due to the conductive nature of graphene and ATP depletion due to interruption in the electron transport chain leads to cell death Syama and Mohanan, ; Mohammed et al.

In accordance with this mechanism, graphene sheets were used as nano blades against E. aureus was more susceptible to killing than E. coli due to the extra outer membrane in gram-positive bacteria, although the peptidoglycan layer is thinner than in gram-negative bacteria Akhavan and Ghaderi, The sharp monolayered edges and increased lateral area of nano blades are known to boost the bactericidal activity of the nano knife by allowing for the extraction of large patches of membrane phospholipids Mohammed et al.

For graphene nanostructures, biocompatibility has been reported upon functionalisation with polyethylene glycol, polyethyleneimine, and bovine serum albumin, but contradictory cytotoxicity dependent on concentration, size, and shape are also reported Linklater et al.

Graphene nanostructures less than 5nm may get inserted into the mammalian membrane and subsequently internalised by macrophages, while mammalian cells may spread and wrap around larger graphene nanostructures.

Hence, biocompatibility and cytotoxicity must be assessed before implementation Lin et al. The durability of bactericidal nanostructures is inconclusive due to the need for long-term experiments in various in vivo conditions.

The possibility of nanostructures fragmenting from the device surface, exceptionally flexible nanostructures with weak modulus, raises the concern of loss of antibacterial activity over time in vivo and cytotoxicity to the mammalian cells Lin et al.

The robustness of the bactericidal effect of the nanostructured surface following inevitable protein conditioning on implantable devices is also still being determined.

Nanostructured surfaces encountered by high bacterial load may be contaminated by bacterial debris, leading to inflammation due to immune responses. Nanostructured surfaces kill encountering bacteria and potentially prevent biofilm formation, but it jeopardises host microbiota.

So, the possibility of manipulating surface chemistry through the functionalisation of the nanostructures to increase the lysing rate of pathogenic bacteria and the specificity of the bactericidal action towards certain pathogenic bacterial species can be considered in the design of the device surface Figure 2.

The ability of the surface to repel bacteria is founded in engineering surface nano topographies. The bacterial attachment to nanoporous topography is reduced by physiochemical forces, including repulsive, electrostatic, and acid-base forces originating from pores Feng et al.

Hydrophobic surface coatings exhibiting high water contact angle WCA and low surface energy give low drag under flow conditions which reduces the strength of adhesion of bacteria to surfaces, thereby preventing microbial contamination Linklater et al.

The surface protrusions of anti-biofouling surfaces of lotus leaf entrap air bubbles between structures, acting like a hydrophobic surface with incomplete wetting, repel bacteria that encounter the surface as the air layer reduces the surface area for bacterial anchorage.

However, the entrapped air is replaced by water or other fluids when immersed in a liquid medium for a prolonged period Hwang et al. The wings of dragonflies not only exhibit antibacterial activity but also illustrate anti-adhesive properties Figure 2B. The moderately dense nanoscale features reduce bacterial adhesion due to the reduced contact area between bacteria and the surface; bacteria cannot locate the nanostructures for their anchorage Linklater et al.

The surface features for antifouling are replicated with inspiration from shark skin, exhibiting low drag and resistance to the adhesion of bacteria. Anti-adhesive property is also enhanced by the mucous on shark skin, providing lubricating and antifouling benefits Bixler and Bhushan, The normal cell functions are disrupted under the stress gradient, impelling bacteria to spend energy to adjust the contact area to equalise the stresses.

It becomes thermodynamically unfavourable for the bacteria to expend much energy to counteract stress, directing them to search for a different surface to attach Chung et al. This creates a natural anti-adhesive surface. In vitro and in vivo studies with rat models show effective multifold reduction in S.

aureus and P. aeruginosa adherence to micropatterned percutaneous medical device surface Xu et al. This property is contributed by a series of diamond-shaped assemblies with 3 μm height and 2 μm width.

High-touch surfaces are a source of microbial pathogens that often prove to be the origin of HAI. Antimicrobial touch surfaces attempt to reduce microbial contamination on most frequently touched surfaces, primarily of interest in a hospital environment. Copper and its alloys have broad-spectrum antimicrobial activity against bacteria, fungi, and viruses, including SARS-CoV-2, constantly killing The U.

Environmental Protection Agency approved copper and its alloys as antimicrobial public health materials widely used in antimicrobial coatings. Copper can inhibit the germination of fungal spores, including Candida albicans and hence has been recommended to replace aluminium coils in air conditioners in hospitals to reduce the susceptibility of patients to fungal diseases efficacy of copper antimicrobial touch surfaces in clinical settings has been studied and recommended for use in near-patient environments to decline the risk of transmission Weaver et al.

The antimicrobial activity of copper is attributed to the release of copper ions upon the chemical decomposition of the material Villapún et al. Copper ions destroy microbes by damaging the cell membrane integrity, directly degrade bacterial proteins and induce a Fenton-like reaction which releases hydroxyl ions that interact with DNA, proteins, and enzymes, peroxidise lipids leading to membrane damage.

Copper alloys used as anti-microbial touch surfaces reduce horizontal gene transfer HGT , thus effectively killing the pathogens on the surface and curbing the spread of antimicrobial resistance by HGT Warnes et al. Apart from using copper for frequently touched surfaces, copper taps, and pipes can also be fitted in hospitals to reduce water-borne pathogens and associated diseases.

Silver is also highly recognised for its antimicrobial properties. However, due to the high cost of silver, it is mainly used in the form of nano-formulations and in applications that only require small concentrations. The self-cleaning property of the superhydrophobic surface removes biofouling by controlling wettability and particle adhesion confined in surface roughness Wisdom et al.

Self-cleaning behaviour was extensively exhibited in lotus leaves Lotus effect , which repels water that rolls off the surface, picking up all the contaminants, including microorganisms leaving behind a clean surface Wu et al. The concept of superhydrophobicity revolves around two models, namely the Wenzel model and Cassie—Baxter, where liquid droplet penetratesthe nanopillar in the former model and does not penetrate in the latter Figure 4 Erbil and Cansoy, The models are used to optimise the contact angle and surface roughness for obtaining a superhydrophobic surface by assessing the contact area Parvate et al.

A water droplet on the superhydrophobic lotus leaf exhibits a cassie state contact angle of °, low contact angle hysteresis of 3° degrees, and a low tilting angle TA of less than 5° for the impending motion of water droplets Koch et al. The water-repellent nature of lotus leaves is due to nanoscale epicuticular wax crystalloids on the epidermal papillae rendering microroughness and reduced adhesion of contaminating particles Barthlott and Neinhuis, The nanostructures on the micro-papillae with a diameter of ~nm heighten the surface roughness, reducing the contact area of contaminants and water droplets and endowing low adhesion to the surfaces Feng et al.

The contaminants, including microorganisms on the surface, adhere to the encountering rolling water droplet due to higher adhesion energy and are carried away, leaving a clean surface. The lotus effect has been widely replicated for medical devices to prevent the adhesion of pathogens and biofilm formation.

It is supported by the fact that most microorganisms require a wettable surface for adhesion and biofouling Koch et al.

The lotus-inspired self-cleaning effect imposed on the TiO 2 nanotubes restricted the surface adherence of S. aureus and E. coli , thereby preventing biofilm formation Patil et al.

The major drawback is that the nanostructures causing superhydrophobicity are fragile and easily damaged by mechanical abrasion, leading to reduced WCA and superhydrophobicity.

Hence, for applications, high mechanical strength and low-density carbon nanotubes CNT with epoxy resin composites were used to fabricate superhydrophobic surfaces possessing low contact angle hysteresis Jung and Bhushan, Mechanically robust superhydrophobic surfaces have been realised with simple hierarchical micro-nano structures where nanostructure provides a lotus effect and microscale structures provide durability.

The microstructure acts as an interconnected armour harbouring the nanostructures in inverted pyramidal pockets, preventing damage to the nanofeatures by abradants larger than the microstructures, including sandpaper and sharp blade. These surfaces resist shear force and vertical pressure, and regardless of abrasion cycles, harsh conditions like high temperature ° C , high velocity of water jet and high humidity exhibit superhydrophobicity with a static WCA of ° and the TA of fewer than 12° degrees Ivanova et al.

The super hydrophobic self-cleaning mechanism is also exhibited by cicada wings possessing waxy coated, hexagonally packed dense nanostructured surface with an average WCA of The surface of cicada wings was exposed to various gram-negative and gram-positive bacteria and was proved to be highly effective against gram-negative than gram-positive bacteria Hasan et al.

The sliding water droplet removes the contaminants, similar to the lotus leaf effect. These insects also demonstrate an intriguing autonomous self-cleaning effect by the condensed dew droplets, independent of environmental water supply and control by the gravity.

In the presence of water vapour, contaminants are partially or enclosed by the dew condensates. Due to the acquired surface energy, the dew condensates coalesce and jump on the superhydrophobic surface. As a result, the contaminants are spontaneously eliminated from the surface by the self-propelled jumping motion of the dew condensates Wisdom et al.

In particular, self-cleaning by jumping condensate phenomenon effectively removes adhered bacteria by challenging adhesion involving van der Waals forces. Rice leaves Orysa sativa , butterfly wings Morpho aega, Morpho didius , and duck feathers Anatidae illustrate self-cleaning by superhydrophobic unidirectional wettability with low adhesion properties.

This self-cleaning method combines anisotropic flow resulting in low drag from shark skin and a lotus effect Bixler et al. The water droplets on the surface easily roll out of the surface along with the rice leaf papillae or radially outward direction but adhere to the surface in the opposite direction.

Rice leaves have a transverse sinusoidal arrangement of longitudinal ridges providing anisotropic flow. The longitudinal ridges consist of micropapillary with waxy nanobumps facilitating superhydrophobicity with WCA of °, lowest contact angle hysteresis at 3° degrees and low adhesion properties enhancing self-cleaning.

Similarly, anisotropic flow is facilitated by shingle-like scales in butterfly wings, and microgrooves on scales provide superhydrophobicity with WCA of °, and water droplets roll off the surface at a tilted angle of 9° degrees Zheng et al. The porous structure and preening oil coating on the duck feathers furnish a superhydrophobic character.

The porous structure is established by the branches of feathers further dividing into barbules, enhancing the air-water interface and resulting in water repellence Cassie and Baxter, The rear side of the fish scales and shark skin also exhibit self-cleaning effects potentiated by hydrophilicity and oleophobicity.

These surfaces prevent microbial adhesion and biofouling through complete water wettability and enhanced oil repellence, enabling water to get in between contaminant and surface, washing away the impurities. Fish scales exhibited hydrophilicity and super oleophobicity oil contact angle of ° stemming from the micro-nano hierarchical structures and were replicated on silicon wafers by lithography technique Liu et al.

The micro-nano hierarchical structures entrap water, preventing contaminants from contacting the surface. Likewise, the super hydrophilicity and superoleophobicity properties of lotus leaves are contributed by convex micropapillary covered with nano grooves in the range of nm Cheng et al.

Sharkskin possesses dermal denticles containing parallel riblets along the swimming direction, facilitating a typical self-cleaning through hydrophilicity and anisotropic fluid flow, leading to low drag Yu et al. As the water flows, vortices develop on the surface, causing high shear stress lifted by the riblets, exposed to only the tips of riblets.

The minimised shear stress reduces drag across the surface, enabling swift movement of water adjacent to the shark skin and washing away the adhered microorganisms. The Riblet patterns were also studied for drag reduction efficiency on various materials Bixler and Bhushan, Omniphobic surfaces, named slippery liquid-infused porous surfaces SLIPS inspired by Nepenthes pitcher plants, are similar to superhydrophobic surfaces, wherein an additional component is a lubricating film on the surface Figure 5.

The surface displays self-cleaning by repelling various simple, complex, broad-range surface tension liquids like water, crude oil, and blood. In SLIPS, the rough substrates in the micro-nano scale immobilise thoroughly wetting and incompressible lubricating fluid resulting in a homogeneous, molecularly smooth surface with exceptional low friction that repels impacting immiscible liquids.

The presence of lubricating fluid in SLIPS counteracts the downside of superhydrophobic surfaces like poor stability, low mechanical strength, and durability due to loss of entrapped air over a short period of time, leading to the exposure of rough surface favouring bacterial attachment is overcome by the presence of lubricating fluid in SLIPS Figure 6 Wang and Guo, The combination of substrate and lubricating film must be worked out based on interfacial energies and physical and chemical properties.

Pitcher plant-inspired synthetic liquid-repellent surface was developed with ordered poly-fluoroalkyl silane functionalised nano-post array and random teflon based porous nanofiber network with perfluorinated liquids e. Fluorinert FC as lubricating film. They exhibited low CAH of less than 2.

SLIPS show impressive pressure stability and self-healing upon recurring, large-area damage by abrasion or impact within 1 second Wong et al. SLIPS were also applied for the enamel surface, and results revealed significant inhibition of salivary mucins adsorption, adherence of Streptococcus mutans in vitro , and dental plaque formation in vivo Yin et al.

Owing to the repellence of blood and other liquids on the surface, omniphobic coating has been applied to tubing and catheters. A flexible molecular layer of perfluorocarbon is covalently tethered to the device surface and further infiltrated by a mobile film of medical-grade perfluorodecalin to produce an omniphobic coating with a TA of only 0.

This coating effectively prevents the adhesion of fibrin, platelets, and their activation and also reduces the adhesion of P. aeruginosa and E. coli bacteria and subsequent biofilm formation by eight folds over 6.

The impressive characteristics of omniphobic surfaces can be compromised gradually owing to lubricant evaporation and shear stress under high flow conditions. Hence, a self-replenishing SLIPS with an integrated lubricant reservoir called nanotubes combination of nanohole and nanopillar was fabricated using non-volatile and high-viscous lubricants to enable prolonged operation Wong et al.

Figure 6 Comparison of Slippery liquid-infused porous surface SLIPS to superhydrophobic surface. Self-cleaning surfaces have been realised with photocatalysts like TiO 2 , ZnO, and CdS coated on medical devices and equipment to achieve antimicrobial surfaces in near-patient environments and highly contaminated areas in hospitals.

TiO 2 is considered a promising application as a super hydrophilic photocatalytic coating due to non-toxicity, environmental friendliness, chemical inertness in the absence of light, photostability, durability, abundance, and low-cost production.

TiO 2 semiconductor, upon irradiation with UV light, decomposes the organic contaminants adsorbed on the surface by OH - , H 2 O 2 , and O 2 - ROS generated from photocatalytic oxidation activity.

Subsequently, the decomposed contaminants are washed away from the surface and sterilised by sheeting water owing to super hydrophilicity induced by photons. TiO 2 demonstrates a broad-spectrum bactericidal effect and kills yeast and green algae Padmanabhan and John, Moreover, photocatalysis of TiO 2 brings down air pollutants like nitrogen oxides and boosts air quality like plants Nishimoto and Bhushan, aureus and Pseudomonas putida , established on flat and porous glass functionalised with TiO 2, were killed with Phosphorous and fluorine-modified TiO 2 coating revealed photocatalytic activity against E.

coli , S. Medical devices can be coated with titania nanosheet with a surface roughness of 0. In general, the heightened photocatalytic effect of TiO 2 can be realised in the form of nanocrystalline particles, nanowires, nanotubes, and nanoflowers with dimensions in the range of nm, due to effective oxidation and reduction processes releasing ROS in large amounts Ragesh et al.

It was reported that a thin layer of WO 3 deposited on TiO 2 coating upgrades sensitivity to weak UV light intensity for the photoinduced super hydrophilic conversion Nishimoto and Bhushan, The current research trend focuses on tuning the excitation wavelength for the photocatalytic activity to the visible region by doping with metals and non-metals, hybridisation with organic and inorganic groups, and using the dye photosensitisation method.

N-doped TiO 2 films impregnated with synergistic silver nanoparticles, under white light presented, antimicrobial photoactivity against gram-positive and gram-negative bacteria, particularly MRSA and E.

coli Dunnill et al. TiO 2 doped with Bi and N, coated on dental implants, demonstrated photocatalytic anti-bacterial properties upon visible light excitation and was retained even in darkness.

It showed bacterial reduction and cleared biofilm formed by Streptococcus sanguinis and Actinomyces naeslundii Padmanabhan and John, Copper 0. aureus with 5 fold reduction in bacterial viability within 30 mins when excited with visible light Mathew et al.

TiO 2 co-doped with fluorine and copper demonstrated antibacterial activity against S. aureus following excitation with visible light-inducing photocatalysis combined with copper ion toxicity.

Fluorine dopant renders sensitivity to visible light for photocatalytic activity, and co-doping with copper dramatically improves the efficiency of bacterial inactivation in both light and dark conditions due to the intrinsic antimicrobial activity of copper ions, acting in synergy with the photoactivity of fluorine-doped TiO 2 Leyland et al.

Thus, the difference in the efficiency of photocatalytic activity against gram-positive and gram-negative bacteria owing to variations in cell wall composition, gram-negative bacteria being more resistant to TiO 2 photoinduced bactericidal activity, can be mitigated with the introduction of synergistic antimicrobial metal ions like copper, silver, gold into the coating.

Photocatalytic coatings can also be incorporated into filter systems of water purifiers to eliminate pathogens in water. The biofouling of ship hulls is prevented by conventional self-polishing coatings on surfaces, releasing toxic biocides like tributyltin TBT and cuprous oxide on the gradual erosion of the coating.

The constant surface erosion results in the exposure of fresh biocides and self-renewal of a clean surface. However, the potential side effects of this coating include the development of resistant microbes, marine pollution, and sexual pattern change in marine organisms as consequences of the unnecessary release of biocides.

The coating has to be renewed periodically. Tributyltin and other toxic coatings are also banned and restricted by International Marine Organisation IMO because of their toxic effects Bieser et al. Consequently, much research effort has been devoted to promising self-polishing coating with natural antifoulants.

The self-polishing coatings in the marine field can be extended to the medical field, where parallel toxicity problems and the emergence of antimicrobial resistance persist, complicating treatments and prevention of device-related and hospital-acquired infections.

Recently, the potential of natural compounds has been explored to address AMR owing to its minimal side effects, synergistic activity with existing antimicrobials, sensitising resistant bacteria to antimicrobials, and reversing the AMR Álvarez-Martínez et al.

These natural antifouling compounds can be loaded into natural biodegradable resins like water-soluble resin, which has the potential for extended-release. Polycaprolactone PCL —Polyurethane PU copolymer rosin blend incorporated with butenolide presented an antifouling self-polishing effect for up to 3 months.

The release of butanolide due to the hydrolysis of ester linkages and self-renewal of the surface contributes to the self-polishing of the surface Ma et al.

Borneol extracted from medicinal herbs like chamomile, and lavender synthesises isobornyl methacrylate IBOMA polymer with broad-spectrum antibacterial activity apart from anti-inflammatory, anti-thrombogenic and vasorelaxant effects.

Self-polishing coatings can be produced with IBOMA polymer incorporated with antifouling agents. On slow degradation, release borneol and antifouling agent, thereby self-renewing the surface and preventing bacterial adhesion Hu et al. These coatings can find applications in the short-term usage of urinary catheters.

Surfaces heavily contaminated with microorganisms can be refreshed by detaching the outermost contaminated layer. Such self-decontamination surfaces are achieved with layer-by-layer deposition of alternating dextran aldehyde and carboxymethyl chitosan connected with imine linkages, which are cleaved in response to acidic conditions stimulated by bacterial biofilms Xu et al.

A self-polishing coating based on cellulose polymer has been produced, which erodes in response to cellulase produced by various microbial strains. Thus, the release of antifoulants is regulated by the adherence of microorganisms Bieser et al. Such self-polishing coatings are promising for mitigating bacterial adherence and biofilm formation within a few hours or days after implantation.

They are effective for coatings on implants purposed to integrate with host tissues like orthopaedic implants, temporary implants and devices, walls, bed rails and near patient highly touched surfaces.

The device-related healthcare-associated infections plague the medical field, and bacterial contaminations are inevitable despite following aseptic conditions while performing the procedures.

The current strategies of local or systemic administration of antibiotics are associated with extreme cytotoxic effects on the patients. The various release-based antimicrobial coatings for devices also suffer from limitations, including burst release of antimicrobial compounds, precocious degradation within the body, and decreasing antimicrobial efficacy due to elution of antimicrobial agents resulting in susceptibility to infections.

Inappropriate usage of antimicrobial agents induced the emergence of antimicrobial resistance, posing a world of challenges to researchers and engineers to be solved for the realisation of next-generation devices.

Multifunctional approaches inspired by nature provide convincing solutions to these challenges, and various concepts of antibacterial surfaces, as discussed in this review, are validated against a few leading pathogens. However, an ideal antibacterial approach does not exist, and direct implementation of natural design parameters for all practical applications is impossible.

This requires optimisation for various applications involving different surface materials and working conditions. The dimensional parameters and aspect ratio of micro-nano topographical structures of antibacterial surfaces and anti-adhesive surfaces must be determined for bactericidal effect against different sized bacteria apart from broad-spectrum antibacterial effect.

Incorporating them in multifunctional surfaces combining anti-adhesive and killing strategies could meet clinical demands and abate HAIs.

Nanostructured antibacterial surfaces integrated with self-cleaning properties can effectively clean off the debris of killed bacteria, indefinitely sustaining the functionality and efficiency of the surface.

The surface features reviewed in this article are fragile and can be damaged under mechanical stress. Hence, hierarchical mechanically robust designs that have been reported must be considered while modelling medical devices for applications. The antibacterial surfaces can also be fabricated with adhesive back for easy implementation on existing devices.

New high-throughput technologies and data, including omics, computational modelling, and network pharmacology, can be employed to identify the synergistic activity between natural compounds and the resulting systemic effects for developing promising combinations for incorporation in self-polishing surfaces.

Further, the prolonged controlled release of natural antifoulants and the rate of the detachment of the outermost layer of the self-polishing surface are essential issues to be considered.

In the future, multifunctional surfaces combining various modification concepts can be engineered to overcome the limitations of other approaches and effectively mitigate infections.

The developments in these antibacterial surfaces over the past decade have spurred further investigations and would aid in combating antimicrobial resistance and healthcare-associated infections. Original draft manuscript preparation and writing: SR and HS; Image editing: SR, HD, and AS; Reviewing and editing: KS, RD, and APS.

All authors contributed to the article and approved the submitted version. The authors are grateful to SASTRA university for providing us with an excellent infrastructure. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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