TY - JOUR
AU - PhD, Mina Izadjoo,
AB - ABSTRACT Novel approaches including nonpharmacological methodologies for prevention and control of microbial pathogens and emerging antibiotic resistance are urgently needed. Procellera is a wound care device consisting of a matrix of alternating silver (Ag) and zinc (Zn) dots held in position on a polyester substrate with a biocompatible binder. This electroceutical medical device is capable of generating a direct current voltage (0.5–0.9 Volts). Wound dressings containing metals such as Ag and/or Zn as active ingredients are being used for control of colonized and infected wounds. Reports on the presence of electric potential field across epithelium and wound current on wounding have shown that wound healing is enhanced in the presence of an external electrical field. However, majority of the electrical devices require an external power source for delivering pulsed or continuous electric power at the wound site. A microelectric potential-generating system without an external power source is an ideal treatment modality for application in both clinical and field settings. The research presented herein describes efficacy evaluation of a wireless bioelectric dressing against both planktonic and biofilm forms of wound pathogens including multidrug resistant organisms. INTRODUCTION Skin protects the body from infection and maintains moisture balance.1 The human skin also has an innate ability to regenerate itself after trauma. Acceptable practice in treatment of skin lesions after injury or surgery is to protect the site from further trauma or infection by covering the injured site with a clean gauze. This barrier method has been the standard of care for hundreds of years, and in modern times, silver (Ag)-based wound care products are used. A recent critical finding is the presence of a primitive, physiologic electrical signal generated immediately at the time of skin injury. This electrical signal begins within the layers of skin and with skin injury, the electrical field lines project into the wound space directing the migration of cells and stimulating additional energy production required for cell migration and proliferation.2,–4 This measurable signal can externally be replicated to enhance the normal healing process or to jump start a stalled healing event.4,–7 In addition, electricity plays an important role in bioburden inhibition.8,–10 As a result of the emergence of antibiotic and multidrug resistant (MDR) wound pathogens, there is a growing need for development of novel and effective wound care products. Next generation approaches, such as nonpharmacologic strategies against hard-to-eradicate wound pathogens are being introduced in clinical settings. There is growing recognition that energy-based technologies (electroceuticals) can have a diverse transformative impact on the health care field including wound care. Procellera (Vomaris Innovations, Tempe, Arizona) is a Food and Drug Administration-cleared, microcurrent generating antimicrobial wound dressing consisting of a matrix of alternating Ag and zinc (Zn) dots held in position on a polyester substrate with a biocompatible binder (Fig. 1). The antimicrobial activity existing in Ag-coated wound dressings is due to Ag's ability to block the energy metabolism functioning across bacterial membranes.11 The broad-spectrum antimicrobial activity of Ag and Zn impregnated on the polyester has great activity against wound pathogens including antibiotic-sensitive or -resistant bacterial strains. This next generation electroceutical device is easily activated in presence of a conductive fluid, such as wound exudate or exogenous fluids like saline, and generates a physiologic level of electrical energy. This microelectric field can augment the natural electric field of injury initiated following skin wounding. FIGURE 1. View largeDownload slide Bioelectric dressing with dot-matrix pattern of embedded elemental silver and zinc microcell batteries. FIGURE 1. View largeDownload slide Bioelectric dressing with dot-matrix pattern of embedded elemental silver and zinc microcell batteries. It has been known that a physiological current is necessary for initiation of the wound healing and transport of cells to the wound site.12,13 An electrical stimulus is essential for skin repair and regeneration,14,15 as it is the earliest guidance signal on tissue wounding to initiate cell migration and reepithelialization.3,4 In addition, electricity plays an important role in bioburden inhibition.8,–10 In human skin, multicellular epithelia have dynamic barriers to protect host from potential threats such as infections and toxic materials and organize to pass selective ion transport across epithelial barriers.16,17 The polarized ion transport generates endogenous transepithelial electric potentials (TEPs) at millivolt levels.18,19 Since TEPs play multiple roles in biological events during development and regeneration of damaged tissues,15,–17 once they collapse at the wound site, it results in generation of wound currents toward wound center from wound edge because of differences in electric potentials (EPs) between sites.19 These electrical properties in living organisms are commonly called bioelectricity. Bioelectricities play overriding roles in directional migrations of various cell types to organize the wound healing processes.20 Through various reports on accurate measurement of bioelectric currents,21 effects of microelectric stimulation on wound healing,22,23 microcurrent therapy for wound healing,22,–24 and damaged cornea,25 the EPs and currents demonstrated improved healing effects. However, most electrical wound care devices require an external power source that delivers pulsed or continuous electric power at the wound site. Therefore, the microelectric potential-generating system without an external power source will have significant application in both clinical and military field settings. Our service members are injured and disabled in the line of duty. In battlefield the speed and effectiveness of emergency treatment can mean the difference between life and death. A wound treatment paradigm aimed at accelerating tissue repair, reduced pain, dysregulated inflammatory response, and bioburden precisely suits the unique requirements of our Military Health System. The current standard of care to repair tissue damage due to burn, trauma, or surgery relies mainly on the body's own regenerative ability. The increase in infection-related injury, amputations, and death requires a fresh look at the regenerative process and how external intervention may play a significant role in reducing time to heal and in the prevention and treatment of wound-related infections. In this review, we will describe the efficacy of a novel bioelectric wound care device against clinical wound pathogens including MDR organisms, generation of the electrical signals, and the wound healing properties of an electroceutical wound care technology. Antibacterial Efficacy Against Clinical Wound Pathogens We postulated that the bioelectric dressing, consisting of a discrete Ag and Zn matrix pattern of microcell batteries could decrease wound infection by exerting an electricidal antimicrobial effect. Our testing method and procedures are described as follows: Swatches of test and control textile materials were tested quantitatively for antibacterial activity by Method 147 entitled “Antibacterial Activity Assessment of Textile Materials: Parallel Streak Method (http://www.aatcc.org)” from the American Association of Textile Chemists and Colorists. In brief, an overnight bacterial culture was diluted to 105 colony forming units (CFUs) and applied on the sample and control fabrics each for 0 hour and 24 hours contact times at 37°C to compare the survival rate as CFUs. All of the sample (Procellera 2″ × 2″) and control (gauze and blank polyester) fabrics were inactivated with quencher, including sodium thioglycolate in phosphate buffered saline (PBS) solution and washed off with PBS. Bacteria were mechanically separated from the fabric by vigorous vortexing and sonication to count surviving bacterial colonies using the agar plating method.26 To examine the in vitro broad-spectrum antibacterial efficacy of the composite bioelectric dressing against clinically important bacterial wound pathogens, we tested the efficacy of the bioelectric dressing against various antibiotic-sensitive Gram-positive and -negative bacteria such as Acinetobacter baumannii, Acinetobacter calcoaceticus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and controls, P. aeruginosa American Type Culture Collection (ATCC) 27853, and S. aureus ATCC 25923. A total of 28 bacterial isolates were tested from which 20 strains were Gram-positive and eight were Gram-negative. This dressing showed superior in vitro bactericidal activities against most of the nosocomial bacterial pathogens. However, it showed bacteriostatic activity against the E. faecalis isolate. Later, we tested the efficacy of this bioelectric dressing against 6 antibiotic-resistant clinical pathogens, such as extended spectrum beta-lactamase-resistant K. pneumoniae, MDR P. aeruginosa, and methicillin-resistant S. aureus strains. We observed 100% kill (Fig. 2) against all of the MDR organisms tested. In addition, seven vancomycin-resistance strains such as vancomycin-intermediate (VISA) and -resistant S. aureus (VRSA) species were tested to determine any associations between bacteriostatic activity and vancomycin resistance. As shown in Figure 3, all of the bacteria tested were killed by the bioelectric dressing at 24 hours. These findings demonstrated bactericidal efficacy against VISA and VRSA isolates. FIGURE 2. View largeDownload slide Antibacterial properties of the bioelectric dressing showing bacterial numbers in colony forming units at 0 hour and 24 hours against multiple drug-resistant clinical wound isolates Acineto bacter b/c_complex_MDR, A. baumannii_MDR, E. coli_ESBL, K. pneumoniae_ESBL, P. aeruginosa_MDR, and S. aureus_MRSA (ESBL, Extended spectrum beta lactamase; MDR, multidrug resistant; MRSA, methicillin-resistant S. aureus). There was a 100% kill of the bioelectric dressing treated bacteria at 24 hours. FIGURE 2. View largeDownload slide Antibacterial properties of the bioelectric dressing showing bacterial numbers in colony forming units at 0 hour and 24 hours against multiple drug-resistant clinical wound isolates Acineto bacter b/c_complex_MDR, A. baumannii_MDR, E. coli_ESBL, K. pneumoniae_ESBL, P. aeruginosa_MDR, and S. aureus_MRSA (ESBL, Extended spectrum beta lactamase; MDR, multidrug resistant; MRSA, methicillin-resistant S. aureus). There was a 100% kill of the bioelectric dressing treated bacteria at 24 hours. FIGURE 3. View largeDownload slide Antibacterial properties of the bioelectric dressing showing bacterial numbers in colony forming units at 0 hour and 24 hours against vancomycin-intermediate S. aureus VISA and vancomycin-resistant S. aureus VRSA strains (VRS 1, VRS 9, VRS 116, NRS 1, NRS 12, NRS 73, and NRS 116) and controls (MRSA 507 and S. aureus). There was a 100% kill of the bioelectric dressing treated bacteria at 24 hours. FIGURE 3. View largeDownload slide Antibacterial properties of the bioelectric dressing showing bacterial numbers in colony forming units at 0 hour and 24 hours against vancomycin-intermediate S. aureus VISA and vancomycin-resistant S. aureus VRSA strains (VRS 1, VRS 9, VRS 116, NRS 1, NRS 12, NRS 73, and NRS 116) and controls (MRSA 507 and S. aureus). There was a 100% kill of the bioelectric dressing treated bacteria at 24 hours. This bioelectric dressing demonstrated strong bacterial killing effects reaching 100% kill at 24 hours, except for E. faecalis isolates, which showed some efficacy after 48 hours incubation period26 indicating that prolonged incubation may be required to eradicate the Enterococcus species. Membrane modification or efflux pump overexpression in the cell wall structure or other cell membrane of Enterococcus species may be associated with the bacteriostatic activity. Clearly, the antimicrobial properties of this dressing is derived from the effect of Ag and Zn antimicrobials in addition to the bioelectric currents. Anti-Biofilm Efficacy Against Clinical Wound Pathogens Clinical bacterial wound pathogens in chronic infections are mostly associated with the formation of mono- or multi-species biofilms leading to difficult-to-treat infections, antibiotic resistance, and recurrent infections.27,–29 Chronic wound pathogenic bacteria are mostly engaged in the wound biofilm formation, therefore, the eradication and treatment for infection control and prevention becomes complicated. The presence of biofilms in chronic and nonhealing wounds is a major clinical concern.30 A number of approaches and testing methodologies for anti-biofilm efficacy assessment are being used in the wound care field. Surviving bacteria could form biofilms on a number of abiotic surfaces under static, continuous agitating, and hydrodynamic conditions. The bioelectric dressing was tested for its anti-biofilm efficacy against biofilms formed by both the poloxamer and colony drip-flow reactor (DFR) biofilm models, which are described below. Poloxamer Biofilm Model We evaluated the anti-biofilm efficacy of the bioelectric dressing in poloxamer biofilms generated under static conditions. We used poloxamer since it can be used for antimicrobial efficacy testing and supports growth of bacteria in a biofilm state.31 We established a poloxamer biofilm model using glass coverslips against both mono- and multispecies. In the mono-species biofilm testing against 10 clinical wound pathogens, we observed approximately 2- or 3-fold log10 reduction in bacterial growth after 24 hours incubation compared to those of controls such as no treatment, gauze, and blank polyester without Ag and Zn metals. In addition, we developed multispecies biofilms in the poloxamer model employing a mix of 4 bacterial pathogens for efficacy testing against polymicrobial biofilms. The bioelectric dressing demonstrated approximately 1- or 2-fold log10 reduction in chromogenic agar plates, which is an alternative approach for isolation of several bacterial strains (DRG International Inc., Springfield, New Jersey) compared to those of controls. Our poloxamer hydrogel biofilm model is appropriate for anti-biofilm efficacy evaluation of this dressing and demonstrated anti-biofilm activity against not only mono- but also multispecies biofilms formed by MDR clinical pathogens compared to those of controls such as gauze and blank polyester.32 DFR Biofilm Model We also employed an in vitro colony DFR biofilm model for making biofilms under low shear condition (5 mL/h) similar to natural environments (Fig. 4).33,34 The bioelectric dressing and controls such as gauze and blank polyester as controls were applied directly on the biofilms that are continuously deposited onto hydrophobic filter membranes for 72 hours at room temperature. Biofilm formation was confirmed by crystal violet staining and subsequent microscopic observation. Through vigorous shaking and sonication processes, the released bacteria were serially diluted and plated onto bacterial agar plates. The surviving bacterial colonies were counted after 24 hours incubation at 37°C. During the 72 hours incubation time period, it was shown that the A. baumannii biofilms were well deposited onto the blank polyesters but not onto the bioelectric dressing. We observed inhibition in bacterial growth on the bioelectric dressing when compared to those of blank polyester treatments. Crystal violet staining and microscopic examination of the blank polyester showed development of large and fully grown biofilms. The anti-biofilm activity of the bioelectric dressing against A. baumannii biofilms in colony DFR was more than 10-fold effective in reducing bacterial numbers compared to that of blank polyester which showed accumulation of more than 109 CFUs/mL (Kim H, Bower B, Izadjoo M: In vitro Efficacy Testing of a Novel Wound Dressing against Clinical Bacterial Biofilms. Presentation at the Symposium of Advanced Wound Care. Las Vegas, NV. September 2013). FIGURE 4. View largeDownload slide Colony drip-flow reactor biofilm model set up. The bioelectric or control dressing was applied directly onto the biofilms developed on hydrophobic filter membranes after 72 hours incubation at room temperature under low shear force (5 mL/h). FIGURE 4. View largeDownload slide Colony drip-flow reactor biofilm model set up. The bioelectric or control dressing was applied directly onto the biofilms developed on hydrophobic filter membranes after 72 hours incubation at room temperature under low shear force (5 mL/h). Bioelectric Measurement There are growing number of reports on the beneficial effects of microelectric currents on wound healing, including antimicrobial effects and impact on common cellular functions including development and physiology.16,35 The (Ag–Zn)-printed bioelectric dressing as a wound care device was designed to accommodate (Ag–Zn) half-cell potentials by alternatively printing them on a woven polyester material in a well-characterized dot-matrix pattern. This wound care device can accommodate conceptually 200 embedded microcell batteries per square inch among neighboring Ag and Zn elements tightly printed elemental grains (2–10 microns) of Ag (900 mg/cm2) and Zn (300 mg/cm2) dots on a polyester sheet as a test specimen under various conditions (Fig. 5).36 FIGURE 5. View largeDownload slide Micro currents of the bioelectric dressing is in the range of 2 to 10 μA, similar to physiologic electric fields at the site of injury. The bioelectric dressing, which consists of a dot-matrix pattern of imbedded elemental silver and zinc microcell batteries generates continuous direct current (0.5–0.9 Volts) at its surface promoting wound healing and exerting an antimicrobial effect. FIGURE 5. View largeDownload slide Micro currents of the bioelectric dressing is in the range of 2 to 10 μA, similar to physiologic electric fields at the site of injury. The bioelectric dressing, which consists of a dot-matrix pattern of imbedded elemental silver and zinc microcell batteries generates continuous direct current (0.5–0.9 Volts) at its surface promoting wound healing and exerting an antimicrobial effect. We measured the amount of generated relative EPs on the device (2″ × 2″) using a calibrated microprobing system on a three-axis micrometer stage (Fig. 6) following presoaking with various conductive solutions (500 μL) such as 0.85% saline solution, culture media, or bacterial culture suspensions (approximately 105 CFUs of E. coli to mimic infections), respectively. We observed constant generation of microelectric potential of the Ag- and Zn-printed dressing under all tested conductive solutions.37 FIGURE 6. View largeDownload slide Electric potential measurement system set up. (A) The microprobe system was established to measure microelectric potentials generated on the bioelectric dressing under various test conditions. (B) Two probes, which were attached to the x-y-z stage with a digital micrometer were slightly contacted with the bioelectric dressing placed on a petri-dish as shown in. (C) The reference probe was fixed onto a white empty space at the corner of the dressing and the recording probe was placed onto a silver (Ag) dot, a zince (Zn) dot and white empty place (white arrow) at 100 μm intervals as shown in (C). FIGURE 6. View largeDownload slide Electric potential measurement system set up. (A) The microprobe system was established to measure microelectric potentials generated on the bioelectric dressing under various test conditions. (B) Two probes, which were attached to the x-y-z stage with a digital micrometer were slightly contacted with the bioelectric dressing placed on a petri-dish as shown in. (C) The reference probe was fixed onto a white empty space at the corner of the dressing and the recording probe was placed onto a silver (Ag) dot, a zince (Zn) dot and white empty place (white arrow) at 100 μm intervals as shown in (C). Taken together, the (Ag-Zn)-printed device could generate and successfully sustain EPs without changing electrical properties including stable polarities under the presence of various conductive fluids, which can be encountered in wound environments. Numerous microelectrical circuits are expected to be created between these two neighboring Ag and Zn dots tightly printed on the polyester sheet without requiring any external power source. Thus, the consistently generated EPs at each battery couple with (Ag–Zn)-based dressing would restore disrupted physiologic bioelectric signals on wound sites leading to improved wound healing with antimicrobial activity. Wound Healing Efficacy Recent studies assessing the bioelectric dressing have yielded encouraging findings, including a rapid increase in degree and rate of epithelial migration of deep partial-thickness wounds versus controls in an in vivo porcine study.13 Accelerated human keratinocyte migration, improved mitochondrial function, and improved integrin expression were reported in a series of in vitro studies.36 A growing body of evidence supports the use of this technology in the reepithelialization of acute and chronic wounds of varying complexities and etiologies, and has consistently demonstrated significantly faster healing times versus controls,12,38 sharper wound closure trajectory and a more robust wound healing trend,38 and improved scar appearance and subjective patient outcomes.12 Procellera is an FDA-cleared bioelectrical dressing, which has been used for various acute and chronic wound indications. DISCUSSION Recent research indicates that pathogens exist as discrete species but can coinhabit a space, communicate intra- and interspecies, and set up defenses against certain microbial species. In an early state, these microorganisms exist as free floating, planktonic organisms looking for a place to latch onto. These organisms are in their weakest state in this form. Once the organisms have latched onto a site they begin to replicate. When the number of organisms reach a threshold or “quorum” they are able to function as multicellular communities and can communicate between each individual organism as well as with the entire mass. One common result of this communication is the excretion of a film to coat all the organisms, called a biofilm. This biofilm becomes a protective shield allowing the inhabitants to proliferate under the shield and, through genetic manipulation, modify their resistance to antibiotics and antimicrobials.39 Infections with MDR pathogens within the military environments are spreading at an alarming rate,40 with combat-related injuries at greater inherent risk of infectious complications, whether from colonization before injury, environmental contamination, or nosocomial infections.41,42 The debilitating nature of wound infections in service members has potentially devastating consequences. Despite best infection control methods, failure of traditional antibiotic therapies in combating MDR organism colonization and infection in military treatment facilities remain a topic of significant concern. The overuse of antimicrobial prophylaxis, associated complications, and consequent microbial resistance has brought increased focus to the unmet need for innovative and aggressive nonpharmacologic approaches to control, reduce bioburden. Energy is produced within human cells and is essential for cellular metabolism. The energy must increase during the wound repair cycle, to stimulate cell migration, deposition of an extracellular matrix, and cell “proliferation.”43 In the sterile environments, this energy is used exclusively by the cells. However, when pathogenic microorganisms are present, there is competition for the energy. Although various energy-based modalities with differing methods of action have been developed for treatment of soft-tissue wounds, many are complex in use, capital intensive, require tethered access, and myriad consumables, posing considerable limitations for clinical or home use. Challenges with prolonged wound-healing times and multifactorial sources of microbial contamination have created a need for portable, antimicrobial wound dressing, and treatment solutions. “Procellera,” a microcurrent generating antimicrobial dressing, is currently being used in the United States for various acute and chronic wound indications, including partial and full thickness wounds such as pressure ulcers, venous ulcers, diabetic ulcers, burns, surgical incisions, and donor and/or recipient graft sites. A growing body of preclinical and clinical data support the efficacy of this device in treating soft tissue wounds, burns, and inflammatory conditions. Unique in its method and mode of action, the portable, wireless nature of this bioelectric dressing is the evolution of an electrical stimulation device into a dressing-like form. This electric stimulus was previously shown to nonpharmacologically downregulate quorum-sensing genes and downregulate the antibiotic resistant genes within a biofilm environment.36 An alternative method of action also observed was the downregulation of Glycerol-3-phosphate dehydrogenase (GPDH), an enzyme within the organisms required for metabolism. Its versatility, portability, and ease of use make it ideally suited for military field applications as well as clinical and home applications. A growing body of research on the bioelectric dressing demonstrates significant benefits in the treatment of partial and full thickness, acute and chronic wounds, including electroceutical antimicrobial efficacy and enhanced cellular migration impacting wound healing. Laboratory studies conducted by our team successfully demonstrated significant efficacy of the bioelectric dressing against various MDR wound pathogens and anti-biofilm properties of this dressing in both mono- and poly-microbial biofilm models. Given the findings presented in this article, the use of a next generation, close proximity electrically active technology to optimize the wound-healing environment may better control bioburden, potentially reducing the need for local and/or systemic antibiotics, and improving the quality of life of injured military personnel. This dressing has significant utility to treat wounds and wounds infected with antibiotic and MDR pathogens. Results from our findings point to the bioelectric dressing as a viable and useful option for military caregivers to add as an anti-infection modality in clinical practice and may serve as a promising treatment modality for battlefield-acquired wounds. REFERENCES 1. 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TI - An Overview of the Efficacy of a Next Generation Electroceutical Wound Care Device
JF - Military Medicine
DO - 10.7205/MILMED-D-15-00157
DA - 2016-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/an-overview-of-the-efficacy-of-a-next-generation-electroceutical-wound-D1PfsMIv3B
SP - 184
EP - 190
VL - 181
IS - suppl_5
DP - DeepDyve
ER -