Wound pH Research Articles

A Multifunctional Pro‐Healing Zwitterionic Hydrogel for Simultaneous Optical Monitoring of pH and Glucose in Diabetic Wound Treatment

AbstractDiabetic ulcer is the most common kind of chronic wound worldwide. Though great efforts have been devoted, diabetic ulcer still remains as a challenge that requires constant monitoring and management. In this work, a multifunctional zwitterionic hydrogel is developed to simultaneously detect two fluctuant wound parameters, pH and glucose level, to monitor the diabetic wound status. A pH indicator dye (phenol red) and two glucose sensing enzymes, glucose oxidase (GOx) and horseradish peroxidase (HRP), are encapsulated in the anti‐biofouling and biocompatible zwitterionic poly‐carboxybetaine (PCB) hydrogel matrix. The visible images are collected by a smartphone and transformed into RGB signals to quantify the wound parameters. Results show that the activity and stability of both two enzymes are improved within PCB hydrogel, and the Kcat/Km value of PCB‐HRP is ≈5.5 fold of free HRP in artificial wound exudate. This novel wound dressing can successfully monitor the pH range of 4–8 and glucose level of 0.1–10 × 10−3 m. Meanwhile, it also provides a moist healing environment that can promote diabetic wound healing. This multifunctional wound dressing may open vistas in chronic wound management and guide the diabetes treatment in clinical applications.

Wound monitoring of pH and oxygen in patients after radiation therapy

ObjectivesPostradiogenic wound healing disorders are an important clinical problem. While a variety of treatment modalities are available, there is no strategy to objectively judge treatment success. The aim of this study was to evaluate a 2D luminescence imaging system for pH and oxygen in non-healing wounds after radiotherapy.MethodsLuminescence 2D imaging was performed with the VisiSens (Presens, Regensburg, Germany) 2D imaging systems A1 and A2 for oxygen and pH, respectively. Biocompatible planar luminescent sensor foils were applied to non-irradiated and irradiated skin as well as to radiogenic wounds of five patients and the pH and the oxygen saturation was determined.ResultspH measurements showed significant differences between non-irradiated skin (6.46 ± 0.18) and irradiated skin (6.96 ± 0.26). Radiogenic wounds exhibited the highest pH values (7.53 ± 0.26). Oxygen measurements revealed a mean oxygen saturation of non-irradiated skin of 6.19 ± 0.83 mmHg. The highest value of oxygen saturation (28.4 ± 2.4 mmHg) was found on irradiated skin while irradiated wounds had a poor oxygen saturation (9.4 ± 2.2 mmHg) (mean ± s.e.m.).ConclusionWe found that routine measurement of pH and pO2 in patients could be easily integrated into the clinical routine. The results of the measurements show unfavorable pH and oxygen saturation conditions for wound healing in irradiated wounds. Interestingly, irradiated wounds exhibit a more pronounced hypoxia than irradiated skin which is reflected by an altered pH and pO2 compared to unirradiated skin, which has the potential to serve as a prognostic marker in the future. In addition to the objectification of the treatment success of postradiogenic wound healing disorders, the extent of skin toxicity could already be predicted during radiotherapy with this method.

Challenges and opportunities of pH in chronic wounds.

Regarded as a silent epidemic, chronic wounds are a global public health issue. Wound healing is a complex, synchronized cascade of physiological processes restoring the anatomic and functional integrity of the skin; however, chronic wounds fail to proceed through the wound healing cascade. Wound pH oscillates during wound healing, usually traversing from a neutral pH to an acidic pH, while chronic wounds perpetuate in an elevated alkaline milieu. Although a neglected clinical parameter, pH has implications for relatively all pathologies of wound healing affecting oxygen release, angiogenesis, protease activity, bacterial toxicity and antimicrobial activity. Despite the array of wound healing products currently marketed, understanding the implications of pH on arresting wound healing can stimulate innovation within this vast market.

A near-infrared fluorescent pH sensing film for wound milieu pH monitoring.

Studies have shown that wound pH is a potentially influential factor in the healing process. Due to the flaws of traditional pH measurement approaches, wound pH measurement has not become part of current standard of care. A near-infrared pH-sensitive ratiometric film was created and characterized for measuring wound pH. This film was fabricated by physically absorbing poly (N-isopropyl Acrylamide) nanoparticles conjugated with pH-sensitive (CypHer5E) and pH-insensitive (Cy7) fluorescent dyes into 2-hydroxyethyl methacrylate hydrogel film. The pH pattern on wounds can be indirectly measured by pressing freshly discarded wound dressing on top of the pH-sensitive film and imaging it. In vitro tests show that the film can accurately and rapidly detect a wide range of pH (from pH 4 to 8) in wound milieu. Further, patient studies showed that, by measuring pH on wound contact side of discarded wound gauze, the pH and its non-homogeneous distribution on wounds can be indirectly determined. By comparing patients with different wound conditions, we find that near-infrared pH sensing film can be used to measure wound exudate pH with high accuracy and efficiency. In addition, wound pH determination can provide an accurate assessment of wound healing activity in real time.

An Intelligent and Smart Environment Monitoring System for Healthcare

Skin wound healing is influenced by two kinds of environment i.e., exterior environment that is nearby to wound surface and interior environment that is the environment of the adjacent part under wound surface. Both types of environment play a vital role in wound healing, which may contribute to continuous or impaired wound healing. Although, different previous studies provided wound care solutions, but they focused on single environmental factors either wound moisture level, pH value or healing enzymes. Practically, it is insignificant to consider environmental effect by determination of single factors or two, as both types of environment contain a lot of other factors which must be part of investigation e.g., smoke, air pollution, air humidity, temperature, hydrogen gases etc. Also, previous studies didn’t classify overall healing either as continuous or impaired based on exterior environment effect. In current research work, we proposed an effective wound care solution based on exterior environment monitoring system integrated with Neural Network Model to consider exterior environment effect on wound healing process, either as continuous or impaired. Current research facilitates patients by providing them intelligent wound care solution to monitor and control wound healing at their home.

Orange‐Emissive Carbon Quantum Dots: Toward Application in Wound pH Monitoring Based on Colorimetric and Fluorescent Changing

Monitoring of wound pH is critical for interpreting wound status, because early identification of wound infection or nonhealing wounds is conducive to administion of therapies at the right time. Here, novel orange-emissive carbon quantum dots (O-CDs) are synthesized via microwave-assisted heating of 1,2,4-triaminobenzene and urea aqueous solution. The as-prepared O-CDs exhibit distinctive colorimetric response to pH changing, and also display pH-sensitive fluorescence. Benefiting from the response of O-CDs over a wound-relevant pH range (5-9), medical cotton cloth is selected to immobilize O-CDs through hydrogen bond interactions, the resultant O-CDs-coated cloth with emission at 560 nm shows a high response to pH variation in the range of 5-9 via both fluorescence and visible colorimetric changes. Moreover, the sensitivity of fluorescence to pH is capable of establishing an analytical mode for determining pH value. Further, the O-CDs-based pH indicator possesses not only superior biocompatibility and drug compatibility but also excellent resistance leachability and high reversibility. Importantly, the usage of O-CDs-coated cloth to detect pH is free from the interference of blood contamination and long-term storage, thus providing a valuable strategy for wound pH monitoring through visual response and quantitative determination.

Continuous pH monitoring in wounds using a composite indicator dressing — A feasibility study

PurposeModern burn care strives for new means to guarantee optimised wound healing. Several studies have shown a correlation between the pH value in a (burn) wound and successful wound healing. A multitude of devices to monitor pH is available, all requiring direct wound contact and removal of the dressing for pH monitoring. The aim of this feasibility study was to create a sterile and easy to handle method for pH monitoring while simultaneously using an advanced wound dressing. Materials and methodsDressing sheets of biotechnologically generated nanofibrillar cellulose (epicitehydro) were chemically functionalised with the indicator dye GJM-534. pH-donors with increasing pH were subsequently applied to the created indicator dressing. To investigate temporal resolution and continuous monitoring we used circular pH-donors with different pH (7 and 10) and decreasing diameters that were placed on another dressing sheet. Clinically relevant spatial resolution was checked by a wound bed simulation with small areas (8 mm) of higher pH (10) on a field of lower pH (7) and vice versa. ResultsThe indicator dressing showed a gradual colouring from yellow to dark orange with increasing pH in steps of 0.3. After conversion of digital pictures to greyscale values, a sigmoidal distribution with a pKa-value of 8.4 was obtained. A ring-like pattern with alternating colour change corresponding to the pH was observed in the continuous monitoring experiment and the wound bed simulation delivered excellent local resolution. ConclusionSince the pH of a (burn) wound can have a significant influence on wound healing, a pH indicator was successfully linked to an advanced, temporary, alloplastic wound dressing material. We were able to show the possibility of pH monitoring by the dressing itself. Additional testing, including studies with large case numbers for optimisation are necessary before clinical implementation.

Elevated wound fluid pH correlates with increased risk of wound infection

There is no definitive method to determine infection status in non-healing wounds. Measurement of wound pH might be a promising indicator of infection as it is relatively easy to perform, provides objective results within a few seconds, and is inexpensive. The aim of this investigation was to determine if wound pH could be a potential indicator of early or established infection in non-healing wounds. We explored the relationship between wound pH and two indicators of wound infection: expert clinical judgement and elevated neutrophil-derived enzyme activity. Data was used from 120 wound samples previously collected at Medisch Spectrum Twente hospital. With increasing wound pH, there was also an increase in the proportion of infected wounds as determined by expert clinical judgement. In addition, increases in the activities of myeloperoxidase, elastase and lysozyme were also associated with elevated pH. The strength of the relationship between wound pH and clinical judgement or enzyme activities observed in this study is not sufficient to promote the use of elevated pH alone as an indicator for wound infection. However, the use of pH in combination with other indicators for wound infection, such as elevated neutrophil enzyme activity, warrants further research.

Advances in the research of influence of pH value on healing of chronic wounds

Chronic wounds are with characteristics of long last time and cannot heal in time, which is a problem in clinic. Wound pH value plays an important role in the process of healing of chronic wounds. In this paper, we review the relative researches on wound pH value and wound microenvironment, summarize the potential relationship between wound pH value and healing of chronic wounds, as well as the method to change pH value of chronic wounds, thereby to provide theoretical basis for the treatment of chronic wounds in clinic.

Smart Hydrogel for the pH‐Selective Drug Delivery of Antimicrobial Compounds

Infection is a major prompt of chronic wounds, increasing the pH on the injury tissues. Thus, pH can be used as trigger for antimicrobial agents’ delivery, preventing chronic wounds. Hence, the present work aimed to develop a hydrogel with drug delivery capacity, modulated by environmental pH. Chitosan was used as electrolyte monomer and it was crosslinked with hydroxypropyl methylcellulose and 2‐hydroxypropyl‐β‐cyclodextrin. The polymeric network assembly was confirmed by FTIR and thermal analysis. The developed hydrogels behaved as superabsorbent systems, with higher swelling at pH 7. Caffeic acid loading was ruled by the inclusion complex formation between the phenolic acid and cyclodextrin. Chitosan hydrogels delivery capacity was pH‐dependent and, also, more efficient at pH 7. Based on the Peppas–Sahlin model, fickian diffusion was the main mechanism responsible for caffeic acid release. Based on the results, the developed hydrogel can be used to prevent wound infection, due to its ability to release antimicrobial agents when the wound pH rises.

Electrospun asymmetric membranes for wound dressing applications

To accomplish a rapid wound healing it is necessary to develop an asymmetric membrane with interconnected pores consisting of a top layer that prevents rapid dehydration of the wound and bacteria penetration and a sub-layer with high absorption capacity and bactericidal properties. Polycaprolactone (PCL)/polyvinyl acetate (PVAc) asymmetric membranes loaded with the bactericidal monoterpene carvacrol (CRV) were synthesized and characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. Mechanical properties in dry and wet conditions and fluid handling behavior were also assessed. In addition, biological studies regarding their bactericidal effects, cytocompatibility and wound closure properties were also developed. Loading efficiencies of 40–50% were achieved in the prepared samples and 85–100% of the loaded CRV was released in simulated wound pH evolution medium. The significant inhibition of Gram negative (Escherichia coli S17) and Gram positive (Staphylococcus aureus ATCC 25923) bacteria growth clearly showed the suitability of the fabricated membranes for wound healing applications. Furthermore, cytocompatibility of the loaded membranes was demonstrated both in 2D and 3D human dermal fibroblast cultures, as well as cell migration was not impaired by released carvacrol from the membranes. These results highlight the potential of these polymeric electrospun membranes for wound healing.

Synthesis and characterization for novel Cu(II)-thiazole complexes-dyes and their usage in dyeing cotton to be special bandage for cancerous wounds

New series of Cu(II)-thiazole complexes were synthesized using variable p-substituted, N-aryl-2-oxo-2-(thiazol-2-ylamino)-acetohydrazonoyl cyanide. All new syntheses were elucidated by, analytical, spectral and conformational study. The binuclear feature (2 M:1L), was proposed for all complexes, through mono-negative tetra-dentate chelation mode in octahedral or square-planer geometry. The formulae of chosen compounds, were confirmed by, 1HNMR and mass spectral analysis. The ideal distribution for atomic-skeletons, was performed utilizing Gaussian09 software, to confirm the bonding mode. Also, substantial parameters were extracted from output-files (log &chk), beside others calculated based on frontier energy gaps. The superiority of Cu(II) complexes, was predicated from such conformational study. Also and by applying MOE module, the docking process was performed for most syntheses against selected pathogen proteins (1miu, 4k9g and 5jm5), which have been tested practically in application. The extracted docking-data, showed clear superiority and promising efficiency for Cu(II) complexes as anticancer drugs compared to free derivatives. Traditional screening was conducted over new complexes against three carcinoma cell lines (HCT-116, MCF-7 & HepG-2) as well as healthy cell line (HSF). IC50 values showed considerable toxicity of Cu(II)-4e complex versus HCT-116 cell line. The antitumor screening was conducted over cotton fabric after dyeing by complexes, to test the degree of success to be used as a special bandage for cancerous wounds. The most lighted observation was, the effect of released-pigmenting complex on colon cancer cell line, while the absence of any effect on healthy cell. Also, the released-pigment, controlled the pH of cancerous wound, which is significantly preferable.

Two-layer Electrospun System Enabling Wound Exudate Management and Visual Infection Response.

The spread of antimicrobial resistance calls for chronic wound management devices that can engage with the wound exudate and signal infection by prompt visual effects. Here, the manufacture of a two-layer fibrous device with independently-controlled exudate management capability and visual infection responsivity was investigated by sequential free surface electrospinning of poly(methyl methacrylate-co-methacrylic acid) (PMMA-co-MAA) and poly(acrylic acid) (PAA). By selecting wound pH as infection indicator, PMMA-co-MAA fibres were encapsulated with halochromic bromothymol blue (BTB) to trigger colour changes at infection-induced alkaline pH. Likewise, the exudate management capability was integrated via the synthesis of a thermally-crosslinked network in electrospun PAA layer. PMMA-co-MAA fibres revealed high BTB loading efficiency (>80 wt.%) and demonstrated prompt colour change and selective dye release at infected-like media (pH > 7). The synthesis of the thermally-crosslinked PAA network successfully enabled high water uptake (WU = 1291 ± 48 − 2369 ± 34 wt.%) and swelling index (SI = 272 ± 4 − 285 ± 3 a.%), in contrast to electrospun PAA controls. This dual device functionality was lost when the same building blocks were configured in a single-layer mesh of core-shell fibres, whereby significant BTB release (~70 wt.%) was measured even at acidic pH. This study therefore demonstrates how the fibrous configuration can be conveniently manipulated to trigger structure-induced functionalities critical to chronic wound management and monitoring.

Observational Study of pH and Temperature Behavior in Chronic Wounds and its Correlation with the Bacterial Colonization Phase

Observational Study of pH and Temperature Behavior in Chronic Wounds and its Correlation with the Bacterial Colonization Phase

Color-changing smart fibrous materials for naked eye real-time monitoring of wound pH.

Real-time monitoring of wound pH may provide information about the wound healing status and potential bacterial infection. Herein, we integrated the biocompatible color changing substance curcumin into a fibrous material, capable of in situ real-time visually monitoring the wound pH. The results indicate that the curcumin-loaded fibrous mat exhibits an obvious pH-dependent color change from yellow to red brown with a change in pH from 6.0 to 9.0, which can be easily detected by the human naked eye. Moreover, the wound pH conditions can be determined with the aid of a smart phone App after image analysis. Due to their flexibility, the fibrous materials have been further processed into various shapes from 1D to 3D for fitting the irregular wounds. It is believed that smart fibrous materials that can simultaneously real-time monitor the wound pH and repair the wound may change wound management to a convenient and comfortable way.

Systematic Evaluation of a Diclofenac-Loaded Carboxymethyl Cellulose-Based Wound Dressing and Its Release Performance with Changing pH and Temperature.

Development of drug-loaded wound dressings is often performed without systematic consideration of the changing wound environment that can influence such materials' performance. Among the crucial changes are the wound pH and temperature, which have an immense effect on the drug release. Detailed release studies based on the consideration of these changing properties provide an important aspect of the in vitro performance testing of novel wound dressing materials. A sodium carboxymethyl cellulose-based wound dressing, with the incorporated non-steroidal anti-inflammatory drug diclofenac, was developed and characterised in regard to its physico-chemical, structural and morphological properties. Further, the influence of pH and temperature were studied on the drug release. Finally, the biocompatibility of the wound dressing towards human skin cells was tested. Incorporation of diclofenac did not alter important properties (water retention value, air permeability) of the host material. Changes in the pH and temperature were shown to influence the release performance and have to be accounted for in the evaluation of such dressings. Furthermore, the knowledge about the potential changes of these parameters in the wound bed could be used potentially to predict, and potentially even to control the drug release from the developed wound dressing. The prepared wound dressing was also proven biocompatible towards human skin cells, making it interesting for potential future use in the clinics.

Surface pH and acute burn wound healing

Context: There is a lacuna in our knowledge to objectively assess the progression of healing in an acute burn wound. Aim: This study aims to validate if a trend in changes of wound surface pH can be used as a reliable indicator to prognosticate wound healing in acute thermal burns. Materials and Methods: Hospital-based longitudinal observational study was conducted in the department of burns of a tertiary care center. One hundred and twenty-three patients with acute thermal burns in the age group of 15–60 years with total burn surface area between 30%–60% were included in the study. Surface pH of wound from a specific area of dimension 10×10 cm was measured on day 1, 3, 5, 7, 9, 11, 13, and 15 using HANNA HI 99181 pH meter and the trend of wound surface pH level changes over time was observed. Wound healing was clinically assessed by wound grading chart on day 7 and 15. Results: The trend of reducing pH values had a negative correlation coefficient of - 0.95 with improved wound healing, and the trend of increasing pH values had a positive correlation coefficient of 0.74 with deteriorating wound. This is statistically highly significant with P Conclusion: The analysis showed that the trend of change in pH value over time has high statistical significance with wound healing in burns patients with reducing trend, i.e., toward slightly acidic pH being associated with better wound healing and increasing trend, i.e., toward alkalinity suggesting worsening of wounds. Hence, wound surface pH can be used as a reliable indicator to prognosticate wound healing in acute thermal burns.

A Sensor Gauze With Multi-Channel Moisture and pH Monitoring for Chronic Wound Care

Chronic wounds (CWs) usually happen in diabetic foot ulcers, venous leg ulcers, and pressure ulcers. When wounds fail to achieve sufficient healing within four weeks, it indicates that bacteria in the wounds are promoting chronicity through relapse infections. Therefore, how to observe changes in a wound after it is covered with gauze to avoid the formation of CWs is important for clinical care. Previous studies showed that wound pH value distribution can be used as an important basis for infection and healing assessment. This paper proposed the design of sensor gauze with multi-channel moisture and pH monitoring for CWs. The moisture sensing analysis of different areas could be used to determine the distribution of the corresponding wound tissue fluid, as well as automatically carry out multi-area pH value measurements and wound analysis. The analysis results were graphically displayed on a monitoring device. The results indicated that the proposed design could measure pH values with high sensitivity (0.01 pH/mV) in the range of 3 to 10. Statistical correlation analysis revealed a strong correlation ( $R^{2} = 0.97$ ) between the standard meter and each pH sensing point. In the experimental correlation between the proposed device and the moisture device, the results show that there was a high correlation ( $R^{2} = 0.97$ ). The response time of the whole wound scan with four channels was within one second. This design has the potential to provide assistance for related clinical care applications.

A pH-regulated drug delivery dermal patch for targeting infected regions in chronic wounds.

This work presents a low-cost, passive, flexible, polymeric pump for topical drug delivery which uses wound pH as a trigger for localized drug release. Its operation relies on a pH-responsive hydrogel actuator which swells when exposed to the alkaline pH of an infected wound. The pump enables slow release (<0.1 μL min-1) of aqueous anti-bacterial solution for up to 4 hours and sustains against up to 8 kPa of backpressure. Featuring a scalable layer-by-layer fabrication technique to expand the pump into a 2 × 2 array, the device can dispense 50 μl onto a 160 mm2 dermal coverage within 4 hours. Robustness tests show that when integrated within a medical adhesive, the device can be worn around the forearm and can withstand various daily activities (non-intensive) for up to 12 hours. In vitro experiments demonstrate a 58 times decrease of live P. aeruginosa after 24 hours of the pump assisted antibiotics treatment.

Smart release of antimicrobial ZnO nanoplates from a pH-responsive keratin hydrogel

A smart antibacterial biomaterial based on a keratin hydrogel with pH-dependent behavior and Zinc Oxide nanoplates as biocide agent has been developed. The pH of a chronic wound is basic due to bacterial metabolism. Originally shrank at acid pH, keratin hydrogels swell upon contact with a bacterial contaminated media leading to the release of the nanoparticles. The material has been thoroughly characterized by infrared spectroscopy, Raman, scanning electron microscope, swelling behavior, Differential scanning calorimetry, Small-angle X-ray scattering, rheology, antimicrobial activity and cytotoxicity. The results show that 5% of Zinc Oxide nanoparticles concentration is the optimum for wound dressing applications.