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1. Hoang LQ, Pal S, Liu Z, Senkowsky J, Tang. A time-dependent survival analysis for early prognosis of chronic wounds by monitoring wound alkalinity. Int J Wound Care 2022


The objective is to determine whether monitoring wound alkalinity between visits may help prognosticate chronic wound healing. The alkalinity of 167 wounds during the first 3 visits was assessed using disposable DETEC® pH. Wounds grouped by frequency of alkaline results were compared by % wound size reduction during each visit and 120-day healing probability. The Cox proportional hazards model for time-dependent variables was used to generate non-healing probability curves, where variables are binary (alkaline/non-alkaline, infection/no infection), categorical (wound type), and continuous (wound area); the response is time to complete wound healing; and the event of interest is complete wound healing in 120 days. Results show that wounds with frequent alkaline results have significantly smaller % size reduction per visit. Logistic regression shows an increase in 120-day healing probability with fewer alkaline results. Survival analysis shows that the instantaneous healing rate of non-alkaline or non-alkaline transitioning wounds is 1.785, 2.925, and 5.908 times that of alkaline or alkaline-transitioning wounds for 1, 2, and 3 alkalinity measurements, respectively. Furthermore, the concordance statistic of each survival model shows that goodness of fit increases with more alkalinity measurements. Overall, frequent wound alkalinity assessments may serve as a novel way to prognosticate wound healing outcomes.

2. Senkowsky J, Li S, Nair A, Pal S, Hu W, Tang L. A wound alkalinity measurement to predict non-healing wound outcomes. J Wound Care. 2022

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As wound pH could influence wound healing rates, this study examined the alkalinity of the entire wound during patients' follow-up visits to predict the final non-healing outcome.
Wound alkalinity of patients with diabetic foot ulcers (DFUs), venous leg ulcers, and other wounds during three follow-up visits within a four week period was recorded. All wounds were followed until 12 weeks to confirm that healed wounds did not relapse. The alkalinity of various wounds over multiple visits with varying durations was compared with final wound status to assess whether one-time wound alkalinity measurement could predict non-healing wounds. The effect of wound types, infection, age and sex on such determinations was also studied.
A total of 96 patients were included in this study. Based on probability variations of pre- and post-test non-healing outcomes from multiple visits over 12 weeks, second visit assessment gave the highest increase in risk of non-healing for an alkaline test result (+8.0%) and decrease in risk of non-healing for a non-alkaline test result (–19.7%). Moreover, a second visit (7–21 days from first visit) showed a greater change in risk for non-healing based on alkaline and non-alkaline test results (+15.7% and –38.1% respectively), compared with a visit within seven days (+6.3% and –12.5%, respectively). Wound type, infection, age and sex did not affect the prognostic ability of wound alkalinity.
The results of this study support that a single wound alkalinity measurement during the second visit (7–21 days from first visit) can be used to predict non-healing wounds. Wound alkalinity may be routinely assessed to predict non-healing wounds and to determine whether the wounds are healing as expected following initial treatment.

3. Vu H, Nair AM, Tran L, Pal S, Senkowsky J, Hu W, Tang  L. A device to predict short term healing outcome of chronic wounds. Advances in Wound Care 2019 

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Objective: While myriads of studies have suggested that a survey of wound pH environment could indicate wound healing activities, it is not clear whether wound alkalinity can be used as a prognostic indicator of nonhealing wounds. Currently available systems cannot reliably assess the pH environment across wounds, which is the objective of this study. 

Approach: A disposable device, DETEC pH, was developed and characterized on its ability to map wound alkalinity by pressing a freshly recovered wound dressing against its test surface. By comparing the wound’s alkalinity and size reduction rates (*7 days) following pH measurement, we assessed the capability of wound alkalinity to prognosticate subsequent short-term wound size reduction rates.

Results: The device had high accuracy and specificity in determining the alkalinity of simulated wound fluids soaked onto wound dressing. The type of wound dressing type had an insignificant effect on its detection sensitivity. Upon testing discarded wound dressings from human patients, the device quickly determined alkaline and acidic wounds. Finally, statistical analyses of wound size reduction rates in wounds with various alkalinities confirmed that wound alkalinity has a strong influence on, at least, short-term wound healing activity.

Innovation: Without directly contacting the patient, this device provides a quick assessment of wound alkalinity to prognosticate immediate and short-term wound healing activities.

Conclusion: DETEC pH may serve as a prognosis device for wound care specialists during routine wound assessment to predict wound healing progress. This information can assist the decision-making process in a clinical setting and augur well for chronic wound treatment. DETEC pH can also be used as an aid for home health care nurses or health care providers to screen nonhealing wounds outside clinics.

4. Li S, Mohamedi A, Senkowsky J, Nair A, Tang L. Imaging in chronic wound diagnostics. Advances in Wound Care 2019


Significance: Chronic wounds affect millions of patients worldwide, placing a huge burden on health care resources. Although significant progress has been made in the development of wound treatments, very few advances have been made in wound diagnosis.

Recent Advances: Standard imaging methods like computed tomography, single-photon emission computed tomography, magnetic resonance imaging, terahertz imaging, and ultrasound imaging have been widely employed in wound diagnostics. A number of noninvasive optical imaging modalities like optical coherence tomography, near-infrared spectroscopy, laser Doppler imaging, spatial frequency domain imaging, digital camera imaging, and thermal and fluorescence imaging have emerged over the years.

Critical Issues: While standard diagnostic wound imaging modalities provide valuable information, they cannot account for dynamic changes in the wound environment. In addition, they lack the capability to predict the healing outcome. Thus, there remains a pressing need for more efficient methods that can not only indicate the current state of the wound but also help determine whether the wound is on track to heal normally.

Future Directions: Many imaging probes have been fabricated and shown to provide real-time assessment of tissue microenvironment and inflammatory responses in vivo. These probes have been demonstrated to noninvasively detect various changes in the wound environment, which include tissue pH, reactive oxygen species, fibrin deposition, matrix metalloproteinase production, and macrophage accumulation. This review summarizes the creation of these probes and their potential implications in wound monitoring.

5. Li S, Vu H, Senkowsky J, Hu W-J, Tang L. A near-infrared fluorescent pH sensing film for wound milieu pH monitoring. Experimental Dermatology, 2020, 29: 107-111

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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.

6. Dacy A, Haider N, Davis K, Hu W-J, Tang L. Design and evaluation of an imager for assessing wound inflammatory responses and bioburden in a pig model. Journal of Biomedical Optics, 2019, 25(3):032002

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Our work details the development and characterization of a portable luminescence imaging device for detecting inflammatory responses and infection in skin wounds. The device includes a CCD camera and close-up lens integrated into a customizable 3D printed imaging chamber to create a portable light-tight imager for luminescence imaging. The chamber has an adjustable light portal that permits ample ambient light for white light imaging. This imager was used to quantify in real time the extent of two-dimensional reactive oxygen species (ROS) activity distribution using a porcine wound infection model. The imager was used to successfully visualize ROS-associated luminescent activities in vitro and in vivo. Using a pig full-thickness cutaneous wound model, we further demonstrate that this portable imager can detect the change of ROS activities and their relationship with vasculature in the wound environment. Finally, by analyzing ROS intensity and distribution, an imaging method was developed to distinguish infected from uninfected wounds. We discovered a distinct ROS pattern between bacteria-infected and control wounds corresponding to the microvasculature. The results presented demonstrate that this portable luminescence imager is capable of imaging ROS activities in cutaneous wounds in a large animal model, indicating suitability for future clinical applications.

7. Peng Z, Zhou J, Dacy A, Zhao D, Kearney V, Zhou W, Tang L, Hu W-J. Design of a portable imager for near-infrared visualization of cutaneous wounds. Journal of Biomedical Optics, 2017, 22(1), 016010.

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A portable imager developed for real-time imaging of cutaneous wounds in research settings is described. The imager consists of a high-resolution near-infrared CCD camera capable of detecting both bioluminescence and fluorescence illuminated by an LED ring with a rotatable filter wheel. All external components are integrated into a compact camera attachment. The device is demonstrated to have competitive performance with a commercial animal imaging enclosure box setup in beam uniformity and sensitivity. Specifically, the device was used to visualize the bioluminescence associated with increased reactive oxygen species activity during the wound healing process in a cutaneous wound inflammation model. In addition, this device was employed to observe the fluorescence associated with the activity of matrix metalloproteinases in a mouse lipopolysaccharide-induced infection model. Our results support the use of the portable imager design as a noninvasive and real-time imaging tool to assess the extent of wound inflammation and infection.

8. Zhou J, Weng H, Huang YH, Gu Y, Tang L, Hu W-J. Ratiometric reactive oxygen species nanoprobe for noninvasive in vivo imaging of subcutaneous inflammation/infection. Journal of Biomedical Nanotechnology, 2016, 12(8):1679-87.

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Release of reactive oxygen species (ROS) accompanied with acute inflammation and infection often results in cell death and tissue injury. Several ROS-reactive bioluminescent probes have been investigated in recent years to detect ROS activity in vivo. Unfortunately, these probes cannot be used to quantify the degree of ROS activity and inflammatory responses due to the fact that the extent of the bioluminescent signals is also probe-concentration dependent. To address this challenge, we fabricated a ratiometric ROS probe in which both ROS-sensitive chemiluminescent agents and ROS-insensitive fluorescent reference dye were conjugated to particle carriers. The bioluminescence/reference fluorescence intensity ratios were calculated to reflect the extent of localized ROS activities while circumventing the variations in bioluminescent intensities associated with the ROS probe concentrations. The physical and chemical properties of the ratiometric probes were characterized. Furthermore, we assessed the accuracy and reproducibility of the probe in detecting ROS in vitro. The ability of the ratiometric probes to detect ROS production in inflamed/infected tissues was also examined using animal models of inflammation and infection. The overall results imply that ratiometric ROS probes can rapidly and non-invasively detect and quantify the extent of inflammatory responses and bacterial infection on wounds in real time.

9. Tang EW, Nair A, Baker DW, Hu W-J, Zhou J. In vivo imaging of infection using a bacteria-targeting optical nanoprobe. Journal of Biomedical Nanotechnology, 2014, 10(5): 856-63.

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Wound and device-associated infection is a leading cause for morbidity and mortality. As such, rapid and early diagnosis of bacterial colonization is critical to infection treatment. The current diagnostic methods however, are not able to meet this requirement. Therefore, there is a practical need for the development of a new method to rapidly identify colonized bacteria. This study aims to develop optical nanoprobes that can detect and quantify the number of colonized bacteria in real time. To this end, we have synthesized an imaging nanoprobe with three elements: Concanavalin A (Con A) as a bacterial targeting ligand, a nanoparticle carrier, and a near infrared fluorescent dye. An MTS assay revealed that the bacteria nanoprobe is cell compatible. In vitro testing further showed that the bacteria nanoprobe had a very high specificity and affinity to bacteria. Using a murine wound and catheter infection model, we found that the bacteria nanoprobes can rapidly detect and quantify the extent of bacterial colonization on wounds and catheters in real time.

10. Tsai Y-T,* Zhou J,* Weng H, Tang L, Hu W-J. Real-time noninvasive monitoring of in vivo inflammatory responses using a pH ratiometric fluorescence imaging probe. Advanced Healthcare Materials, 2013, 3(2): 221-229.

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It is often difficult to continuously monitor and quantify inflammatory responses in vivo. These dynamic responses however are often accompanied by specific pH changes. A new ratiometric optical pH probe is developed by combining pH‐sensitive (CypHer5E) and pH‐insensitive (Oyster800) fluorescent dyes into nanoparticles for in vivo optical imaging. By taking the ratio of fluorescence intensities at different wavelengths, these nanosized sensors provide excellent measurement capabilities, and unique mapping, of the continuous in vivo pH changes for three different inflammation models. In each model a strong positive correlation is found between ratiometric pH changes and the corresponding inflammatory response measured by histological analyses. These results indicate that ratiometric imaging can provide a noninvasive, rapid, and highly sensitive optical readout for the pH‐ratio changes in vivo. Furthermore, this technique may be used to monitor the real‐time dynamics of inflammatory processes.

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