Millions of people in the United States have chronic wounds, including those living with diabetes, patients recovering from burns, post-surgical patients and other people with injuries. For clinicians, early detection of infection, inflammation or other recovery setbacks can be challenging to detect, primarily because patients may be self-reporting or awaiting lab results. This can result in a worsening infection, long-term damage and, in some cases, amputation.
To combat this, a team of Penn State researchers has developed a portable, electronic sensor system that can monitor multiple biomarkers in wounds and detect early signs of infection or inflammation before symptoms worsen, and potentially before visible symptoms appear. They published their findings in npj 2D Materials and Applications.
"We have developed a multi-sensor chip that can detect metabolic, microbial, inflammatory and physicochemical - such as pH levels - indicators on a single chip," said first author Heshmat "Amir" Asgharian, a doctoral candidate in electrical engineering at Penn State who lead much of the device design, fabrication and experimental validation of the chip, for which the researchers have filed a provisional patent application.
The chip detects pH levels, the level of acidity or alkalinity of a substance, because infected wounds often become more alkaline. The chip also detects uric acid, which could indicate tissue damage and metabolic activity; Phenazine-1-carboxylic acid (PCA), a chemical compound produced by certain wound-associated pathogens; and Interleukin-6, which is a protein released during inflammation. The ability to track and detect all four at once presents a broader picture of wound progress and potential setbacks to recovery, the researchers said.
"While detecting, we need to ensure the biomarkers do not interfere with one another," Asgharian said. "We selected PCA [to detect] bacterial infection and uric acid for metabolic infection because their peak intensity and charge transfer signature are completely different from one another. One is from negative voltage, the other positive."
Aida Ebrahimi, Roell Early Career Associate Professor of Electrical Engineering and Biomedical Engineering, principal investigator and corresponding author of the research, explained that traditional methods to detect wound infection biomarkers often have slow turnaround times, and require extensive sample processing and analysis that hinder clinical decision-making.
"They are typically incompatible with one another, rely on bulky and costly laboratory equipment, and are poorly suited for continuous, real-time monitoring," Ebrahimi said. "In contrast, our approach enables multimodal and multiplexed sensing on a single chip by functionalizing the same material, allowing integration, scalability and real-time operation in a way that is difficult to achieve with conventional approaches."
The researchers developed their sensor with laser-induced graphene (LIG) - atomically thin carbon produced by a laser interacting with a material that contains carbon. It is a lower-cost and more scalable alternative to other graphene films, such as the more commonly used chemical vapor deposition (CVD) graphene, which involves dispersing a vapor on a substrate to produce a graphene.
"Chemical vapor deposition graphene typically offers very high crystalline quality and uniformity, which can be beneficial for certain electronic devices," Asgharian said.
The downside of CVD is that it requires specialized equipment, high temperatures and multiple processing steps, including transferring the graphene to another substrate. In addition to the other benefits of LIG, it also has a naturally porous structure and high surface area, which provide many active sites for electrochemical-sensing interactions with biomolecules.
"Laser-induced graphene generally has a more disordered structure compared to CVD graphene, but for sensing applications this morphology can actually be beneficial," Asgharian said.
The sensor sends signals to a wireless printed circuit board, which processes and transmits them to a mobile application for real-time results of biomarker level results. According to the researchers, in the future, this feature could potentially be programmed for use with smartphones, mobile tablets or clinical monitoring systems to enable continuous remote biomarker tracking.
The researchers simulated a wound designed to approximate aspects of injuries, such as the fluids that seep from the source, in the lab to evaluate the sensors and their performance over various. To mimic the tissue interface, the researchers used a thin layer of agar gel, which is a firm, jelly-like substance derived from red algae. The agar gel was placed over the sensors, allowing biomolecules to diffuse through the gel before reaching the sensing surface. This allowed the team to evaluate the system's in vitro performance when the biomarkers passed through a tissue-like layer before detection.
"The medium contains biomaterial components, which helped approximate aspects of the chemical complexity and ionic environment of wound fluids," Asgharian said.
The researchers' goal is to combine the sensing platform with technologies that can collect small amounts of biological fluid in a minimally invasive way, offering alternatives to syringe use or other collection methods that might be painful or stress-inducing for patients. One possibility might be microneedle-based systems, which can access interstitial fluid, or the fluid between cells just beneath the skin surface, without the need for conventional blood draws.
"Microneedle-based systems are one potential direction to help collect or transport fluid from the wound environment or surrounding tissue, while the sensor platform performs the biochemical analysis," Asgharian said. "This could potentially enable continuous monitoring of wound-related biomarkers without the need for repeated manual sampling."
In addition to Asgharian and Ebrahimi, Vinay Kammarchedu, a doctoral candidate in electrical engineering, and Scott Gu, an undergraduate student in electrical engineering, also contributed to the experimental work and development of the sensing system.
The U.S. National Science Foundation (NSF) under the Designing Materials to Revolutionize and Engineer our Future program (award no. 2323296), the NSF CAREER program (award no. 2236997), the National Institutes of Health (NIH, award no. 1R01NS138879-01), NSF I/UCRC Phase II: Center for Atomically Thin Multifunctional Coatings (ATOMIC; Award #2113864); and Roell Early Career Professorship funded this work. The authors also expressed gratitude to the Materials Characterization Lab at the Penn State Materials Research Institute.
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