Frances Ligler’s Portable Optical Biosensors Improve Environmental Detection of Toxins, Pollutants

Dr. Frances Ligler. From the National Inventors Hall of Fame website.

The term “biosensor” covers a variety of analytical devices which use a biological component, such as cells or tissue, which interact with the particular chemical being examined, and then a physicochemical detector which transforms the interaction of the biological component and the analyte to generate a signal which can be measured. Market research on biosensors and bio-analytical devices indicates that such technologies have applications in a wide range of industries including food toxicity detection, agriculture, environmental pollution control, medical testing, and industrial processing and monitoring. A recent market research report from Global Market Insights indicates that the medical applications contributed to 66 percent of the overall biosensor market during 2015, reaching a value of $9.8 billion.

According to recent academic research in the field of biosensors, optical biosensors are the most common type of biosensor in use today. Compared to many conventional analytical techniques, optical biosensors offer many advantages including high sensitivity, a relatively smaller size compared to other bio-analytical devices and better cost-effectiveness. Such biosensors utilize optical transducer systems which are capable of converting light energy into electronic signals based on the measure of the light produced by the interaction of the biological component with the analyte. The use of optical biosensors is especially helpful in medical and pharmaceutical applications, such as for analysis quantifying the amount of the active component in a pharmaceutical formulation.

This New Years’ Eve 2017 marked the 26th anniversary of the issue of a foundational patent in the field of portable optical biosensors, devices which are more adept at providing biological analysis in the field and outside of clinical lab settings. Listed as lead inventor on the patent is Dr. Frances Ligler, a pioneer in biosensor activity and a member of the 2017 class of inductees into the National Inventors Hall of Fame.



The Early Development of Optical Biosensors from the Early 1940s through the 1980s

Early biosensor research stems back to the mid-20th century to 1943 when the first chemical sensor was proposed by a researcher named Norton who conceived of a macroscopic bimetallic plate to serve as a platform for hydrogen detection. Biosensor developments for medical applications would take a major step forward in 1962 when Leland Clark and Champ Lyons, both of the Medical College of Alabama in Birmingham, published a paper describing electrode systems for the continuous monitoring of patients during cardiovascular surgery. Such systems could be used intravascularly to monitor hydrogen appearance or detect changes in oxygen tension; previously, only external devices for blood monitoring had been contemplated.

The mobility of biological components had posed a difficult challenges for early researchers in the field of biosensors. However, in 1967, researchers Updike and Hicks published papers describing the strides which they had made in immobilizing an enzyme, glucose oxidase in their case, with the use of a polyacrylamide gel to stabilize the enzyme on an oxygen electrode to accomplish the rapid quantification of glucose in a sample. In the early 1980s, surface plasmon resonance (SPR) biosensors were being developed for the detection of biomolecular interactions. SPR biosensors generate electronic signals in response to a phenomenon involving the illumination of a metallic surface positioned at the interface between two other media, such as glass and liquid, when the surface is illuminated by polarized light at an angle.

A few years prior to these developments in SPR optical biosensors, Frances Ligler received her D.Phil degree in 1977 from Oxford University, which she attended as a National Science Foundation (NSF) Graduate Fellow. Ligler had an interest in scientific discovery instilled within her by her family at a young age and credits a lot of her success on her penchant for hands-on learning. After Oxford, Ligler served as a post-doctoral fellow or research assistant at a few institutions including the University of Texas – San Antonio Health Center, Southwestern University Medical School and Hahnemann Medical College. A YouTube video posted by the National Inventors Hall of Fame shows Ligler discussing her process of interviewing for work as a graduate student and she recalled a question asked by a researcher who hired her. The researcher, who was also a gourmet cook, asked Ligler how she liked to cook. “I said, ‘The first time I follow the recipe and after that I get creative,’” Ligler said. “Well, that was the right answer.” Between 1980 and 1985, Ligler was an immunologist at E.I. duPont de Nemours before heading to Washington, D.C., to work at the U.S. Naval Research Laboratory (NRL) in 1985.


Frances Ligler Further Improves Immobilization of Active Agents for Portable Biosensors

Over the course of the next 30 years, Ligler would develop many innovations in the field of optical biosensors, such as automated biosensors for continuous monitoring for the sampling of air or water environments by drone equipment. Ligler’s contributions would go on to aid U.S. military personnel taking part in Operation Desert Storm, providing them with tactical sensor field equipment they could use to detect levels of botulinum toxin and anthrax. Her advances have led to the optical biosensors of today which are much more compact in size while also being more versatile and sophisticated.

On December 31st, 1991, Ligler and a team of researchers were listed as inventors on U.S. Patent No. 5077210, titled Immobilization of Active Agents on Substrates With a Silane and Heterobifunctional Crosslinking Agent. It disclosed a method for modifying a substrate to activate the substrate for the immobilization of active agents by selecting a substrate having hydroxyl groups on a surface, coating that surface with a thiol-terminal group silane containing a group which is reactive to the hydroxyl groups on the surface to create a silane layer with an available reactive thiol group, and then coating the silane layer with a heterobifunctional succinimide group-containing crosslinking agent to form a layer of crosslinking agent having an available free succinimide group capable of reacting with an amino group of the acting agent. The resulting invention improved the immobilization of proteins, such as antibodies, onto quartz or glass substrates in a way which reduced the tendency of such proteins to leech or wash away from the substrate.

Ligler’s work at the NRL would lead to the commercialization of 11 biosensor products for use in monitoring food safety, pollution control and even hazardous materials for homeland security. One such biosensor developed in part by Ligler includes the RAPTOR bioassay detection system which has been used by NATO to analyze biological toxins and pathogens and by the U.S. Navy to test water deliveries in the Middle East. Ligler’s work also led to the first airborne biosensor which was configured to detect biological warfare agents. Along with the recent National Inventors Hall of Fame induction, Ligler’s career includes many honors such as receiving the Christopher Columbus Foundation Homeland Security Award in 2003, attaining the Presidential Rank of Distinguished Senior Professional the same year, election to the National Academy of Engineering in 2005 and then being recognized with the Presidential Rank of Meritorious Senior Professional in 2012. Ligler holds a total of 29 patents and still works in academia, currently as part of the faculty at both North Carolina State University and the University of North Carolina at Chapel Hill.


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