Online Master's in Biomedical Engineering @ Case.edu
A Mighty Force - read full story

Pioneering Bleeding-Edge Research

The BEAT Lab leads initiatives to create bioinspired therapeutics
and diagnostics for transfusion medicine and critical care.

Motor vehicle crashes are a leading cause of civilian deaths in the United States, with more than 36,000 fatalities in 2019, according to the National Highway Traffic and Safety Administration. For the U.S. military, 90% of fatalities occur due to combat-associated severe injuries. A contributing factor for such civilian and military fatalities is trauma-induced coagulopathy (TIC), which is a complex imbalance in bleeding, clotting and clot lysis in the early stages of trauma.

“If somebody gets injured in a car accident or in the battlefield, by the time an emergency medic can access, evaluate and stabilize the patient and take him or her to a well-equipped medical facility, perhaps an hour or more has passed,” says Anirban Sen Gupta, professor of biomedical engineering at Case Western Reserve University. “Whatever the patient’s blood status was in the early phases after injury may have changed by the time the patient reaches the hospital. So, what the hospital may assess may be less effective in guiding how the patient should be treated.”

Diagnosing, monitoring and adequately treating trauma-induced coagulopathy as early as possible after injury is critical in saving lives at the roadside and in the battlefield. “But such approaches are not possible right now for two primary reasons. First, the machines required to evaluate and monitor TIC are printer-sized and not easily portable. In addition, the treatment of TIC often requires transfusion of blood products, which are also not readily available pre-hospital,” says Sen Gupta. He and his colleagues hope to address these limitations by creating artificial blood surrogates for emergency transfusion, as well as developing portable, hand-held diagnostic systems for point-of-injury and en route comprehensive assessment of TIC to guide early treatment.

 

Tackling Clot Stability

Sen Gupta and his Bio-inspired Engineering for Advanced Therapies (BEAT) Laboratory began their work in 2007 on the therapeutic side, developing platelet-inspired technologies for hemorrhage control, targeted thrombolysis and drug delivery. One of the lab’s inventions is SynthoPlate™ , an artificial platelet nanotechnology. These synthetic platelets use a combination of bioactive peptides decorated on nanoparticles to mimic the functional aspects of how natural platelets form clots to stop bleeding. SynthoPlate has subsequently been licensed to Haima Therapeutics LLC, a biotechnology company that Sen Gupta co-founded in 2016, for further research and development.

“The long-term vision is advancing toward a fully artificial whole blood surrogate (WBS), not just a platelet surrogate,” says Sen Gupta, who is chair of Haima’s scientific advisory board and serves as a consultant to the company. To this end, Haima is partnering with experts at the University of Pittsburgh, the University of Maryland, the U.S. Army Institute of Surgical Research and the company Teleflex

In July 2020, Sen Gupta received a $3.8 million, 3-year grant from the Department of Defense (DoD), which includes collaboration with Haima Therapeutics and the University of Pittsburgh to develop and evaluate freeze-dried SynthoPlate that can be potentially carried by emergency medics for point-of-injury hemorrhage treatment in battlefield and civilian settings. Haima Therapeutics also received additional awards from the National Science Foundation (NSF) and DoD totaling approximately $4 million over the next three years to scale up SynthoPlate manufacture and study the combination of SynthoPlate with freeze-dried plasma made by Teleflex, and with Erythromer™, a red blood cell surrogate developed by the University of Maryland and the company Kalocyte.  

Meanwhile, the BEAT Lab continues work on other therapeutic technologies, most notably in two areas – advancement of synthetic platelet systems that enhance clot stability and creation of nanoparticle-based platforms that target harmful clots by leveraging the interactions between platelets, blood proteins and white blood cells. “SynthoPlate captures a critical subset of platelet function – initiating blood clotting,” says Sen Gupta. “But there are other parts of platelet involvement and functions that provide cues for additional technologies.”

One of those functions is to facilitate the formation of the protein fibrin to provide clot stability. Sen Gupta compares the role of platelets to that of sandbags used to prevent flooding. Stacking sandbags is an important barrier against flooding, but the sandbags are often secured with netting so the force of the flood doesn’t topple them over. Fibrin is a net-like protein that secures the platelet plug to stabilize the clot. “We’ve gone back to the drawing board in the lab and created a new synthetic platelet design that can enhance the production and stabilization of fibrin at the site of injury,” says Sen Gupta. “This is important for treating patients who suffer from fibrin instability in the clot.” This includes acutely injured patients with hyperfibrinolysis, as well as people with certain kinds of liver disease, vascular disease and infections.

In 2019, the BEAT Lab partnered with researchers at the University of Michigan and the University of North Carolina at Chapel Hill to study the new synthetic platelet design. Led by Sen Gupta, the team received a $2.1 million, 4-year R01 grant from the National Institutes of Health in January 2021 to advance these studies.

 

Studying Platelet-Leukocyte Interactions in Diseases

In addition, Sen Gupta works with multiple collaborators to investigate the interaction of platelets with other blood proteins and leukocytes, then leverage these interactions to create nanomedicine platforms for targeted therapeutics. These include partnerships with the University of Pittsburgh, the Case Western Reserve School of Medicine and the Louis Stokes Cleveland VA Medical Center. Leukocytes like neutrophils act as the body’s first line of defense against infection, but their aberrant interactions with platelets can drive many pathologies. Research in this area could benefit patients with a wide array of conditions, ranging from diabetic ulcers and deep vein thrombosis to lupus and atherosclerosis.

“The diseases are all different but they have specific underlying pathology framework of platelet interactions with certain kinds of leukocytes,” says Sen Gupta. The overarching aim of his collaborations is to create therapeutic systems that treat an array of medical conditions without affecting the beneficial immune functions of leukocytes.

One of Sen Gupta’s collaborators in this area is Evi Stavrou, MD, an associate professor in the Case Western Reserve University School of Medicine and a member of the Molecular Oncology Program at the Case Comprehensive Cancer Center. Stavrou is the primary investigator on an $1.8 million, 5-year NIH R01 grant with Sen Gupta to research therapeutic systems for chronic wounds. The team has also subsequently received a 4-year, $700,000 VA Merit Award, as well as $200,000 in research funding  from the Case-Coulter Translational Research Partnership (CCTRP), the Clinical and Translational Science Collaborative of Cleveland (CTSC) and the NIH Center for Accelerated Innovations at Cleveland Clinic (NCAI-CC) to advance neutrophil-modulating nanomedicine systems to treat thrombo-inflammatory pathologies. 

“We have worked closely in developing nanoparticle platforms that selectively interact in disease microenvironments with primed, activated neutrophils and neutrophil-platelet aggregates,” says Dr. Stavrou. “We have generated exciting results that demonstrate specificity of targeting, but also therapeutic effect in sterile inflammatory diseases.” 

These results are important, she adds, because other efforts to develop therapeutic approaches that modulate neutrophils have presented obstacles, such as impairment of the patient’s ability to fight infections and limited penetration of drugs in tissues. “Presently, a major unmet clinical need is the development of new treatments with enhanced efficacy and an improved safety profile,” says Dr. Stavrou. “Our nanomedicine approach fills this vacuum.” 

In the same vein, Sen Gupta is also advancing collaborative research as a co-principal investigator with several faculty members at the University of Pittsburgh supported by a 5-year NIH R01 award totaling approximately $4 million to develop targeted nanomedicine systems to treat thrombo-inflammatory mechanisms in trauma and sickle cell disease.

 

Creating Point-of-Injury Diagnostic Systems

Sen Gupta’s move into diagnostics for transfusion medicine and critical care also aims to fill a void in healthcare. Smaller hospitals and pre-hospital settings – point-of-injury locations, such as accident scenes and military battlefields – don’t have access to sophisticated labs to diagnose bleeding and clotting problems. “There is a big need to create diagnostic systems that go to the patient rather than waiting for the patient to come to the diagnostic system,” says Sen Gupta. To that end, he has teamed up with colleagues to design and evaluate TraumaChek, a field-deployable dielectric coagulometer for comprehensive assessment of TIC.

TraumaChek, a field-deployable dielectric coagulometer for comprehensive assessment of TIC.

Development of TraumaChek began serendipitously when Sen Gupta had a chance conversation at an on-campus meeting with Pedram Mohseni, chair of the Department of Electrical, Computer and Systems Engineering at Case Western Reserve University, and Michael Suster, senior research associate in the BioMicroSystems Laboratory directed by Mohseni. Mohseni and Suster previously led development of the ClotChip™  system, a hand-held, point-of-care device to evaluate the hemostatic status of patients in minutes. The technology has since been licensed to XaTek, which is pursuing commercialization of the system for anticoagulation therapy and hemophilia care management.

In discussions with Mohseni and Suster about ClotChip, Sen Gupta recognized the potential for refining the instrument’s design to make it more sensitive and applicable in trauma. Together, the researchers conceptualized the TraumaChek system in 2019 and began working on hardware and electrode components of the device.

“Anirban has a lot of experience on the therapeutic side to stem bleeding and control hemorrhage, and we have experience on the diagnostic side,” says Mohseni. “The marriage of the two approaches can ultimately create a closed loop system in which the information we gain in real time at the point of injury using TraumaChek can act as decision support to inform the nature of the therapy that needs to be administered to the injured patient on site. A large percentage of fatalities from hemorrhage and TIC is preventable if guidance and treatment actions can be taken in the golden hour after injury.”

Experimentation on ClotChip and TraumaChek use in TIC began in 2020, and the team recently received funding totaling $4.8 million over the next two to four years from the DoD, as well as $200,000 in funding from CCTRP and NCAI-CC to advance the technologies in collaboration with University Hospitals in Cleveland and the University of Pittsburgh. 

Sanjay Ahuja, MD, director of the hemophilia program at University Hospitals Cleveland Medical Center and a professor in the Case School of Medicine, is involved in both the ClotChip and TraumaChek development. His role in the multidisciplinary development of TraumaChek is to validate and optimize the tool by testing it in TIC-relevant deficiencies and disorders. Matthew Neal, MD, professor of surgery and trauma expert at the University of Pittsburgh, is also collaborating to test TraumaChek with patient samples. “The crux [of the project] is to take a leap from a complex measurement to a simple point-of-care testing measurement,” says Ahuja. “That leap truly requires a meeting of the minds, and that’s what this project brings forward.”

If the team succeeds, the impact will be profound. “Imagine taking all of that expertise [in TIC], putting it into a hand-held device and making it available at the community level in small hospitals and in the battlefield?” says Ahuja. “That is a game-changer in terms of saving lives.”

 

Looking Ahead

The potential to save lives through therapeutic and diagnostic systems has garnered the BEAT Lab, its collaborators and Haima Therapeutics nearly $22 million in grants in the past two years – and counting. Sen Gupta envisions the activities growing into a full-fledged research center. 

 “Our lab has been very fortunate to work on our own technologies, as well as establish highly productive collaborations within Case Western Reserve University and elsewhere, that have helped move the needle toward creating therapeutics and diagnostics that can hopefully save lives someday soon,” says Sen Gupta.  “Looking at the big picture, so many impactful technologies can be developed and clinically translated under the umbrella of trauma, emergency medicine and critical care. This is just the beginning.”

 

 

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