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On a Mission to Save Lives

 

Researchers are fighting to save patients with the creation of synthetic blood platelets that promote hemostasis and healing.  


Photo by Russell Lee

 

Too often, trauma events lead the daily newscast, whether it is a car accident or a mass shooting event like the ones in Las Vegas or Parkland, Fla., that left dozens dead and many injured. Any loss of life is tragic. And trauma-associated severe bleeding remains the most common cause of death in people 1 to 46 years old. One researcher at Case Western Reserve University is trying to mitigate the losses.

“Deaths in trauma are often preventable,” says Anirban Sen Gupta, associate professor of biomedical engineering. “They happen because first responders don’t have access to blood components like platelets at the point of injury.” Platelets are blood cells that promote hemostasis, helping clots form at the site of an injury and stop bleeding. Trauma patients often require transfusion of platelets to rapidly reduce blood loss and save their lives. But platelet transfusions are unavailable through emergency medical services or at small hospitals, so many patients may die before they can be brought to a large trauma center that has platelets.

Sen Gupta is the founder and director of the Bioinspired Engineering for Advanced Therapies (BEAT) Laboratory, which has developed synthetic platelets. “Imagine if you could put synthetic platelets in ambulances so emergency medical technicians can treat civilian patients at the roadside or military patients in the field, stabilize the patients and buy time to take them to a trauma center?” says Sen Gupta.

The artificial platelets created in the BEAT Lab — called SynthoPlate™ — have wider applications than hemostasis in trauma patients. They could also be potentially utilized in blood transfusions for patients with cancer, congenital blood disorders, gastrointestinal bleeds or undergoing major surgery. “Our hypothesis was that we could make artificial platelets from modular design components and customize these components to tailor their purpose and function, depending on the target disease or injury,” says Sen Gupta.

Taking Inspiration from Nature

In 2007, Sen Gupta started his lab, simply called the Sen Gupta Lab at the time. It began with a grant from the American Heart Association to study functionally integrated liposomes as synthetic platelet substitutes. Since then, the lab has expanded its scope and received approximately $6 million in funding from a variety of sources, most notably the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD). The lab seeks mechanistic understanding of biological and pathological phenomena at the cellular, sub-cellular and biomolecular levels, then uses that knowledge to create bioinspired therapeutic and diagnostic technologies to interrogate, support or treat various phenomena.

"All the research we do is based in determining how things work in nature and what we can leverage from nature," says Sen Gupta. “The focus of my interest isn’t just the biology part only or the materials part only, but the interface between the two.” That interest in bioinspired research led him and a team of student researchers to rename the lab the Bioinspired Engineering for Advanced Therapies Lab several years ago.

Today, the main focus of the BEAT Lab is in the field of platelet-inspired technologies for hemostasis and drug delivery. Sen Gupta works alongside a dozen or so researchers, ranging from postdoctoral researchers to high school students. “We are trying to make synthetic platelets that work like real platelets, going to the area of bleeding and acting like sandbags to stack upon each other and stop the bleeding,” he says. “We have mimicked the functional aspect of how platelets form clots, using a combination of synthetic peptides on nanoparticles.”

Collaborating on a Larger Goal

Each year in the United States, approximately 2 million platelet transfusions are given to treat bleeding complications in the management of trauma, surgery, myelosuppression and congenital blood disorders. However, such platelet products suffer from supply shortages, the need for blood typing, a high risk of bacterial contamination, limited portability and shelf life, and biologic side effects. This has prompted research in synthetic platelet products that can offer high availability, portability, extended storage life and point-of-injury applications.

While the work done by the BEAT Lab focuses on synthetic platelets for enabling hemostasis, other researchers in the broader field of blood substitution are taking a different approach. For instance, some labs are creating synthetic or semi-synthetic red blood cell substitutes for facilitating oxygen transport. Others are developing white blood cell substitutes for enabling cell-specific immune response.

“We all collaborate with the vision that someday we can put together one lab’s artificial red blood cells, another lab’s artificial platelets and still another lab’s artificial plasma and essentially come up with a surrogate formulation for blood,” says Sen Gupta. “The goal is not to replace blood, but to make something that works like blood when blood is not readily available.”

That has significant implications. Consider the military. According to the DoD, the U.S. has 1.3 million men and women on active duty, many deployed in conflict zones like Afghanistan, Iraq and Syria. When troops are injured in the field, medics have very limited access to blood components. Synthetic blood products could be given to wounded soldiers, stabilizing them while they are transported to a major trauma center, which could save lives

The BEAT Lab works with many collaborators, including researchers and clinicians from the Cleveland Clinic, Harvard University, University Hospitals Cleveland Medical Center, the University of Pittsburgh, the University of Cincinnati, Marshall University and the U.S. Army Institute of Surgical Research.

Testing the Synthetic Platelets

The BEAT Lab has conducted in vitro lab scale studies on its synthetic platelets, as well as several in vivo biologic studies. The goal of the first in vivo study was to see if the synthetic particles would go to the point of bleeding and work with existing platelets to form blood clots. When that succeeded, the researchers substituted real platelets with synthetic particles. “The first job was to prove our particles work like platelets,” says Sen Gupta. “The second job was to prove that if there aren’t any platelets, the particle can still do its job. And it did.”

The next study examined the viability of SynthoPlate in a test subject with acute injuries. “If somebody gets shot in Mansfield, Ohio, 80 miles southwest of Cleveland, by the time the person can be transported to a major trauma center, like at MetroHealth, they may die,” says Sen Gupta. “That’s the problem we try to solve, and our study signified we can keep the subject alive for the average time period it takes to reach a trauma center and receive a blood transfusion.”

The studies were supported by the NIH Center for Accelerated Innovations at Cleveland Clinic (NCAI-CC), Case-Coulter Translational Research Partnership (CCTRP) and Ohio Technology Validation and Start-up Fund (TVSF) Phase I programs. The findings were recently published in Nature Scientific Reports.

With these promising findings, Sen Gupta has established a collaboration with the University of Pittsburgh to study a biologic model that mimics diffused injuries sustained in traumatic car accidents or when a soldier steps on an improvised explosive device. The model will combine extremity and truncal injuries, and the study will compare treatment with synthetic platelets to a control group that receives saline administration (the current point-of-injury standard of care). These findings and collaborations have also contributed to the BEAT Lab receiving a $1 million grant from the DoD last fall to evaluate the treatment efficacy of SynthoPlate in the biologic polytrauma model, as well as its influence in healing burn wounds.

Creating a Spin-off Technology Company

Lab studies can be limited for clinical translation. So in 2016, Sen Gupta founded a company with Christa Pawlowski, one of his former students who is currently working in the lab as a postdoctoral researcher, for translation and commercialization of SynthoPlate. Taking its name from the Greek word for blood, Haima Therapeutics has received funding from various sources, including a Phase 1 Small Business Innovation Research (SBIR) grant totaling $225,000 from the National Science Foundation to pursue chemistry, manufacturing and controls (CMC) characterization of the SynthoPlate technology.

Pawlowski began working in Sen Gupta’s lab as an undergraduate at Case Western Reserve and continued there through graduate school. “I was enthralled with the research topic,” says Pawlowski, chief scientific officer of Haima Therapeutics. “The idea of using nanoparticles to provide a therapeutic effect or deliver payload in a site-selective manner, thereby reducing harmful side effects and enhancing drug response, was exciting to me. I got to use an engineering approach to solve real-world human health problems.”

She continues to use her engineering background and experience from the BEAT Lab at Haima Technologies. “The BEAT Lab has done a fantastic job at characterizing the SynthoPlate technology and evaluating proof of concept in vitro, as well as in several small and large animal models,” says Pawlowski. “Haima’s work includes further vetting of the technology from a drug development standpoint.”

This year, the BEAT Lab is collecting data on batch-to-batch reproducibility of the product, conducting a shelf-life analysis and performing pharmacology/toxicology studies to determine maximum tolerated dose and half-life. These studies are being supported with the assistance of an NIH-sponsored program called Science Moving Towards Research Translation and Therapy (SMARTT), as well as an award from the Council to Advance Human Health (CAHH) program at Case Western Reserve School of Medicine. This data will be combined with CMC data from Haima for a pre-investigational new drug meeting with the U.S. Food and Drug Administration. 

The work that Sen Gupta began more than a decade ago may be coming closer to clinical reality. That’s good news for him, his lab and millions of people worldwide. “SynthoPlate has the potential to address the unmet clinical need for a widely available agent that can act rapidly to staunch internal, non-compressible hemorrhage,” says Pawlowski. “Ultimately, SynthoPlate has the potential to save many lives.

 

How SynthoPlateTM Works


Image credit: Erika Woodrum