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UK Researchers Seek to Commercialize 15-Minute, POC Test for Traumatic Brain Injury

NEW YORK ─ Using spectroscopic technology, researchers from the University of Birmingham in the UK have developed a test they believe will allow for the detection of traumatic brain injuries at the point of care, something that has so far eluded diagnostic developers.

While the test may still be a few years down the road, the researchers announced recently that they have achieved high levels of sensitivity while conducting early validation of a proof-of-concept prototype that leverages surface-enhanced Raman scattering (SERS) to detect neurological biomarkers in blood. They are proceeding with plans to develop a commercial test.

"This is a highly sensitive spectroscopic technique that relies on surface morphology to control the achievable signal enhancement of a target molecule," Pola Goldberg Oppenheimer, one of the test's developers and a professor of chemical engineering at the University of Birmingham, said in an interview.

The test would require further engineering, validation, and regulatory clearance before being made available for clinical use, but the technology "enables miniaturization and retains sensitivity so that it can be deployed outside laboratories at the point of care without compromising performance," Goldberg Oppenheimer said.

The portable spectrometer consists of an optofluidic chip with specially designed surfaces over which blood plasma flows. The surfaces cause target biomarkers to vibrate in plasma under a laser, enabling an instrument to capture fingerprints reflective of the presence and severity of brain injury.

To fabricate the optofluidic surfaces for the test, the group developed an electrohydrodynamic micromanufacturing technique, Goldberg Oppenheimer said. The technique is a microlithography patterning process for the fabrication of submicron-sized features on the optofluidic chip.

The investigators described using the platform to evaluate three biomarkers associated with TBI ─ N-acetylasparate (NAA), S100B, and glial fibrillary acidic protein ─ in a study published earlier this year in Nature Biomedical Engineering.

For the study, they collected samples from patients attending the Surgical Reconstruction and Microbiology Research Center at Queen Elizabeth Hospital in Birmingham. A total of 48 patients were enrolled, with 139 samples from patients with TBI and 82 samples from healthy patients.

To evaluate levels of biomarkers over time, the investigators took blood samples immediately after an injury and then after four, 12, 24, and 48 hours.

"For this first study, we were looking to detect the lowest possible levels of biomarkers immediately after a head injury in patients with severe traumatic brain injury," Goldberg Oppenheimer said. "Mild and moderate concussions are also of interest and we are investigating them in ongoing studies, but they are more difficult to detect because the biomarker levels are lower than in the severe cases."

The researchers observed that differences in biomarker levels between patients with severe traumatic brain injury and healthy volunteer were most significant for NAA, a molecule found exclusively in neurological tissue. They used receiver operating characteristic (ROC) curves to analyse the ability of all the biomarkers to differentiate patients with severe TBI from healthy patients at various times after the injury. From the ROC curves, they determined the AUC for NAA was 98.7 percent immediately after injury; 90.9 percent at 8 hours after injury; and 91 percent at 48 hours after injury, meaning the device clearly differentiated between healthy patients and those with severe traumatic brain injury, the researchers said.

In the TBI group, the levels of the biomarker were around five times higher than in samples taken from the control group, and biomarker levels tailed off rapidly around one hour after the injury occurred.

Such a test is urgently needed at the point of care and the researchers are mapping out plans for commercialization, Goldberg Oppenheimer said, adding that current methods lack sensitivity, are subjective, and are prone to misdiagnosing patients.

Most research to develop concussion tests that use blood-based biomarkers use high-performance chromatography, mass spectrometry, or enzyme-linked immunosorbent assays that are impractical for use at the point of care, she noted.

According to Antonio Belli, a neurosurgeon who attends to trauma patients at Queen Elizabeth Hospital, "The most promising thing about the new test is that it could be used to provide rapid results on the spot ─ at the roadside, in military settings, or by the sidelines of a football pitch."

Physicians looking to diagnose a concussion immediately after a car accident, during a military exercise, or after a clash of heads during a rugby match don't have a test they can use to detect brain injury, said Belli, who is also an author of the NBE study and conducts clinical research at the University of Birmingham.

Physicians use methods such as the Glasgow Coma Scale, which assesses patients according to three aspects of responsiveness ─ eye-opening, motor, and verbal responses ─ and they apply computer tomography and magnetic resonance imaging to diagnose patients that have been admitted to hospital, he said.

However, because these assessments involve subjective elements, they can contribute to underdiagnosis of TBI, which can be fatal for the patient, and overdiagnosis, which can drive up healthcare expenses, Belli said, adding, "Whether inside the hospital or at the point of care, the diagnosis of traumatic brain injury is an inexact science, and any step toward a more accurate way to diagnose this type of injury is a step in the right direction."

Tests in development

Other organizations are developing diagnostic tests for concussion, including Quadrant Biosciences, which announced recently that it had received a $2.3 million grant from the National Institutes of Health to develop a saliva-based microRNA diagnostic test for concussions in children and adolescents.

For a few years, NanoDiagnostics has been developing a nanowire-based diagnostic platform to detect traumatic brain injury at the point of care, which uses levels of two proteins ─ GFAP and S100 beta.

Additionally, National Institutes of Health researchers have found that levels of the protein marker neurofilament light are correlated with diagnosis and severity of traumatic brain injury. 

Goldberg Oppenheimer said that although her group evaluated single biomarkers in the NBE study, its commercial test is likely to include a combination of the biomarkers evaluated in the study and potentially new undisclosed biomarkers that have not yet been validated.

Additional engineering is needed to prepare the device for production, she said, and the group is seeking funding from the London-based Royal Academy of Engineering for ongoing development.

The commercial platform would integrate a spectroscopic instrument with an optofluidic cartridge, both developed by the researchers. Current portable spectroscopy instruments could also be modified to operate with the cartridge, Goldberg Oppenheimer said.

Though portable spectrometers are less sensitive than larger spectrometers for the lab, the optofluidic chip would compensate for that loss of performance, Goldberg Oppenheimer said.

"Overall, the most important component of the test is the cartridge with its integrated specialized surface and optofluidic chip," she said. "It is sensitive, accurate, and reproducible but it is also disposable and must be made available at a reasonable cost, so we are targeting a price of $25 per cartridge." Pricing for the instrument has not yet been established.

The group is participating in a commercialization program sponsored by Innovate UK to decide on a commercial path and identify potential IVD partners. Goldberg Oppenheimer said that she is evaluating whether to spin out a company or license the technology to partners, or both.

The group has received an undisclosed amount of funding from the National Institute for Health Research to conduct a health economics assessment and plan for regulatory approvals.  For future clinical studies, the group is seeking additional funding from the NIHR.

Future studies will aim to further validate the clinical utility of the device for different levels of TBI, and to enable applications for regulatory clearances, including from the US Food and Drug Administration and for CE marking that would enable its use in Europe and other regions that accept such designation.

For these studies, the group has easy access to TBI patients and their blood samples at Queen Elizabeth Hospital, which houses the Royal Centre for Defense Medicine for military personnel injured in conflict zones. The researchers are also engaging with local sports teams, including rugby and soccer teams, to conduct studies.

Overall, future clinical trials for the test will take time to complete and could require the participation of up to 2,000 patients at multiple clinical centers, so a three- to five-year timeframe for potential commercialization is reasonable, Belli said.