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Mice with an open- and closed-traumatic brain injury were injected with immunomodulatory nanoparticles that reduced brain swelling and damage on MRI.

Investigators used a novel approach to prevent the swelling that can occur after traumatic brain injury (TBI) in a mouse model: they injected nanoparticles that trick white blood cells into going after them instead of rushing to the injured brain and causing an inflammatory and immune response.

Mice with TBI that were given three injections of the immunomodulatory nanoparticles beginning two to three hours after injury showed less brain swelling and damage on MRI as compared with mice with TBI that did not get the nanoparticles; the treated mice also performed better on functional tests.

The immunomodulatory nanoparticle treatment, if further proven in preclinical trials and human trials, would not undo damage from the initial injury to the brain. But it could help prevent the body from setting off a cascade of immune and inflammatory cells in reaction to the injury, which in turn can cause brain swelling and even more damage to brain tissue.

We certainly haven't gone and magically prevented that initial damage, said Jack Kessler, MD, professor of neurology at Northwestern University Feinberg School of Medicine and the senior author of the paper. What we can do is prevent the secondary damage, which is substantial.

Predicting which TBI patients will develop edema of the brain isn't easy, so having a preventive treatment like the nanoparticles that could be administered upfront could be life-altering, Dr. Kessler said.

He said some patients with head injuries come into the hospital walking and talking, but then their brain swells, and they die.

According to background in the study, published January 10 online in Annals of Neurology, each year more than 2.5 million people in the US have a traumatic brain TBI and more than five million Americans live with at least one sequela of TBI.

After the primary injury, there is substantial secondary injury attributable to infiltrating immune cells, cytokine release, reactive oxygen species, excitotoxicity, and other mechanisms, the study authors wrote. Despite many preclinical and clinical trials to limit such secondary damage, no successful therapies have emerged.

The nanoparticles tested in the mouse experiments are made of material used in biodegradable sutures. The paper specifically described the particles as highly negatively charged, 500 nm-diameter particles composed of the Food and Drug Administration (FDA)-approved biodegradable biopolymer carboxylated poly (lactic-co glycolic) acid.

The nanoparticles (IMPs), which seem like foreign invaders to the body's immune system, attract the attention of large white blood cells known as monocytes, which have been implicated in the secondary damage that occurs with TBI.

IMPs bind to the macrophage receptor with collagenous structure (MARCO) on monocytes and monocytes bound to IMPs no longer home to sites of inflammation but rather are sequestered in the spleen, where the cells die, the study authors wrote.

The mouse study involved two types of head injury. In some of the mice, the researchers performed a craniotomy to create a controlled cortical impact. Other mice received a closed head injury involving a direct blow to the head. Both types of injuries were meant to mimic what occurs in humans with TBI.

Injections of the nanoparticles were given two to three hours after the brain injury, and again at 24 hours and 48 hours post-injury. Control animals with similar brain injuries were given saline solution at the same time points.

Outcomes for the mice who received the nanoparticles were better by multiple measures, including MRI and a motor function test called the ladder rung walking test that is used in mouse experiments.

IMP administration resulted in remarkable preservation of both tissue and neurological function, in both models of head injury, the paper said. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiological visual function, improved long-term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination.

Dr. Kessler said that in the case of mice with an open head injury, the size of their brain lesion was 50 percent smaller in the treated animals compared with those that did not get the nanoparticles.

He said MRI showed significantly less brain swelling and less compression of the ventricles, both signs that secondary damage was minimized.

Dr. Kessler said that right now the only recourse for severe brain swelling is to do a craniotomy to relieve pressure in the skull.

He said one of the appeals of the nanoparticle treatment is that an emergency medical technician could do it in the field or the emergency room personnel could inject it.

But Dr. Kessler is also cautious about too many predications based on a pre-clinical study, saying he is fond of telling medical students that if I had a nickel for every mouse we cured, I'd be a rich man.

Sripadh Sharma, PhD, an MD-PhD student at Northwestern and the study's first author, said the nanoparticle therapy needs to be tested further in animal models before it could go into human testing. The researchers also want to learn more about how the nanoparticles bring about a reduced immune response in the body.

Dr. Sharma noted that while immune responses are a good thing in the face of injury or infection, sometimes nature doesn't always get it right, so too much of a good thing is a bad thing. And that can be the case with TBI.

He said it has been shown by another collaborator on the study, Stephen Miller, PhD, that when the scavenger receptors on the monocytes detect the light negative charge of the nanoparticles, the monocytes engulf and bind to the particles and apoptose in the spleen instead of going to the site of injury.

More studies need to be done to optimize what dose and what time these particles need to be given following a head injury, said Dr. Sharma.

Similar nanoparticle therapy is being tested for other medical conditions, including celiac disease and myocardial infarction, Dr. Kessler said.

Michael J. Schneck, MD, FAAN, professor of neurology (and neurosurgery) at Loyola University Chicago, said the study was well-designed and thorough, using two different head injury models and multiple outcome measures, including brain imaging, functional testing, and brain tissue analysis. Dr. Schneck said the paper made him wonder whether a similar approach using immune-modulating nanoparticles could reduce inflammatory-related damage following stroke and spinal cord injury.

Dr. Schneck said the concept of trying to dampen the immune response after TBI to prevent edema is not new, but the Northwestern researchers took the idea in a new direction. The nanoparticle therapy is particularly intriguing, he said, because it is fairly simple and involves the use of a material that is already approved by the US FDA, which could mean that it would take less time to move the therapy from the laboratory into clinical trials.

This is a very elegant study with interesting translational potential, he said. But it is a mouse model and its application to (human) TBI and other forms of central nervous system injury remains to be validated.

Jiangbing Zhou, PhD, associate professor of neurosurgery and biomedical engineering at Yale University, said that as someone who does research in the field of nanomedicine, he was surprised by the study's findings and wants to understand how this simple formulation particle could achieve this marked efficacy.

The study looks very exciting, but I want to know more about the mechanism, said Dr. Zhou, whose research focuses on developing translational nanomedicine, gene therapy, and stem cell therapy for neurological disorders including TBI.

He had these and other questions about the study: Why do the particles interact specifically with the inflammatory monocytes but not the others? How do the particles, which are made of safe biomaterials, efficiently kill the inflammatory monocytes in the spleen? What is happening and why?

Javier Crdenas, MD, director of the Barrow Concussion and Brain Injury Center at the Barrow Neurological Institute, said the study on the immune-modulating nanoparticle therapy for TBI was very promising, though he stressed that he is always cautiously optimistic when he sees a mouse study.

It is definitely a novel approach to addressing the secondary sequelae of brain injury and they might have something that minimizes that and hopefully improves outcomes, Dr. Crdenas said.

He said the study also raises some questions, including how the immune-modulating approach would fare in patients who have multiple injuries, not just to the head.

Dr. Crdenas said brain injuries often do not happen in isolation, with patients also having broken bones, lacerations, and other organ damage.

We don't know how this (nanoparticle treatment) would affect other organs, other immune responses elsewhere in the body, he said.

Dr. Crdenas said the field of TBI research has been disappointed before by studies of new therapies that looked promising in animal models and clinical testing but ultimately failed. He noted, for instance, that progesterone and hypothermia did not turn out to be good at preventing brain swelling.

We will wait and see, he said of the nanoparticles.

Drs. Sharma, Schneck, Zhou, and Crdenas had no disclosures.

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