Blood loss is the major cause of death for soldiers, whether they have been hit by a roadside bomb or by a bullet. And since the main priority for the military is to return wounded soldiers to active duty, many of the emerging military medical techniques focus on the need to reduce blood loss – especially from hard-to-treat internal injuries. At the same time, any system must be portable enough to be carried around on the battlefield.
One ingenious idea uses an everyday plastic, polyurethane (PU), which is used everywhere from shoe soles to mattresses. It takes the form of a solid foam, but is supplied as two liquids – a di-isocyanate and a diol or triol – which when mixed together with water form a foam. US-based Arsenal Medical has devised a special formulation of PU so that the two liquids can be injected into the abdominal cavity via the belly button of wounded soldiers: as the liquids mix and solidify, the resulting foam acts as an ‘internal tourniquet’ by putting pressure on bleeding internal organs.
‘Intra-abdominal haemorrhage is a leading cause of death on the battlefield,’ says Upma Sharma, director of materials science and engineering at Arsenal Medical. ‘The only current solution is to evacuate the wounded as quickly as possible.’
The abdominal cavity is so large and complex that an exact wound diagnosis is difficult, she says. It could be anything from a gunshot wound to the liver, to a punctured spleen. The most effective treatment – performing surgery on the spot – is just not possible in the heat of combat. ‘Our system tries to extend life, by giving enough time to get the patient to surgical care,’ she says. ‘It applies pressure at the wound site and slows the bleeding for long enough to buy time.’
The company has worked with David King, a trauma surgeon at Massachusetts General Hospital in Boston, US, to develop the system. ‘He [King] says that if you could see some of these internal wounds you could stop the bleeding with your thumb,’ says Sharma. By applying pressure across the whole abdominal cavity, the system acts like a ‘thumb’ on every potential wound site. The system is expected to form part of the combat medic’s backpack armoury but will need to be perfected before it can be commercialised, which might take up to 10 years.
Filling a mould to make a PU shoe sole is one thing, but doing the same with the human abdominal cavity is a much more precise operation. Sharma says that a multitude of factors must be taken into account to make it work.
The first complication is that the abdominal cavity is filled with blood from the wound. Sharma likens it to a moat around a castle, stopping the progress of the foam. The PU must force its way through this, and find its way to the wound site. This means that the reaction kinetics – which determine how quickly the injected liquids become a foam – must be considered and carefully controlled.
The liquid components of the foam are hydrophobic, so will not mix with the blood. Rather than ‘absorbing’ the blood within the body – which the company had originally planned to do – the hydrophobic liquid pushes the blood aside, before forming a foam around the internal organs.
The expansion ratio of the material is therefore another important consideration: the volume of the starting liquids has to be as small as possible so that the system is portable, but there needs to be enough so that the resulting foam fits the large expanse of the abdominal cavity. ‘This is not an off-the-shelf grade of PU,’ says Sharma. ‘We have looked at more than 1000 grades to find one that meets all our needs.’
The system has been tested on pigs, in which their liver was severed – an injury that would cause death for 90% of animals in the first hour. But injecting with this PU system helped 100% of the animals to survive the first hour, and 80% were still alive after three hours. The next step is to begin discussions with the US Food and Drug Administration (FDA) to investigate the possibility of starting human trials in the future.
An earlier aspiration, based on a government request, was to develop something to deliver peptides or other ‘therapeutic payloads’ to the injured tissue. In that case, the foam would have acted as the transport mechanism. But the early testing data showed that the current idea could be realised more quickly. ‘As soon as we got the foam data back, we knew we had something good,’ says Sharma.
Acid test
There are other ways of approaching the problem of bleeding on the battlefield. UK researchers at the London School of Hygiene and Tropical Medicine, for example, have convinced the British Army to start using a proven medication to treat blood-loss in its field hospitals. Ian Roberts, professor of epidemiology and public health, led a clinical study into the effectiveness of tranexamic acid – a ‘synthetic amino acid’ that is commonly used in surgery to stem blood flow and reduce the need for a blood transfusion, and also used to treat women suffering with heavy menstrual periods.
Tranexamic acid works by inhibiting the enzyme plasmin, which breaks down blood clots. ‘That’s usually a good thing, because it stops clots forming where you don’t want them,’ says Roberts. ‘But it’s not good when you’re bleeding to death.’ So tranexamic acid promotes blood clotting to stop the bleeding.
The clinical trial involved 20,000 people, who were randomly assigned the drug, or given a placebo. Receiving tranexamic acid within one hour helped to reduce the risk of bleeding to death by 30%. This was reduced to 20% if administered within the first three hours – but was ineffective if used any later. ‘It’s always better to treat sooner rather than later,’ says Roberts, adding, ‘The trial produced a very strong result. I’ve done clinical trials for 20 years, and nothing has gone from trial to treatment so quickly.’
Within two weeks of these results being published, the British Army had introduced tranexamic acid into field hospitals in Afghanistan – though their US colleagues were initially sceptical and refused to follow suit. ‘But there was evidence that it was saving lives – those who received it were less likely to die, and that convinced the Americans to start using it,’ says Roberts.
In a civilian spin-off, UK paramedics will now start carrying – and using – tranexamic acid from April 2013.
Clot formation
Meanwhile, US researchers, led by Erin Lavik at Case Western Reserve University in Ohio, have devised nano-sized polymer particles that bind to blood platelets, helping them to form clots more quickly. This has the potential to slow down bleeding from serious wounds – especially internal injuries – and again keep injured soldiers alive while they are being transferred to surgery. A solution of the nanoparticles could be injected into the patient on the battlefield.
The nanoparticle has three parts, all of which are in common medical use: a polymer core made from a biodegradable plastic (PLGA), which is used for dissolvable sutures; a series of ‘arms’ made from polyethylene glycol (PEG); and, at the end of each arm, a tripeptide (RGD) comprising L-arginine, glycine and L-aspartic acid.
Any kind of blood loss – from a paper cut to a severed artery – activates the body’s repair mechanism. Platelets play an important factor in repairing the wound by coming together and forming a clot. ‘We think that the particle is speeding up the formation of initial clots,’ says Lavik. ‘When they become active, platelets change shape – and expose receptors. The peptide can now bind with these receptors.’
The team has tested the strength of the ‘augmented’ platelets and found them to be equivalent to their ‘natural’ counterparts. At the same time, the clots formed were as robust as a natural clot.
Lavik says that the nanoparticle structure is very simple, although she points out that it has taken six years of research to attain this simplicity. One important factor was getting the ‘arm length’ correct. ‘We spent a lot of time on this,’ she says. ‘If they are too short, the peptide won’t stick to the receptors. If they’re too long, the arms “fold over” and shield the peptide from the receptor: this reduces binding, leading to slower clotting.’
Overall particle size is also of vital importance. Lavik explains: ‘If the particle is too large, it could get stuck in the blood vessel potentially leading to a stroke or a heart attack.’ She adds that the lungs and brain are most likely to be affected because the critical blood vessels leading to them are smaller. ‘If you damage the lining of the blood vessel, it sends out signals that will get platelets to form a clot,’ she explains.
The size of the particle is 200–300nm in diameter, which is quite a lot smaller than the 1–2 microns of a platelet. Particles are cleared from the body within 24 hours, she says.
So far, the experiments have been done on rats, with larger animal tests just beginning. However, the results have been very promising, Lavik says. Surviving the first hour of a lethal liver injury increased from 47% (treatment with saline) to 80% (treatment with the nanoparticles). There was also some evidence that blood loss was slowed.
As ever, animal models are only a starting point for assessing the potential benefit to humans. ‘One big difference between humans and rats is haemodynamics,’ says Lavik. ‘Rats are tougher, and humans bleed faster. We need larger animal testing to see what the proposition in humans would be.’ If this is successful, the next step is human testing, which she thinks is still five to 10 years away.
Serious injury and violent death continue to be a reality for the modern soldier. While injuries like shrapnel and bullet wounds are similar to those seen in the past, the ability to treat them has improved vastly, allowing casualties to be stabilised long enough to evacuate them to a field hospital.
Attacking hypothermia
Blood loss may be the leading cause of death for injured soldiers, but hypothermia can be a complicating factor. The usual treatment on the battlefield is basic: intravenous fluids and a blanket. This can take up to 16 hours to stabilise a patient’s core body temperature.
Now design students at Stevens Institute of Technology in New Jersey, US, have developed a device that could cut this recovery time to just four hours. The ‘Heat Wave’ delivers warm, humid air into the lungs via an oxygen mask. It works on the principle that all blood circulates through the lungs – so this would be an ideal way of raising body temperature because heat transfer is highly dependent on maximising surface area. ‘The surface area of the alveoli – the tiny air sacs in the lungs that take in oxygen – is the same as that of a tennis court,’ explains Vikki Hazelwood, professor of biomedical engineering at Stevens Institute.
The device incorporates a tiny humidifier and an electric motor. To date, it has been used to pump air through an insulated container – simulating the lungs – which is connected to a second container that simulates the cardiovascular system. ‘Controlling the temperature is important, because you don’t want to scorch the lungs,’ says Hazelwood. Heat was transferred between the containers through a water-filled tube, which simulates convection between the lungs and the bloodstream. Heat and humidity were recorded using sensors wired to a laptop computer.
While the device shows proof-of-concept, more work is needs to be done before the researchers can present it to investors for commercialisation.
Lou Reade is a freelance science writer based in Kent, UK.
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