The Problem: Every cell in the body requires a continuous supply of oxygen, a molecule present in the air we breathe. Oxygen is picked up in the lungs and carried by the blood, which distributes it to cells through an intricate network of blood vessels. Oxygen’s role is to remove a by-product of energy production (electrons), allowing cells to continue converting the food we eat into energy they can use. During health, oxygen is available in abundance, and varies with demand (such as during exercise). However, battlefield injuries and many forms of critical illness can compromise oxygen delivery, and this has devastating consequences. Cells that are very active – particularly those in our brain – cannot tolerate deficiencies in energy production that result from oxygen deprivation. Local oxygen deprivation (hypoxia) that lasts even a few minutes can turn a healthy Warfighter into a neurologically devastated patient for life. Therefore, recognizing and treating oxygen deprivation is always an emergency.

Current Treatments: Unfortunately, treating oxygen deprivation can be complex. On the battlefield, a blast injury may severely damage a Warfighter’s face or neck, blocking the airway, or it may damage the lungs themselves. Rescuing such a patient requires a trained professional to create a new pathway for oxygen to get to the lungs, through placement of a breathing tube or a tracheostomy. It also requires the use of concentrated oxygen and a ventilator, neither of which are available on the front lines. For these reasons, approximately 50% of battlefield deaths are due to an inability to provide life-saving measures on the front lines, including treatment of oxygen deprivation; as little as 30 minutes may make the difference between life and death.

The Proposed Solution: This proposal is the culmination of more than 10 years of work by our group towards the goal of developing a way to administer oxygen gas to a patient through an intravenous line. Normally, this is not possible. Through funding from the Department of Defense, we have developed a particle that is smaller than most cells in the bloodstream and can carry oxygen gas from a syringe into the bloodstream. The key to the technology has been developing an exterior lining to the gas – a shell – that has the properties that make this idea possible. Our most recent – and final – shell material is a chemical modification of the most common sugar in the body. We have modified the sugar to change its character from a solid (keeping it stable in a syringe) to fluid (releasing oxygen and making the shell break apart instantly) upon contact with the blood (using the body’s pH as a trigger). We have completed safety studies in rats and pigs, finding the particles to be well tolerated at the doses that we believe will be clinically beneficial to patients. We have also shown that injecting these particles into rats suffering from severe oxygen deprivation significantly increases survival.

What We Propose to Do Next: This grant will fund three development steps that are critical to making intravenous oxygen available to patients. (1) We will complete a well-powered study in pigs to demonstrate that injecting oxygen particles in a simulated Warfighter injury will improve not only survival, but brain function in survivors. (2) We will prepare the drug in a way that it can be administered to humans as part of a clinical trial in the future. Drugs used in humans are regulated by the Food and Drug Administration (FDA), and their manufacture must be very tightly controlled. We have designed a custom device to manufacture the drug in sufficient quantities for a clinical trial. Unbiased outside third parties who are experts in this process will test the raw materials and then the microparticles for important markers of drug purity and quality. This will be the drug we would eventually test in patients. (3) We will then have outside experts test clinical-grade drug in two species of animals (required by the FDA) for safety, for any toxicities, and to determine how long the drug lasts in the body. These three steps will all be carefully documented and submitted as part of the FDA application.

The Clinical Implications: Injectable oxygen would transform many areas of medicine. (1) Warfighters on the front lines would receive an intravenous line and a continuous infusion of oxygen, which would provide just enough oxygen for the cells in the brain to survive and to keep the heart beating. Warfighters who currently die because they cannot get enough oxygen to their organs during evacuation may survive, and without brain injury. (2) Patients suffering from a cardiac arrest – a dire circumstance in which the heart stops beating – may get enough oxygen to the brain and heart during CPR (cardiopulmonary resuscitation) to improve survival and subsequent brain function. In the future, other gases that protect the brain during such clinical situations (such as hydrogen gas) can be added to the particle for intravenous administration. (3) Because oxygen is important to every cell – including cancer cells – oxygen deprivation plays a central role in how cancer cells survive. Administering oxygen into a tumor directly – a place that blood vessels cannot reach – may make previously incurable tumors treatable.