N101-085 TITLE: Hemostatic Agent Development

TECHNOLOGY AREAS: Biomedical

ACQUISITION PROGRAM: Navy Expeditionary Combat Command, Special Operations Command

OBJECTIVE: To explore and develop the deployment of a biodegradable, biocompatible medical aid that can be deployed at the point of use. This medical aid will have the ability to quickly stop bleeding (in less than 60 seconds) and also eliminate or reduce ambient contamination that could cause secondary infection, preserve tissue after injury and facilitate surgical speed.

DESCRIPTION: For soldiers wounded on the battlefield, hemorrhage control is essential to survival. Uncontrolled hemorrhage is the primary cause of death in the pre-hospital period for both military combat and civilian trauma incidents. Immediate action is highly effective in limiting patient mortality, since most bleeding fatalities occur within the first 30 minutes of the injury. It is generally accepted that hemostatic products for forward care in the battle zone must control bleeding quickly, be ready to use, simple to apply for first responders in combat situations, have a shelf life approaching 2 years, and prevent bacterial or viral transmission. The most critical wounds are those for which a tourniquet or simple compression are not feasible, such as internal bleeding in the chest, abdomen, and pelvis, and closed extremity fractures that are not easily accessible. Therefore, internal bleeding usually requires rapid surgical intervention.

In a battlefield setting there are three primary areas of intervention after trauma: at the injury site, in the surgical field hospital and after transport to a traditional surgical suite. There are four major wound types that need to be addressed: large diffuse injuries like burns or shrapnel; shredding wounds; penetrating wounds; and dismemberments. Each setting has the same needs: to stop bleeding in irregular wound sites, preserve tissue and allow for immediate surgical procedures in very dirty environments.

It is also very important to immobilize surface contamination. Whether it is from leaking gastrointestinal (GI) fluids causing peritonitis, airborne infectious agents, self-contamination from debris on the skin surrounding a wound site during surgery, or poorly sterilized instruments, solving the problem of war trauma-associated infection will save lives. First, wounds incurred on the battlefield are grossly contaminated with bacteria due to foreign bodies (wounding projectile fragments, clothing, dirt) being contaminated with bacteria; high-energy projectile wounding (devitalized tissue, hematoma, tissue ischemia) and delays in casualty evacuation. Most will become infected unless appropriate treatment is initiated quickly. Second, bacteria covering the soldier can be hazardous to the medical personnel. By immobilizing bacteria on wounds the contamination can also be isolated from the first responders, transporters, and finally the surgical team. Third, many secondary infections are obtained in the surgical hospital. Too much cleaning and sterilization to kill the bacteria just creates a niche for more potentially virulent strains of bacteria that have no effective treatment, such as strep. By immobilizing the native bacteria on a patient�s skin prior to surgery, the patient�s normal flora and fauna can help combat the foreign bacteria that are trying to gain a foothold on the patient.

The hemostatic agents previously tested for military use fall into four categories: powder/granular; solid (rigid); solid (flexible); and barrier.
1. Powder/granular agents are unable to flow into injured areas and cannot stop internal bleeding from deep wounds. The materials are opaque, preventing visual inspection of the wound prior to removal. Compression must be applied after application and the material must be removed prior to surgery. Many require mixing on site and must be applied by a responder. These hemostatic agents rely on clotting. Stasix, a powder derived from human platelets; QuikClot, zeolite granules which exhibit an exothermic reaction; Celox, chitosan granules that are difficult to remove; Instaclot, an effective composition powder, but with fragile packaging and messy removal; WoundStat, extremely effective at stopping serious bleeding, but associated with a high incidence of blood vessel thrombosis and damage to the vessel wall, and subsequently removed from Army use.
2. Solid (rigid) hemostats must be applied like a bandage or sponge and thus are unable to flow into the crevices of a deep wound. Compression must be used upon application to ensure tight adherence to the wound for clotting to take place. Bandages and sponges must be removed prior to surgery which increases the risk of rebleeding. QuikClot Advanced Clotting Sponge (ACS+), a sponge place on or in a wound to accelerate clotting, but hemorrhage arrest depends on amount of blood present; Chitosan bandage, which does not always adhere well, causing leakage. When it does adhere well it is difficult to remove and may cause rebleeding. There is a slight chance of allergic reaction.
3. Solid (flexible) hemostats can be wrapped around or stuffed into a wound, prior to applying pressure, to cause accelerated clotting. They are not able to create a tight fit in irregular wounds. These materials must be removed prior to surgery and, depending on their adherence, could cause rebleeding while being removed. Chitoflex bandage can fit into a wound and is easy to remove, but it does not adhere well enough to stop bleeding immediately; QuikClot Combat Gauze is a non-woven fiber coated with kaolin to promote clotting. It is easy to apply, removes well but does not fit tight inside irregular wounds; Stasilon is an interwoven bandage made of bamboo and fiberglass which is easy to fit a wound, but has weak absorption and weak clot formation.
4. Barrier agents incorporate swelling as part of their hemostatic action and require extra caution to ensure that the local blood supply is not reduced or stopped, which could cause additional tissue damage or even death. This is particularly crucial when using expanding foams. BioFoam is a protein hydrogel that expands to fill space and seal wounds.

A set of procedures needs to be developed for use in each wound type and within each primary intervention setting. This needs to be done using a single material, one that does not cause any immune response or adverse affect to the injured subject. The next generation of hemostatic agents, which will be used across all three settings, needs to be inert, biodegradable and biocompatible so that it does not need to be removed at any point in the treatment. They must also have these additional qualities: ability to control venous and arterial bleeding in under 1 minute; should be lightweight to carry and/or incorporate into a garment or personal protective equipment in order to automatically deploy during injury; ability for a soldier to carry it in a concentrated form that will allow for coating wounds in excess of a minimum of 50 square inches and to be self-applied with one hand; ability to be thinly sprayed on a wound in a non-temperature sensitive system; ability to be synthetically produced; ability to be stored for long periods of time, at extreme temperatures, without substantial breakdown; prevent bacterial or viral transmission by containing or killing it; ability to coat, cover and/or fill irregular voids or surfaces; be non-immunogenic to remove risk of inflammation; be biodegradable so removal is not necessary; promote healing to begin healing wounds immediately; be optically transparent to stop bleeding and be able to view the wound and operate through the material; ability to include a topical anesthetic to help ease the pain immediately after injury while waiting for additional care; ability to include color indicators to indicate the presence of different types of bacteria in wounds or on the skin; ability to immediately immobilize any contaminant at the molecular or cellular level.

The Navy will only fund proposals that are innovative, address R&D and involve technical risk.

PHASE I: Provide an initial development effort that demonstrates the scientific merit and capabilities of each of the proposed areas of (1) rapid hemostasis; (2) immobilization of surface contaminants in a wound area; (3) tissue preservation; (4) facilitation of the speed of surgery in a field setting, while preventing the entrance of contamination into the wound area; and (5) biodegradability and biocompatibility.

PHASE II: Characterization of the effective limits of the injuries as well as the effectiveness of the medical aid across each of the injury models. A polytrauma model needs to be developed to specifically test the limits of each of these new agents. This is specifically to reduce the number of different materials that need to be carried. Not only should the agents work on venous and arterial bleeding, they should also stop the evaporation of fluid after a burn, or stop the leakage of stomach acid, or stop the intestinal contents from seeping into the IP cavity of the injured person. The materials should be able to stop bleeding in liver, kidney, eyes, brain, etc. To be determined: the coating capacity as well as the durability of the various types of coatings; how long the material will stay in its intended location; frequency of re-application; correct formulation and concentration based on injury. In large, diffuse injuries like burns or shrapnel the material must have the ability to be sprayed in a very thin layer to protect and cover a large area. In shredding wounds the material must have the ability to be applied fast and in large quantities, to stop bleeding and contamination. In penetrating wounds the material must be able to be delivered into the point of penetration while also filling the void without reducing intact vasculature. In dismemberments the material must be able to coat the area of injury as well as the detached limb.

PHASE III: The goal is to develop a polytrauma material that is lightweight when carried and simple enough to be administered by an injured soldier. Ideally, a soldier would carry a device that would automatically heal the tissue and take away the pain so the soldier can stay focused; until then multiple-use materials need to be developed that have the promise of easier application, longer shelf life, will work in all environments both wet and dry, and can be used for many different types of wounds. These delivery devices and materials will save the lives and limbs of both military and civilian medical personnel all over the world. Design and adapt appropriate delivery devices for each of the different settings: field use --lightweight, easily deployed, possibly automatically deployed; deployment by doctor or medic between 15 minutes to 3 hours after injury to start the repair process, reattachment or stabilization of tissue; controlled surgical setting for reattachment of limbs or reconstruction of damage between 30 minutes and 20 days after injury.

PRIVATE SECTOR COMMERCIAL POTENTIAL/DUAL-USE APPLICATIONS: Successful development of the molecular self-assembling medical aid could be developed for use in emergency situations and in the operating room. It could also be developed for use it in remote places of the world to help keep people alive. This type of medical aid could drive development into totally new ways to perform surgery, eliminating wound contamination in a traditional hospital surgical environment.

REFERENCES:
1. Ellis-Behnke RG, Liang YX, Tay DKC, Kau PWF, Schneider GE, Zhang S, Wu W, So KF. Nano hemostat solution: immediate hemostasis at the nanoscale. Nanomedicine 2006 Dec;2(4):207-15.

2. Ye Z, Zhang H, Luo H, Wang S, Zhou Q, Du X, Tang C, Chen L, Liu J, Shi YK, Zhang EY, Ellis-Behnke R, Zhao X. Temperature and pH effects on biophysical and morphological properties of self-assembling peptide RADA16-I. J Pept Sci. 2008 Feb;14(2):152-62.

3. Snow C, Olson C, Melcer T. The Navy Medical Technology Watch: Hemostatic Dressing Products for the Battlefield. Naval Health Research Center, Technical Document No. 07-1A, 2006.

4. Kheirabadi BS, Scherer MR, Estep JS, Dubick MA, Holcomb JB. Determination of efficacy of new hemostatic dressings in a model of extremity arterial hemorrhage in swine. J Trauma. 2009 Sep;67(3):450-9; discussion 459-60.

5. Kheirabadi BS, Edens JW, Terrazas IB, Estep JS, Klemcke HG, Dubick MA, Holcomb JB. Comparison of new hemostatic granules/powders with currently deployed hemostatic products in a lethal model of extremity arterial hemorrhage in swine. J Trauma. 2009 Feb;66(2):316-26; discussion 327-8. Comment in: J Trauma. 2009 Sep;67(3):677-8.

6. Ward KR, Tiba MH, Holbert WH, Blocher CR, Draucker GT, Proffitt EK, Bowlin GL, Ivatury RR, Diegelmann RF. Comparison of a new hemostatic agent to current combat hemostatic agents in a swine model of lethal extremity arterial hemorrhage. J Trauma. 2007 Aug;63(2):276-83; discussion 283-4.

7. Sondeen JL, Pusateri AE, Coppes VG, Gaddy CE, Holcomb JB. Comparison of 10 different hemostatic dressings in an aortic injury. J Trauma. 2003 Feb;54(2):280-5.

8. Arnaud F, Teranishi K, Tomori T, Carr W, McCarron, R. Comparison of 10 hemostatic dressings in a groin puncture model in swine. Vascular Surgery 2009 Sep;50(3):632-639.

KEYWORDS: Haemostasis; Wound care; Trauma; Hemorrhage, Contamination control; Surgery; Burns; Tissue preservation; Temperature control

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