Project Grant R41HL156763

EVALUATION OF STABILITY AND SAFETY OF PLATELET-LIKE PARTICLES FOR TREATING BLEEDING AFTER TRAUMA - PROJECT SUMMARY UNCONTROLLED BLEEDING IS A SIGNIFICANT CLINICAL PROBLEM IN BOTH CIVILIAN AND MILITARY TRAUMATIC INJURIES; IN BOTH CASES, EXSANGUINATION PRIOR TO HOSPITALIZATION IS THE PRIMARY CAUSE OF DEATH FOR BOTH MEN AND WOMEN. FURTHERMORE, HEALING FOLLOWING TRAUMA CAN BE COMPLICATED BY INFECTION, KELOID FORMATION, INSUFFICIENT BLOOD FLOW, OR CONDITIONS SUCH AS DIABETES AND OBESITY. CLOT FORMATION IS CRITICAL TO THE CESSATION OF BLEEDING AFTER TRAUMA AND INVOLVES THE ACTIVATION OF CIRCULATING PLATELETS THAT HONE TO THE SITE OF INJURY AND AGGREGATE TO FORM A PLATELET PLUG, STEMMING BLEEDING. ACTIVATED PLATELETS ALSO BIND FIBRIN FIBERS FORMING AT A SITE OF INJURY TO FORM A PLATELET- FIBRIN MESH. PLATELETS THEN UTILIZE ACTIN-MYOSIN MACHINERY TO APPLY FORCES TO THE CLOT NETWORK, CONTRACTING AND STABILIZING THE CLOT AND FACILITATING ITS ROLE AS A PROVISIONAL MATRIX TO SUPPORT SUBSEQUENT CELLULAR INFILTRATION OF THE WOUND ENVIRONMENT. IN CASES OF TRAUMATIC INJURY, EXSANGUINATION CAN CAUSE PLATELETS TO BECOME DEPLETED, IMPAIRING THEIR ABILITY TO STOP BLEEDING AND PROMOTE HEALING. PLATELET TRANSFUSION IS THE CURRENT STANDARD OF CARE; HOWEVER, ISOLATED PLATELETS HAVE A SHORT SHELF-LIFE, CONTRIBUTING TO MAJOR SUPPLY CHAIN ISSUES. ADDITIONALLY, POTENTIAL IMMUNOLOGIC CONCERNS ASSOCIATED WITH TRANSFUSION OF BLOOD PRODUCTS HIGHLIGHTS THE CRITICAL UNMET NEED TO DEVELOP PLATELET ALTERNATIVES TO TREAT BLEEDING AFTER TRAUMA. WE HAVE RECENTLY DEVELOPED SYNTHETIC PLATELET-LIKE PARTICLES (PLPS) CREATED FROM HIGHLY DEFORMABLE MICROPARTICLES COUPLED TO FIBRIN-TARGETING MOTIFS THAT ARE CAPABLE OF HONING TO INJURIES THROUGH HIGH AFFINITY BINDING TO FIBRIN FORMING AT THE SITES OF INJURY. OUR INITIAL STUDIES DEMONSTRATE THAT PLPS ARE ABLE TO RECAPITULATE SEVERAL FUNCTIONS OF NATIVE PLATELETS, INCLUDING CLOT AUGMENTATION IN VITRO, DECREASING BLEEDING TIMES AND OVERALL BLOOD LOSS IN IN VIVO RODENT MODELS OF TRAUMA, AND IMPROVED HEALING RESPONSES IN VIVO FOLLOWING INJURY. THE LONG-TERM GOAL OF THIS PROJECT IS TO DEVELOP HEMOSTATIC PLPS FOR EMERGENCY MEDICINE APPLICATIONS TO AUGMENT CLOTTING AND DECREASE BLOOD LOSS AND ASSOCIATED DEATHS DUE TO EXSANGUINATION. THE OBJECTIVE OF THIS APPLICATION IS TO EVALUATE THE LONG-TERM STABILITY AND SAFETY OF PLPS. OUR CENTRAL HYPOTHESIS IS THAT PLPS WILL HAVE SIGNIFICANTLY SUPERIOR SHELF-LIFE COMPARED TO NATIVE PLATELETS WHILE MAINTAINING A MAXIMUM TOLERATED DOSE WELL ABOVE THEIR THERAPEUTIC DOSAGE, THEREBY SUPPORTING MOVING THIS TECHNOLOGY FORWARD INTO FURTHER PRECLINICAL DEVELOPMENT. THE SPECIFIC AIMS OF THIS PROJECT ARE: 1) DETERMINE PLP STABILITY AND 2) DETERMINE MAXIMUM TOLERATED DOSE.