Anti-microbial platelet-like-particles to treat internal bleeding and augment subsequent healing

PROJECT SUMMARY
Uncontrolled bleeding following trauma represents a significant clinical problem; exsanguination is the major
cause of death in both civilian and battlefield traumas. If hemostasis is achieved, wound repair following trauma
can be impeded by several complications including infection, keloid formation, insufficient blood flow and a
compromised immune system. Traumatic brain injury (TBI) also frequently occurs concurrently with hemorrhage
following trauma and is associated with high risks of infection. Infections are a leading cause of mortality,
morbidity, and economic disruption around the world, highlighting the need for better methods to achieve
hemostasis and improve wound healing following trauma. Clot formation is critical to the cessation of bleeding
and involves the formation of a platelet plug embedded within a fibrin mesh. Platelets bind multiple fibrin fibers
and actively apply forces to contract the network, thereby stabilizing the developing clot. Furthermore, platelet-
mediated clot contraction is thought to augment wound healing following cessation of bleeding by reestablishing
blood flow to downstream tissues and by providing mechanical stimulation to surrounding cells. We have recently
developed platelet-like particles (PLPs) created from highly deformable microgels (gels) conjugated to wound-
targeting motifs, which specifically target wound environments through high affinity binding to the provisional
matrix protein fibrin. Our prior studies demonstrate that PLPs recapitulate a number of functions of natural
platelets, including augmentation of clotting of adult plasma in vitro, decreased bleeding times in rodent models
of traumatic injury, specific homing to injury sites, induction of clot contraction, and enhancement of wound
repair in rodent models of dermal injury. We have also shown in a rodent model of TBI that PLPs decrease blood
brain barrier (BBB) permeability and neuroinflammation after injury.
The long-term goal of this project is to develop intravenous hemostatic PLPs that are triggered by the
body’s native clotting cascade to promote clotting and, following hemostasis, augment wound healing. Our central
hypothesis is that the combination of PLP-mediated clot contraction and delivery of antimicrobial nanosilver will
significantly improve wound healing following traumatic injury by providing mechanical stimulation to
surrounding cells and by preventing/treating infection. This proposal will specifically evaluate stability and safety
of antimicrobial nanosilver containing PLPs. The effectiveness of these particles will then be evaluated in a mouse
model of bleeding and healing in the absence or presence of infection. Additionally, particle efficacy, safety, and
immune system modulation will be evaluated in a rodent polytrauma model of combined traumatic brain injury
(TBI) and hemorrhage.