Erin Lavik

Materials design at the interface of nanoparticles and innate immunity

Engineered nanoparticle platforms have been developed intensely in recent years, yielding significantly broadened applications from interrogating novel biology to new therapies. The mammalian immune system has emerged as perhaps the most powerful physiological system where nanoparticle design parameters have drastic implications for nanoparticle fate and function. In particular, the innate immune system is a major concern due to its role as the first-line defense against foreign invaders, responsible for initiating and maintaining the innate immune response as well as priming the adaptive immune response. Understanding how nanoparticles are perceived from a biological perspective is crucial to informing their design with different immunogenic, immunosuppressive, or stealth properties. Nanoparticles are particularly susceptible to innate immune responses such as opsonization and recognition by receptors that enable phagocytic uptake or evoke strong inflammatory responses due to the recognition of various “danger” signals. In this review, we will summarize some of the key advances in our understanding of how physical and biochemical parameters of nanoparticles interact with innate immunity, and note potential opportunities and emerging frontiers for controlling and evaluating nanoparticle–immune interactions.

Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model

Explosions account for 79% of combat related injuries and often lead to polytrauma, a majority of which include blast-induced traumatic brain injuries (bTBI). These injuries lead to internal bleeding in multiple organs and, in the case of bTBI, long term neurological deficits. Currently, there are no treatments for internal bleeding beyond fluid resuscitation and surgery. There is also a dearth of treatments for TBI. We have developed a novel approach using hemostatic nanoparticles that encapsulate an anti-inflammatory, dexamethasone, to stop the bleeding and reduce inflammation after injury. We hypothesize that this will improve not only survival but long term functional outcomes after blast polytrauma. Poly(lactic-co-glycolic acid) hemostatic nanoparticles encapsulating dexamethasone (hDNPs) were fabricated and tested following injury along with appropriate controls. Rats were exposed to a single blast wave using an Advanced Blast Simulator, inducing primary blast lung and bTBI. Survival was elevated in the hDNPs group compared to controls. Elevated anxiety parameters were found in the controls, compared to hDNPs. Histological analysis indicated that apoptosis and blood-brain barrier disruption in the amygdala were significantly increased in the controls compared to the hDNPs and sham groups. Immediate intervention is crucial to mitigate injury mechanisms that contribute to emotional deficits.

The Chemistry of Lyophilized Blood Products

With the development of new biologics and bioconjugates, storage and preservation have become more critical than ever before. Lyophilization is a method of cell and protein preservation by removing a solvent such as water from a substance followed by freezing. This technique has been used in the past and still holds promise for overcoming logistic challenges in safety net hospitals with limited blood banking resources, austere environments such as combat, and mass casualty situations where existing resources may be outstripped. This method allows for long-term storage and transport but requires the bioconjugation of preservatives to prevent cell destabilization. Trehalose is utilized as a bioconjugate in platelet and red blood cell preservation to maintain protein thermodynamics and stabilizing protein formulations in liquid and freeze-dried states. Biomimetic approaches have been explored as alternatives to cryo- and lyopreservation of blood components. Intravascular hemostats such as PLGA nanoparticles functionalized with PEG motifs, topical hemostats utilizing fibrinogen or chitosan, and liposomal encapsulated hemoglobin with surface modifications are effectively stored long-term through bioconjugation. In thinking about the best methods for storage and transport, we are focusing this topical review on blood products that have the longest track record of preservation and looking at how these methods can be applied to synthetic systems.

Engineering Intravenously Administered Nanoparticles to Reduce Infusion Reaction and Stop Bleeding in a Large Animal Model of Trauma

Bleeding from traumatic injury is the leading cause of death for young people across the world, but interventions are lacking. While many agents have shown promise in small animal models, translating the work to large animal models has been exceptionally difficult in great part because of infusion-associated complement activation to nanomaterials that leads to cardiopulmonary complications. Unfortunately, this reaction is seen in at least 10% of the population. We developed intravenously infusible hemostatic nanoparticles that were effective in stopping bleeding and improving survival in rodent models of trauma. To translate this work, we developed a porcine liver injury model. Infusion of the first generation of hemostatic nanoparticles and controls 5 min after injury led to massive vasodilation and exsanguination even at extremely low doses. In naïve animals, the physiological changes were consistent with a complement-associated infusion reaction. By tailoring the zeta potential, we were able to engineer a second generation of hemostatic nanoparticles and controls that did not exhibit the complement response at low and moderate doses but did at the highest doses. These second-generation nanoparticles led to cessation of bleeding within 10 min of administration even though some signs of vasodilation were still seen. While the complement response is still a challenge, this work is extremely encouraging in that it demonstrates that when the infusion-associated complement response is managed, hemostatic nanoparticles are capable of rapidly stopping bleeding in a large animal model of trauma.