Unaffected clotting cascade by experimental hemostatic nanoparticles when introduced in the presence of recombinant tissue plasminogen activator.

Context: Hemostatic nanoparticles (hNPs) have shown efficacy in decreasing intracerebral hemorrhage (ICH) in animal models and are suggested to be of use to counter tissue plasminogen activator (tPA)-induced acute ICH.

Aims: The objective of this study was to test the ability of an hNP preparation to alter the clotting properties of blood exposed to tPA .

Materials And Methods: Fresh blood samples were obtained from normal male Sprague-Dawley rats (~300 g; = 6) and prepared for coagulation assays by thromboelastography (TEG) methods.

Azithromycin Protects Retinal Glia Against Oxidative Stress-Induced Morphological Changes, Inflammation, and Cell Death.

The reactivity of retinal glia in response to oxidative stress has a significant effect on retinal pathobiology. The reactive glia change their morphology and secret cytokines and neurotoxic factors in response to oxidative stress associated with retinal neurovascular degeneration. Therefore, pharmacological intervention to protect glial health against oxidative stress is crucial for maintaining homeostasis and the normal function of the retina.

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events.

Intravenously infusible nanoparticles to control bleeding have shown promise in rodents, but translation into preclinical models has been challenging as many of these nanoparticle approaches have resulted in infusion responses and adverse outcomes in large animal trauma models. We developed a hemostatic nanoparticle technology that was screened to avoid one component of the infusion response: complement activation. We administered these hemostatic nanoparticles, control nanoparticles, or saline volume controls in a porcine polytrauma model.

On-Demand and Long-Term Drug Delivery from Degradable Nanocapsules.

We have developed polyurethane nanocapsules as a platform for long-term delivery of drugs over weeks as well as on-demand delivery of drugs via ultrasound. We synthesized nanocapsules encapsulating either a model drug, fluorescein, or a clinically relevant drug, acriflavine, a HIF-1alpha inhibitor. Release studies demonstrated delivery of fluorescein or acriflavine over several weeks.

Self-healing biomaterials: The next generation is nano.

The U.S. Agency for Healthcare Research and Quality estimates that there are over 1 million total hip and total knee replacements each year in the U.

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.

Controlled release of photoswitch drugs by degradable polymer microspheres.

Background: QAQ (quaternary ammonium-azobenzene-quaternary ammonium) and DENAQ (diethylamine-azobenzene-quaternary ammonium) are synthetic photoswitch compounds that change conformation in response to light, altering current flow through voltage-gated ion channels in neurons. These compounds are drug candidates for restoring light sensitivity in degenerative blinding diseases, such as age-related macular degeneration (AMD).

Purpose: However, these photoswitch compounds are cleared from the eye within several days, they must be administered through repeated intravitreal injections.

Steroid-Loaded Hemostatic Nanoparticles Combat Lung Injury after Blast Trauma.

In response to the lack of therapeutics for internal bleeding following a traumatic event, we synthesized hemostatic dexamethasone nanoparticles (hDNP) to help alleviate internal hemorrhaging. hDNP consist of a block copolymer, poly(lactic-co-glycolic acid)-poly(l-lysine)-poly(ethylene glycol) conjugated to a peptide, glycine-arginine-glycine-aspartic acid-serine (GRGDS). These particles were evaluated as treatment for primary blast lung injury in a rodent model.

Intravenously administered nanoparticles increase survival following blast trauma.

Explosions account for 79% of combat-related injuries, leading to multiorgan hemorrhage and uncontrolled bleeding. Uncontrolled bleeding is the leading cause of death in battlefield traumas as well as in civilian life. We need to stop the bleeding quickly to save lives, but, shockingly, there are no treatments to stop internal bleeding.

Tuning ligand density on intravenous hemostatic nanoparticles dramatically increases survival following blunt trauma.

Targeted nanoparticles are being pursued for a range of medical applications. Here we utilized targeted nanoparticles (synthetic platelets) to halt bleeding in acute trauma. One of the major questions that arises in the field is the role of surface ligand density in targeted nanoparticles' performance.

A tunable synthetic hydrogel system for culture of retinal ganglion cells and amacrine cells.

The central nervous system consists of complex groups of individual cells that receive electrical, chemical and physical signals from their local environment. Standard in vitro cell culture methods rely on two-dimensional (2-D) substrates that poorly simulate in vivo neural architecture. Neural cells grown in three-dimensional (3-D) culture systems may provide an opportunity to study more accurate representations of the in vivo environment than 2-D cultures.

Tissue engineering the retinal ganglion cell nerve fiber layer.

Retinal degenerative diseases, such as glaucoma and macular degeneration, affect millions of people worldwide and ultimately lead to retinal cell death and blindness. Cell transplantation therapies for photoreceptors demonstrate integration and restoration of function, but transplantation into the ganglion cell layer is more complex, requiring guidance of axons from transplanted cells to the optic nerve head in order to reach targets in the brain. Here we create a biodegradable electrospun (ES) scaffold designed to direct the growth of retinal ganglion cell (RGC) axons radially, mimicking axon orientation in the retina.

Intravenous hemostatic nanoparticles increase survival following blunt trauma injury.

Trauma is the leading cause of death for people ages 1-44, with blood loss comprising 60-70% of mortality in the absence of lethal CNS or cardiac injury. Immediate intervention is critical to improving chances of survival. While there are several products to control bleeding for external and compressible wounds, including pressure dressings, tourniquets, or topical materials (e.

Engineering therapies in the CNS: what works and what can be translated.

Engineering is the art of taking what we know and using it to solve problems. As engineers, we build tool chests of approaches; we attempt to learn as much as possible about the problem at hand, and then we design, build, and test our approaches to see how they impact the system. The challenge of applying this approach to the central nervous system (CNS) is that we often do not know the details of what is needed from the biological side.

Nanospheres delivering the EGFR TKI AG1478 promote optic nerve regeneration: the role of size for intraocular drug delivery.

Promoting nerve regeneration involves not only modulating the postinjury microenvironment but also ensuring survival of injured neurons. Sustained delivery of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been shown to promote the survival and regeneration of neurons, but systemic administration is associated with significant side effects. We fabricated poly(lactic-co-glycolic acid) (PLGA) microspheres and nanospheres containing the EGFR TKI 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) for intravitreal administration in a rat optic nerve crush injury model.

Intravenous hemostat: nanotechnology to halt bleeding.

Blood loss is the major cause of death in both civilian and battlefield traumas. Methods to staunch bleeding include pressure dressings and absorbent materials. For example, QuikClot effectively halts bleeding by absorbing large quantities of fluid and concentrating platelets to augment clotting, but these treatments are limited to compressible and exposed wounds.

Exogenous modulation of intrinsic optic nerve neuroprotective activity.

Background: To characterize the molecular and functional status of the rat retina and optic nerve after acute elevation of intraocular pressure (IOP).

Methods: Retinal ischemia was induced in rats by increasing the IOP (110 mmHg/60 minutes). Microarray analysis, quantitative RT-PCR (qRT-PCR) and immunohistochemistry were used to characterize retinal tissue.

A tissue-engineered approach towards retinal repair: scaffolds for cell transplantation to the subretinal space.

Background: Several mechanisms of retina degeneration result in the deterioration of the outer retina and can lead to blindness. Currently, with the exception of anti-angiogenic treatments for wet age-related macular degeneration, there are no treatments that can restore lost vision. There is evidence that photoreceptors and embryonic retinal tissue, transplanted to the subretinal space, can form new synapses with surviving host neurons.

New platform for controlled and sustained delivery of the EGF receptor tyrosine kinase inhibitor AG1478 using poly(lactic-co-glycolic acid) microspheres.

Inhibition of the epidermal growth factor receptor (EGFR) reduces tumour growth and metastases and promotes axon regeneration in the central nervous system. Current EGFR inhibition strategies include the administration of reversible small-molecule tyrosine kinase inhibitors (TKIs). However, to be effective in vivo sustained delivery is required.

Using polymer chemistry to modulate the delivery of neurotrophic factors from degradable microspheres: delivery of BDNF.

Purpose: Brain-derived neurotrophic factor (BDNF) plays an important role in neuroprotection and repair, but long-term delivery from polymer systems has been challenging. We investigated the role the chemistry of the polymer played in loading and delivery of BDNF via microspheres, which are suitable for minimally invasive administration.

Methods: We synthesized polymers based on PLGA and PEG to determine what components augmented loading and delivery.