A Role for Nanoparticles in Treating Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no eective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more eective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of eective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI

Course Portfolio for Assessing Student Learning Surrounding Biological Examples in BSEN244: Thermodynamics of Biological Systems

Thermodynamics is a course required in many engineering disciplines as it covers concepts utilized in many upper level engineering courses. In the Biological Systems Engineering Department at the University of Nebraska – Lincoln, this course, in a way, acts as a gateway to the major since this will be one of the first classes where the students must apply and hone their problem-solving skills. This course was developed to allow students in the department to have access to a thermodynamics course that relates to their major area of interest – biological systems. However, many concepts in thermodynamics do not have a good, direct biological correlate that can be used to engage student interest. Therefore, my goal in putting together this portfolio was to assess whether introducing thermodynamics concepts within a biological framework improved student learning. To do this, two separate but related concepts were introduced, one without any biological examples and one with. The students were then quizzed on the concepts at the end of the week they were introduced in class. Overall, the class performed significantly better on the quiz assessing concepts that were introduced within a framework of biological systems. This was most pronounced for students with average performance in the quiz assessing concepts introduced without biological examples, whereas high performing students performed well regardless of how the concepts were introduced. These findings suggest that introducing thermodynamics concepts within the framework of biological systems to Biological Systems Engineering majors improves student learning

Nanoparticle Treatment to Counter Reactive Oxygen Species after Traumatic Brain Injury

Traumatic brain injury (TBI) is defined as damage to the brain, resulting from an external mechanical force, such as an impact to the head (Kievit et. al, 2016).There are several examples that could result in a potential TBI; such as falling with contact to the head, car accidents and even physical activities including football, wrestling, and boxing. Because of the several different scenarios that an individual could impact their head, TBI’s have become an all too common aspect of everyday life. TBI is currently the leading cause of death and disability in children and adults under the age of 45, with 1.7 million reported cases annually in the United States alone(Bharadwaj et. al, 2016). The major problem that causes TBIs to be so lethal is the combination of both the initial damage and the secondary corrosive damage on the surrounding brain tissue. The initial damage is capable of being prevented by wearing helmets, seat belts and taking other safety precautions. However, there are currently no treatments that protect the brain from secondary deterioration, spread of the injury beyond primary damage (Kievit et. al, 2016). While some individuals are capable of fully recovering from a TBI without secondary brain damage, unfortunately, roughly 35% of TBI survivors face long-term disabilities (McConeghy et. al, 2012). The lethal progression of this secondary injury is in part caused by the release of reactive oxygen species (ROS) into the surroundings of the normal brain (Kievit et. al, 2016). From this information, it seems that the best way to prevent this secondary spread to the brain would be to reduce or eliminate the spread of ROS. In order to control this release of ROS, there must be a chemical, or biological entity, placed into the brain that reacts with these ROS so that they are incapable of reacting with the healthy portions of the brain. Currently, Dr. Kievit’s lab is developing nanoparticles that can react with these ROS and prevent them from spreading into other areas of the brain

A Role for Nanoparticles in Treating Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no eective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more eective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of eective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI

The Nanotheranostic Researcher’s Guide for Use of Animal Models of Traumatic Brain Injury

Traumatic brain injury (TBI) is currently the leading cause of injury-related morbidity and mortality worldwide, with an estimated global cost of USD 400 billion annually. Both clinical and preclinical behavioral outcomes associated with TBI are heterogeneous in nature and influenced by the mechanism and frequency of injury. Previous literature has investigated this relationship through the development of animal models and behavioral tasks. However, recent advancements in these methods may provide insight into the translation of therapeutics into a clinical setting. In this review, we characterize various animal models and behavioral tasks to provide guidelines for evaluating the therapeutic efficacy of treatment options in TBI.We provide a brief review into the systems utilized in TBI classification and provide comparisons to the animal models that have been developed. In addition, we discuss the role of behavioral tasks in evaluating outcomes associated with TBI. Our goal is to provide those in the nanotheranostic field a guide for selecting an adequate TBI animal model and behavioral task for assessment of outcomes to increase research in this field

CHITOSAN-ALGINATE SCAFFOLD CELL CULTURE SYSTEM AND RELATED METHODS

Methods for culturing cancer cells in vitro using a three dimensional scaffold, scaffolds that include the cultured cancer cells, and methods for using the cultured cancer cells and the scaffolds that include the cultured cancer cells in anticancer therapeutic drug development

Bionanotechnology and the Future of Glioma

Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle‑based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the “ideal” nanoparticle for glioma, a concept that may soon be realized

Ultrasmall Mixed Eu−Gd Oxide Nanoparticles for Multimodal Fluorescence and Magnetic Resonance Imaging of Passive Accumulation and Retention in TBI

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI can have a long-term impact on the quality of life for survivors of all ages. However, there remains no approved treatment that improves outcomes following TBI, which is partially due to poor delivery of therapies into the brain. Therefore, there is a significant unmet need to develop more effective delivery strategies that increase the accumulation and retention of potentially efficacious treatments in the injured brain. Recent work has revealed that nanoparticles (NPs) may offer a promising approach for site-specific delivery; however, a detailed understanding of the specific NP properties that promote brain accumulation and retention are still being developed. Multimodal imaging plays a vital role in the understanding of physicochemical properties that initiate the uptake and accumulation of NPs in the brain at both high spatial (e.g., fluorescence imaging) and temporal (e.g., magnetic resonance imaging, MRI) frequency. However, many NP systems that are currently used in TBI only provide contrast in a single imaging modality limiting the imaging data that can be obtained, and those that offer multimodal imaging capabilities have complicated multistep synthesis methods. Therefore, the goal of this work was to develop an ultrasmall NP with simple fabrication capable of multimodal imaging. Here, we describe the development, characterization, accumulation, and retention of poly(ethylene glycol) (PEG)-coated europium−gadolinium (Eu−Gd) mixed magnetic NPs (MNPs) in a controlled cortical impact mouse model of TBI. We find that these NPs having an ultrasmall core size of 2 nm and a small hydrodynamic size of 13.5 nm can be detected in both fluorescence and MR imaging modalities and rapidly accumulate and are retained in injured brain parenchyma. These NPs should allow for further testing of NP physicochemical properties that promote accumulation and retention in TBI and other disease models

Nanoparticle mediated silencing of DNA repair sensitizes pediatric brain tumor cells to y-irradiation

Medulloblastoma (MB) and ependymoma (EP) are the most common pediatric brain tumors, afflicting 3000 children annually. Radiotherapy (RT) is an integral component in the treatment of these tumors; however, the improvement in survival is often accompanied by radiation-induced adverse developmental and psychosocial sequelae. Therefore, there is an urgent need to develop strategies that can increase the sensitivity of brain tumors cells to RT while sparing adjacent healthy brain tissue. Apurinic endonuclease 1 (Ape1), an enzyme in the base excision repair pathway, has been implicated in radiation resistance in cancer. Pharmacological and specificity limitations inherent to small molecule inhibitors of Ape1 have hindered their clinical development. Here we report on a nanoparticle (NP) based siRNA delivery vehicle for knocking down Ape1 expression and sensitizing pediatric brain tumor cells to RT. The NP comprises a superparamagnetic iron oxide core coated with a biocompatible, biodegradable coating of chitosan, polyethylene glycol (PEG), and polyethyleneimine (PEI) that is able to bind and protect siRNA from degradation and to deliver siRNA to the perinuclear region of target cells. NPs loaded with siRNA against Ape1 (NP:siApe1) knocked down Ape1 expression over 75% in MB and EP cells, and reduced Ape1 activity by 80%. This reduction in Ape1 activity correlated with increased DNA damage post-irradiation, which resulted in decreased cell survival in clonogenic assays. The sensitization was specific to therapies generating abasic lesions as evidenced by NP:siRNA not increasing sensitivity to paclitaxel, a microtubule disrupting agent. Our results indicate NP-mediated delivery of siApe1 is a promising strategy for circumventing pediatric brain tumor resistance to RT

Antioxidant Theranostic Copolymer-Mediated Reduction In Oxidative Stress Following Traumatic Brain Injury Improves Outcome In A Mouse Model

Following a traumatic brain injury (TBI), excess reactive oxygen species (ROS) and lipid peroxidation products (LPOx) are generated and lead to secondary injury beyond the primary insult. A major limitation of current treatments is poor target engagement, which has prevented success in clinical trials. Thus, nanoparticle-based treatments have received recent attention because of their ability to increase accumulation and retention in damaged brain. Theranostic neuroprotective copolymers (NPC3) containing thiol functional groups can neutralize ROS and LPOx. Immediate administration of NPC3 following injury in a controlled cortical impact (CCI) mouse model provides a therapeutic window in reducing ROS levels at 2.08–20.83 mg kg−1 in males and 5.52–27.62 mg kg−1 in females. This NPC3-mediated reduction in oxidative stress improves spatial learning and memory in males, while females show minimal improvement. Notably, NPC3-mediated reduction in oxidative stress prevents the bilateral spread of necrosis in male mice, which is not observed in female mice and likely accounts for the sex-based spatial learning and memory differences. Overall, these findings suggest sex-based differences to oxidative stress scavenger nanoparticle treatments, and a possible upper threshold of antioxidant activity that provides therapeutic benefit in injured brain since female mice benefit from NPC3 treatment to a lesser extent than male mice