Vimala N. Bharadwaj

Bio: Vimala N. Bharadwaj is an academic researcher from Arizona State University. The author has contributed to research in topics: Traumatic brain injury & Magnetic resonance imaging. The author has an hindex of 4, co-authored 11 publications receiving 147 citations. Previous affiliations of Vimala N. Bharadwaj include Stanford University & University of Arizona.

Nanoparticle-Based Therapeutics for Brain Injury.

Abstract: Brain injuries affect a large patient population with major physical and emotional suffering for patients and their relatives; at a significant cost to the society. Effective diagnostic and therapeutic options available for brain injuries are limited by the complex brain injury pathology involving blood–brain barrier (BBB). Brain injuries, including ischemic stroke and brain trauma, initiate BBB opening for a short period of time, which is followed by a second reopening for an extended time. The leaky BBB and/or the alterations in the receptor expression on BBB may provide opportunities for therapeutic delivery via nanoparticles (NPs). The approaches for therapeutic interventions via NP delivery are aimed at salvaging the pericontusional/penumbra area for possible neuroprotection and neurovascular unit preservation. The focus of this progress report is to provide a survey of NP strategies employed in cerebral ischemia and brain trauma and finally provide insights for improved NP-based diagnostic/treatment approaches.

Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size.

Abstract: Nanoparticle (NP) based therapeutic and theranostic agents have been developed for various diseases, yet application to neural disease/injury is restricted by the blood-brain-barrier (BBB). Traumatic brain injury (TBI) results in a host of pathological alterations, including transient breakdown of the BBB, thus opening a window for NP delivery to the injured brain tissue. This study focused on investigating the spatiotemporal accumulation of different sized NPs after TBI. Specifically, animal cohorts sustaining a controlled cortical impact injury received an intravenous injection of PEGylated NP cocktail (20, 40, 100, and 500 nm, each with a unique fluorophore) immediately (0 h), 2 h, 5 h, 12 h, or 23 h after injury. NPs were allowed to circulate for 1 h before perfusion and brain harvest. Confocal microscopy demonstrated peak NP accumulation within the injury penumbra 1 h post-injury. An inverse relationship was found between NP size and their continued accumulation within the penumbra. NP accumulation preferentially occurred in the primary motor and somatosensory areas of the injury penumbra as compared to the parietal association and visual area. Thus, we characterized the accumulation of particles up to 500 nm at different times acutely after injury, indicating the potential of NP-based TBI theranostics in the acute period after injury.

Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury

Abstract: The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

Abstract: Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that are highly selective molecules for neurotransmitter and other nervous system receptors sites, including those associated with pain and analgesia, and so have tremendous potential in pain therapeutics. However, delivery of polypeptides to the nervous system is largely limited due to rapid degradation within the peripheral circulation as well as the blood–brain barrier. One strategy that has been shown to be successful in nervous system deposition of polypeptides is intranasal (IN) delivery. In this narrative review, we discuss the delivery of polypeptides to the peripheral and central nervous systems following IN administration. We briefly discuss the mechanism of delivery via the nasal–cerebral pathway. We review recent studies that demonstrate that polypeptides such as oxytocin, delivered IN, not only reach key pain-modulating regions in the nervous system but, in doing so, evoke significant analgesic effects. IN administration of polypeptides has tremendous potential to provide a non-invasive, rapid and effective method of delivery to the nervous system for chronic pain treatment and management.

早期関節リウマチ：brief overview

Abstract: ▪ 関節リウマチ（RA）の骨破壊が発症後2 年以内に進行することが報告されて以降，windowof opportunity（治療効果が高いと考えられている発症早期の限られた期間）を意識した治療管理が提唱されてきた．▪ 米国リウマチ学会（ACR）は2008 年の推奨で病歴6 ヵ月未満のRA を早期RA と定義し，生物学的製剤を含む積極的な管理を提案した．▪ 2010 年にはRA の分類基準が改定され，治療開始の基準が治療者の間で共有された．RA を目標達成に向けて治療するという指針，treat to target （T2T）が提唱され，以降国際的な基本方針になった．

Towards Improvements for Penetrating the Blood–Brain Barrier—Recent Progress from a Material and Pharmaceutical Perspective

Abstract: The blood–brain barrier (BBB) is a critical biological structure that prevents damage to the brain and maintains its bathing microenvironment. However, this barrier is also the obstacle to deliver beneficial drugs to treat CNS (central nervous system) diseases. Many efforts have been made for improvement of delivering drugs across the BBB in recent years to treat CNS diseases. In this review, the anatomical and functional structure of the BBB is comprehensively discussed. The mechanisms of BBB penetration are summarized, and the methods and effects on increasing BBB permeability are investigated in detail. It also elaborates on the physical, chemical, biological and nanocarrier aspects to improve drug delivery penetration to the brain and introduces some specific drug delivery effects on BBB permeability.

Drug Delivery to the Brain across the Blood–Brain Barrier Using Nanomaterials

Abstract: A major obstacle facing brain diseases such as Alzheimer's disease, multiple sclerosis, brain tumors, and strokes is the blood-brain barrier (BBB). The BBB prevents the passage of certain molecules and pathogens from the circulatory system into the brain. Therefore, it is nearly impossible for therapeutic drugs to target the diseased cells without the assistance of carriers. Nanotechnology is an area of growing public interest; nanocarriers, such as polymer-based, lipid-based, and inorganic-based nanoparticles can be engineered in different sizes, shapes, and surface charges, and they can be modified with functional groups to enhance their penetration and targeting capabilities. Hence, understanding the interaction between nanomaterials and the BBB is crucial. In this Review, the components and properties of the BBB are revisited and the types of nanocarriers that are most commonly used for brain drug delivery are discussed. The properties of the nanocarriers and the factors that affect drug delivery across the BBB are elaborated upon in this review. Additionally, the most recent developments of nanoformulations and nonconventional drug delivery strategies are highlighted. Finally, challenges and considerations for the development of brain targeting nanomedicines are discussed. The overall objective is to broaden the understanding of the design and to develop nanomedicines for the treatment of brain diseases.

Mesoporous silica/organosilica nanoparticles: Synthesis, biological effect and biomedical application

Abstract: The interdisciplinary integration among material science, nanotechnology and biology has been promoting the emergences of a large number of feasible nanoplatforms for diverse biomedical applications. Thanks to the unique mesoporous structure, large specific surface area, abundant surface chemistry and tunable framework composition, mesoporous silica nanoparticles (MSNs) and mesoporous organosilica nanoparticles (MONs) have been extensively applied for diverse therapeutic, or diagnostic applications. The past two decades have witnessed the blooming growth of researches on the elaborate design and fabrication of multifunctional MSNs/MONs-based nanosystems, which have greatly pushed forward the development of next-generation theranostic biomaterials. These mesoporous silica-based nanomaterials feature varied structural, compositional and morphological characteristics, leading to the great diversity in their downstream physicochemical properties and theranostic performances, which further catalyzes the emergence of advanced therapeutic strategies for optimized treatment efficacies and mitigated side effects. In this review, we will comprehensively elucidate very-recent advances on the construction of MSNs/MONs-based theranostic nanoplatforms for various therapeutic and diagnostic applications, and discuss the underlying material chemistry of these exquisite nanosystems that confers varied theranostic functionalities. Especially, the interdependent relationship among the synthesis, biological effects and biomedical applications of MSNs and MONs will be discussed in depth, and their further clinical-translation potential/challenge will be clarified and outlooked. It is highly expected that we will witness a second leap-forward development of the biomedical applications of MSNs and MONs in the next one or two decades, especially for the further clinical translation.