Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems DOI Creative Commons
Felix Neumaier, Boris D. Zlatopolskiy, Bernd Neumaier

et al.

Pharmaceutics, Journal Year: 2021, Volume and Issue: 13(10), P. 1542 - 1542

Published: Sept. 23, 2021

Delivery of most drugs into the central nervous system (CNS) is restricted by blood–brain barrier (BBB), which remains a significant bottleneck for development novel CNS-targeted therapeutics or molecular tracers neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures rate extent brain penetration has led emergence more holistic framework that integrates data from various in vivo, situ and vitro assays obtain comprehensive description delivery distribution within brain. Coupled with ongoing suitable BBB models, this integrated approach promises reduce incidence costly late-stage failures CNS development, could help overcome some technical, economic ethical issues associated vivo studies animal models. Here, we provide an overview structure function summary pharmacokinetic parameters can be used determine We also review different models regard their inherent shortcomings potential usefulness fast-acting neurotracers labeled short-lived radionuclides. In regard, special focus been set those systems are sufficiently well established laboratories without bioengineering expertise.

Language: Английский

Magnetic iron oxide nanoparticles for brain imaging and drug delivery DOI Creative Commons
Ruirui Qiao, Changkui Fu, Helen Forgham

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 197, P. 114822 - 114822

Published: April 21, 2023

Central nervous system (CNS) disorders affect as many 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment CNS disorders. With advent nanotechnologies, controlled drugs with nanoparticles holds great promise in overcoming blood-brain barrier (BBB) improving efficacy. In recent years, magnetic iron oxide (MIONPs) have stood out promising theranostic nanoplatform drug they possess unique physical properties biodegradable characteristics. this review, we summarize advances MIONP-based platforms diseases. We firstly introduce methods synthesis surface functionalization MIONPs emphasis on inclusion biocompatible polymers that allow addition tailored physicochemical properties. then discuss vivo applications using MIONPs. Finally, present perspective remaining challenges possible future directions systems.

Language: Английский

Citations

117
Intrinsic blood–brain barrier dysfunction contributes to multiple sclerosis pathogenesis DOI Open Access
Hideaki Nishihara, Sylvain Perriot, Benjamin D. Gastfriend

et al.

Brain, Journal Year: 2022, Volume and Issue: 145(12), P. 4334 - 4348

Published: Jan. 24, 2022

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the CNS are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction incompletely understood generally thought be a consequence neuroinflammation. Here, we have challenged this view asked if intrinsic alterations in MS patients contribute pathogenesis. To end, made use human induced pluripotent stem cells derived from healthy controls differentiated them brain microvascular endothelial (BMEC)-like as vitro model BBB. MS-derived BMEC-like showed impaired junctional integrity, properties efflux pump activity when compared controls. Also, displayed an inflammatory phenotype with increased adhesion molecule expression interactions. Activation Wnt/β-catenin signalling progenitor enhanced characteristics reduced phenotype. Our study provides evidence for impairment function that can modelled vitro. Human iPSC-derived thus suitable explore molecular underpinnings will assist identification potential novel therapeutic targets stabilization.

Language: Английский

Citations

83
Emerging trends in organ-on-a-chip systems for drug screening DOI Creative Commons
Yanping Wang, Yanfeng Gao, Yongchun Pan

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(6), P. 2483 - 2509

Published: Feb. 15, 2023

New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially pharmaceutical industry and healthcare services. Assessment efficacy safety prior human clinical trials crucial part development, which deserves greater emphasis reduce cost time in discovery. Recent advances microfabrication tissue engineering have given rise organ-on-a-chip, an

Language: Английский

Citations

60
Review: pathophysiology of intracranial hypertension and noninvasive intracranial pressure monitoring DOI Creative Commons
Nicolas Canac, Kian Jalaleddini, Samuel Thorpe

et al.

Fluids and Barriers of the CNS, Journal Year: 2020, Volume and Issue: 17(1)

Published: June 23, 2020

Abstract Measurement of intracranial pressure (ICP) is crucial in the management many neurological conditions. However, due to invasiveness, high cost, and required expertise available ICP monitoring techniques, patients who could benefit from do not receive it. As a result, there has been substantial effort explore develop novel noninvasive techniques improve overall clinical care may be suffering disorders. This review attempts summarize general pathophysiology ICP, discuss importance current state monitoring, describe methods that have proposed for monitoring. These can broken down into four major categories: fluid dynamic, otic, ophthalmic, electrophysiologic. Each category discussed detail along with its associated their advantages, disadvantages, reported accuracy. A particular emphasis this will dedicated based on use transcranial Doppler ultrasound. At present, it appears are either sufficiently accurate, reliable, or robust enough widespread adoption require additional independent validation. several appear promising through study validation, eventually make way practice.

Language: Английский

Citations

119
Emerging Application of Nanorobotics and Artificial Intelligence To Cross the BBB: Advances in Design, Controlled Maneuvering, and Targeting of the Barriers DOI Creative Commons
Ajay Vikram Singh,

Vaisali Chandrasekar,

Poonam Janapareddy

et al.

ACS Chemical Neuroscience, Journal Year: 2021, Volume and Issue: 12(11), P. 1835 - 1853

Published: May 19, 2021

The blood–brain barrier (BBB) is a prime focus for clinicians to maintain the homeostatic function in health and deliver theranostics brain cancer number of neurological diseases. structural hierarchy situ biochemical signaling BBB neurovascular unit have been primary targets recapitulate into vitro modules. microengineered perfusion systems development 3D cellular organoid culture given major thrust research neuropharmacology. In this review, we on revisiting nanoparticles based bimolecular engineering enable them maneuver, control, target, theranostic payloads across as nanorobots or nanobots. Subsequently provide brief outline specific case studies addressing payload delivery tumor disorders (e.g., Alzheimer's disease, Parkinson's multiple sclerosis, etc.). addition, also address opportunities challenges nanorobots' design. Finally, how computationally powered machine learning (ML) tools artificial intelligence (AI) can be partnered with robotics predict design next generation interact without causing damage, toxicity, malfunctions. content review could references multidisciplinary science clinicians, roboticists, chemists, bioengineers involved cutting-edge pharmaceutical research.

Language: Английский

Citations

103
Biology and Models of the Blood–Brain Barrier DOI Creative Commons
Cynthia Hajal, Baptiste Le Roi,

Roger D. Kamm

et al.

Annual Review of Biomedical Engineering, Journal Year: 2021, Volume and Issue: 23(1), P. 359 - 384

Published: July 13, 2021

The blood–brain barrier (BBB) is one of the most selective endothelial barriers. An understanding its cellular, morphological, and biological properties in health disease necessary to develop therapeutics that can be transported from blood brain. In vivo models have provided some insight into these features transport mechanisms adopted at brain, yet they failed as a robust platform for translation results clinical outcomes. this article, we provide general overview major BBB describe various been designed replicate neurological pathologies linked with BBB. We propose several key parameters design characteristics employed engineer physiologically relevant interface highlight need consensus measurement fundamental barrier.

Language: Английский

Citations

101
In vitro blood brain barrier models: An overview DOI
Ekta Jagtiani,

Mihika Yeolekar,

Shivraj Naik

et al.

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 343, P. 13 - 30

Published: Jan. 10, 2022

Language: Английский

Citations

55
Organ‐On‐A‐Chip Models of the Blood–Brain Barrier: Recent Advances and Future Prospects DOI
Satoru Kawakita, Kalpana Mandal, Lei Mou

et al.

Small, Journal Year: 2022, Volume and Issue: 18(39)

Published: Aug. 17, 2022

The human brain and central nervous system (CNS) present unique challenges in drug development for neurological diseases. One major obstacle is the blood-brain barrier (BBB), which hampers effective delivery of therapeutic molecules into while protecting it from blood-born neurotoxic substances maintaining CNS homeostasis. For BBB research, traditional vitro models rely upon Petri dishes or Transwell systems. However, these static lack essential microenvironmental factors such as shear stress proper cell-cell interactions. To this end, organ-on-a-chip (OoC) technology has emerged a new modeling approach to better recapitulate highly dynamic vivo microenvironment so-called neural vascular unit (NVU). Such BBB-on-a-chip have made substantial progress over last decade, concurrently there been increasing interest various diseases Alzheimer's disease Parkinson's using OoC technology. In addition, with recent advances other scientific technologies, several opportunities improve platform via multidisciplinary approaches are available. review, an overview NVU provided, applications personalized medicine discovery discussed, current future directions delineated.

Language: Английский

Citations

51
Experimental Models of In Vitro Blood–Brain Barrier for CNS Drug Delivery: An Evolutionary Perspective DOI Open Access
Bivek Chaulagain, Avinash Gothwal, Richard Nii Lante Lamptey

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2710 - 2710

Published: Jan. 31, 2023

Central nervous system (CNS) disorders represent one of the leading causes global health burden. Nonetheless, new therapies approved against these are among lowest compared to their counterparts. The absence reliable and efficient in vitro blood–brain barrier (BBB) models resembling vivo properties stands out as a significant roadblock developing successful therapy for CNS disorders. Therefore, advancement creation robust sensitive BBB drug screening might allow us expedite neurological development. This review discusses major developed now exploring cerebral vasculature. Our main focus is describing existing models, including 2D transwell covering both single-layer co-culture 3D organoid microfluidic with construction, permeability measurement, applications, limitations. Although better at recapitulating than other gaps still exist use predicting performance neurotherapeutics. However, this comprehensive account can be useful researchers create improved future.

Language: Английский

Citations

29
Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications DOI Creative Commons
Moritz Steinruecke,

Rebecca Murphy Lonergan,

Bhuvaneish T. Selvaraj

et al.

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2023, Volume and Issue: 43(5), P. 642 - 654

Published: Jan. 26, 2023

There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment blood-central nervous system (BCNSB) occurs during pre-symptomatic ALS, mechanisms underlying this pathology are likely also involved in ALS disease process. In review, we explore how drivers disease, particularly mitochondrial dysfunction, astrocyte neuroinflammation, may contribute to BCNSB impairment. Mitochondria highly abundant tissue contributes motor neuron death. Likewise, astrocytes adopt key physical, transport metabolic functions barrier, which impaired ALS. Astrocytes show raised expression inflammatory markers ablating ALS-causing transgenes slows progression. addition, TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation systemic inflammation, affect integrity Finally, discuss translational implications development biomarkers onset progression, approaches aimed restoring vitro modelling neurogliovascular system.

Language: Английский

Citations

28