Journal articles: 'Blood-brain-barrier-on-a-chip'

1

Deosarkar, Sudhir P., Balabhaskar Prabhakarpandian, Bin Wang, Joel B. Sheffield, Barbara Krynska, and Mohammad F. Kiani. "A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip." PLOS ONE 10, no. 11 (November 10, 2015): e0142725. http://dx.doi.org/10.1371/journal.pone.0142725.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Reshma, S., K. B. Megha, S. Amir, S. Rukhiya, and P. V. Mohanan. "Blood brain barrier-on-a-chip to model neurological diseases." Journal of Drug Delivery Science and Technology 80 (February 2023): 104174. http://dx.doi.org/10.1016/j.jddst.2023.104174.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Cui, Baofang, and Seung-Woo Cho. "Blood-brain barrier-on-a-chip for brain disease modeling and drug testing." BMB Reports 55, no. 5 (May 31, 2022): 213–19. http://dx.doi.org/10.5483/bmbrep.2022.55.5.043.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Liang, Yan, and Jeong-Yeol Yoon. "In situ sensors for blood-brain barrier (BBB) on a chip." Sensors and Actuators Reports 3 (November 2021): 100031. http://dx.doi.org/10.1016/j.snr.2021.100031.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Phan, Duc TT, R. Hugh F. Bender, Jillian W. Andrejecsk, Agua Sobrino, Stephanie J. Hachey, Steven C. George, and Christopher CW Hughes. "Blood–brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood–central nervous system interface." Experimental Biology and Medicine 242, no. 17 (February 14, 2017): 1669–78. http://dx.doi.org/10.1177/1535370217694100.

Full text

Abstract:

The blood–brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood–brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer’s disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood–brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood–brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood–brain barrier pathology, recent advances in the development of novel 3D blood–brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood–brain barrier, and provide an outlook on how these blood–brain barrier-on-a-chip systems can be used for central nervous system disease modeling. Impact statement The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood–Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer’s disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB – something that until recently had not been well modeled by in vitro systems. Our hope is that this review will provide a launch pad for new ideas and methodologies that can provide us with truly physiological BBB models capable of yielding new insights into the function of this critical interface.

APA, Harvard, Vancouver, ISO, and other styles

6

Staicu, Cristina Elena, Florin Jipa, Emanuel Axente, Mihai Radu, Beatrice Mihaela Radu, and Felix Sima. "Lab-on-a-Chip Platforms as Tools for Drug Screening in Neuropathologies Associated with Blood–Brain Barrier Alterations." Biomolecules 11, no. 6 (June 21, 2021): 916. http://dx.doi.org/10.3390/biom11060916.

Full text

Abstract:

Lab-on-a-chip (LOC) and organ-on-a-chip (OOC) devices are highly versatile platforms that enable miniaturization and advanced controlled laboratory functions (i.e., microfluidics, advanced optical or electrical recordings, high-throughput screening). The manufacturing advancements of LOCs/OOCs for biomedical applications and their current limitations are briefly discussed. Multiple studies have exploited the advantages of mimicking organs or tissues on a chip. Among these, we focused our attention on the brain-on-a-chip, blood–brain barrier (BBB)-on-a-chip, and neurovascular unit (NVU)-on-a-chip applications. Mainly, we review the latest developments of brain-on-a-chip, BBB-on-a-chip, and NVU-on-a-chip devices and their use as testing platforms for high-throughput pharmacological screening. In particular, we analyze the most important contributions of these studies in the field of neurodegenerative diseases and their relevance in translational personalized medicine.

APA, Harvard, Vancouver, ISO, and other styles

7

Ahn, Song Ih, and YongTae Kim. "Human Blood–Brain Barrier on a Chip: Featuring Unique Multicellular Cooperation in Pathophysiology." Trends in Biotechnology 39, no. 8 (August 2021): 749–52. http://dx.doi.org/10.1016/j.tibtech.2021.01.010.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Thakkar, S., T. Fowke, A. Nicolas, A. L. Nair, M. Pontier, and N. Wevers. "LP-17 Blood-brain barrier on-a-chip to study compound-induced disruption." Toxicology Letters 368 (September 2022): S289—S290. http://dx.doi.org/10.1016/j.toxlet.2022.07.759.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Brown, Jacquelyn A., Virginia Pensabene, Dmitry A. Markov, Vanessa Allwardt, M. Diana Neely, Mingjian Shi, Clayton M. Britt, et al. "Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor." Biomicrofluidics 9, no. 5 (September 2015): 054124. http://dx.doi.org/10.1063/1.4934713.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Kim, Jin, Kyung-Tae Lee, Jong Seung Lee, Jisoo Shin, Baofang Cui, Kisuk Yang, Yi Sun Choi, et al. "Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier." Nature Biomedical Engineering 5, no. 8 (June 14, 2021): 830–46. http://dx.doi.org/10.1038/s41551-021-00743-8.

Full text

APA, Harvard, Vancouver, ISO, and other styles

11

Lowman, John, Nienke Wevers, Xandor Spijkers, Karlijn Wilschut, Remko van Vught, Sebastiaan Trietsch, and Paul Vulto. "BBB-on-a-chip: A 3D In vitro model of the human blood-brain barrier." Drug Metabolism and Pharmacokinetics 34, no. 1 (January 2019): S54. http://dx.doi.org/10.1016/j.dmpk.2018.09.191.

Full text

APA, Harvard, Vancouver, ISO, and other styles

12

Yu, Fang, Nivasini D/O Selva Kumar, Lynette C. Foo, Sum Huan Ng, Walter Hunziker, and Deepak Choudhury. "A pump‐free tricellular blood–brain barrier on‐a‐chip model to understand barrier property and evaluate drug response." Biotechnology and Bioengineering 117, no. 4 (January 18, 2020): 1127–36. http://dx.doi.org/10.1002/bit.27260.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Sood, Ankur, Anuj Kumar, Atul Dev, Vijai Kumar Gupta, and Sung Soo Han. "Advances in Hydrogel-Based Microfluidic Blood–Brain-Barrier Models in Oncology Research." Pharmaceutics 14, no. 5 (May 5, 2022): 993. http://dx.doi.org/10.3390/pharmaceutics14050993.

Full text

Abstract:

The intrinsic architecture and complexity of the brain restricts the capacity of therapeutic molecules to reach their potential targets, thereby limiting therapeutic possibilities concerning neurological ailments and brain malignancy. As conventional models fail to recapitulate the complexity of the brain, progress in the field of microfluidics has facilitated the development of advanced in vitro platforms that could imitate the in vivo microenvironments and pathological features of the blood–brain barrier (BBB). It is highly desirous that developed in vitro BBB-on-chip models serve as a platform to investigate cancer metastasis of the brain along with the possibility of efficiently screening chemotherapeutic agents against brain malignancies. In order to improve the proficiency of BBB-on-chip models, hydrogels have been widely explored due to their unique physical and chemical properties, which mimic the three-dimensional (3D) micro architecture of tissues. Hydrogel-based BBB-on-chip models serves as a stage which is conducive for cell growth and allows the exchange of gases and nutrients and the removal of metabolic wastes between cells and the cell/extra cellular matrix (ECM) interface. Here, we present recent advancements in BBB-on-chip models targeting brain malignancies and examine the utility of hydrogel-based BBB models that could further strengthen the future application of microfluidic devices in oncology research.

APA, Harvard, Vancouver, ISO, and other styles

14

Santa-Maria, Ana R., Fruzsina R. Walter, Ricardo Figueiredo, András Kincses, Judit P. Vigh, Marjolein Heymans, Maxime Culot, et al. "Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood-brain barrier model." Journal of Cerebral Blood Flow & Metabolism 41, no. 9 (February 9, 2021): 2201–15. http://dx.doi.org/10.1177/0271678x21992638.

Full text

Abstract:

Microfluidic lab-on-a-chip (LOC) devices allow the study of blood-brain barrier (BBB) properties in dynamic conditions. We studied a BBB model, consisting of human endothelial cells derived from hematopoietic stem cells in co-culture with brain pericytes, in an LOC device to study fluid flow in the regulation of endothelial, BBB and glycocalyx-related genes and surface charge. The highly negatively charged endothelial surface glycocalyx functions as mechano-sensor detecting shear forces generated by blood flow on the luminal side of brain endothelial cells and contributes to the physical barrier of the BBB. Despite the importance of glycocalyx in the regulation of BBB permeability in physiological conditions and in diseases, the underlying mechanisms remained unclear. The MACE-seq gene expression profiling analysis showed differentially expressed endothelial, BBB and glycocalyx core protein genes after fluid flow, as well as enriched pathways for the extracellular matrix molecules. We observed increased barrier properties, a higher intensity glycocalyx staining and a more negative surface charge of human brain-like endothelial cells (BLECs) in dynamic conditions. Our work is the first study to provide data on BBB properties and glycocalyx of BLECs in an LOC device under dynamic conditions and confirms the importance of fluid flow for BBB culture models.

APA, Harvard, Vancouver, ISO, and other styles

15

Choi, Jin-Ha, Mallesh Santhosh, and Jeong-Woo Choi. "In Vitro Blood–Brain Barrier-Integrated Neurological Disorder Models Using a Microfluidic Device." Micromachines 11, no. 1 (December 24, 2019): 21. http://dx.doi.org/10.3390/mi11010021.

Full text

Abstract:

The blood–brain barrier (BBB) plays critical role in the human physiological system such as protection of the central nervous system (CNS) from external materials in the blood vessel, including toxicants and drugs for several neurological disorders, a critical type of human disease. Therefore, suitable in vitro BBB models with fluidic flow to mimic the shear stress and supply of nutrients have been developed. Neurological disorder has also been investigated for developing realistic models that allow advance fundamental and translational research and effective therapeutic strategy design. Here, we discuss introduction of the blood–brain barrier in neurological disorder models by leveraging a recently developed microfluidic system and human organ-on-a-chip system. Such models could provide an effective drug screening platform and facilitate personalized therapy of several neurological diseases.

APA, Harvard, Vancouver, ISO, and other styles

16

Li, Yan, Yan Liu, Chuanlin Hu, Qing Chang, Qihong Deng, Xu Yang, and Yang Wu. "Study of the neurotoxicity of indoor airborne nanoparticles based on a 3D human blood-brain barrier chip." Environment International 143 (October 2020): 105598. http://dx.doi.org/10.1016/j.envint.2020.105598.

Full text

APA, Harvard, Vancouver, ISO, and other styles

17

Ahn, Yujin, Ju-Hyun An, Hae-Jun Yang, Dong Gil Lee, Jieun Kim, Hyebin Koh, Young-Ho Park, et al. "Human Blood Vessel Organoids Penetrate Human Cerebral Organoids and Form a Vessel-Like System." Cells 10, no. 8 (August 9, 2021): 2036. http://dx.doi.org/10.3390/cells10082036.

Full text

Abstract:

Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood–brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31+ endothelial tubes coated with SMA+ or PDGFR+ mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days.

APA, Harvard, Vancouver, ISO, and other styles

18

Jeong, Sehoon, Jae-Hyeong Seo, Kunal Sandip Garud, Sung Woo Park, and Moo-Yeon Lee. "Numerical approach-based simulation to predict cerebrovascular shear stress in a blood-brain barrier organ-on-a-chip." Biosensors and Bioelectronics 183 (July 2021): 113197. http://dx.doi.org/10.1016/j.bios.2021.113197.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

Iyer, Jayashree, Adam Akkad, Nanyun Tang, Sen Peng, Michael Berens, Frederic Zenhausern, and Jian Gu. "Abstract 195: A focused ultrasound blood brain barrier disruption model to test the influence of tight junction genes to treat brain tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 195. http://dx.doi.org/10.1158/1538-7445.am2022-195.

Full text

Abstract:

Abstract A major hindrance to advances in the care of patients with malignant gliomas is the presence of the blood brain barrier (BBB) and blood-brain tumor barrier (BBTB) that greatly restricts drug access from the plasma to the tumor cells. Bubble-assisted Focused Ultrasound (BAFUS) has proven effective in opening the BBB for treatment of glial tumors in adults and pediatric cases. BAFUS has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. However, there is a lack of an in vitro preclinical model suitable for testing the genetic determinants of endothelial cell tight junction integrity and vulnerability to the physical disruption. Our BBB organ-on-chip platform will enable precision medicine of brain cancers through identifying patient-specific parameters by which to open the BBB allowing use of drugs and drug combinations otherwise unsuitable. We intend to sequence these in vitro models to verify that the genotype (alleles/SNPs) of tight junction proteins contribute to BBB structure and integrity. To initiate this effort, we report the development of an ultrasound transparent organ-on-chip model populated by iPSC-derived endothelial cells (iPSC-EC) co-cultured with astrocytes. Western blot, immunocytochemistry, permeability, and transelectrical endothelial resistance (TEER) studies all convey expression of key EC proteins and marked barrier integrity. Further benchmarking of device-ultrasound interactions, successful iPSC differentiation, tight junction formation, and fabrication of nanobubbles and their assistance in ultrasound BBB disruption will be presented. Efforts are underway to analyze nine characteristic BBB tight junction genes from WGS data to determine associations between iPSC-EC genotype and phenotype. Citation Format: Jayashree Iyer, Adam Akkad, Nanyun Tang, Sen Peng, Michael Berens, Frederic Zenhausern, Jian Gu. A focused ultrasound blood brain barrier disruption model to test the influence of tight junction genes to treat brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 195.

APA, Harvard, Vancouver, ISO, and other styles

20

Noorani, Behnam, Aditya Bhalerao, Snehal Raut, Ehsan Nozohouri, Ulrich Bickel, and Luca Cucullo. "A Quasi-Physiological Microfluidic Blood-Brain Barrier Model for Brain Permeability Studies." Pharmaceutics 13, no. 9 (September 15, 2021): 1474. http://dx.doi.org/10.3390/pharmaceutics13091474.

Full text

Abstract:

Microfluidics-based organ-on-a-chip technology allows for developing a new class of in-vitro blood-brain barrier (BBB) models that recapitulate many hemodynamic and architectural features of the brain microvasculature not attainable with conventional two-dimensional platforms. Herein, we describe and validate a novel microfluidic BBB model that closely mimics the one in situ. Induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) were juxtaposed with primary human pericytes and astrocytes in a co-culture to enable BBB-specific characteristics, such as low paracellular permeability, efflux activity, and osmotic responses. The permeability coefficients of [13C12] sucrose and [13C6] mannitol were assessed using a highly sensitive LC-MS/MS procedure. The resulting BBB displayed continuous tight-junction patterns, low permeability to mannitol and sucrose, and quasi-physiological responses to hyperosmolar opening and p-glycoprotein inhibitor treatment, as demonstrated by decreased BBB integrity and increased permeability of rhodamine 123, respectively. Astrocytes and pericytes on the abluminal side of the vascular channel provided the environmental cues necessary to form a tight barrier and extend the model’s long-term viability for time-course studies. In conclusion, our novel multi-culture microfluidic platform showcased the ability to replicate a quasi-physiological brain microvascular, thus enabling the development of a highly predictive and translationally relevant BBB model.

APA, Harvard, Vancouver, ISO, and other styles

21

Cameron, Tiffany, Tanya Bennet, Elyn Rowe, Mehwish Anwer, Cheryl Wellington, and Karen Cheung. "Review of Design Considerations for Brain-on-a-Chip Models." Micromachines 12, no. 4 (April 15, 2021): 441. http://dx.doi.org/10.3390/mi12040441.

Full text

Abstract:

In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when selecting or designing an appropriate device for investigating a specific scientific question. Building microfluidic Brain-on-a-Chip (BoC) models from the ground-up will allow for research questions to be answered more thoroughly in the brain research field, but the design of these devices requires several choices to be made throughout the design development phase. These considerations include the cell types, extracellular matrix (ECM) material(s), and perfusion/flow considerations. Choices made early in the design cycle will dictate the limitations of the device and influence the end-point results such as the permeability of the endothelial cell monolayer, and the expression of cell type-specific markers. To better understand why the engineering aspects of a microfluidic BoC need to be influenced by the desired biological environment, recent progress in microfluidic BoC technology is compared. This review focuses on perfusable blood–brain barrier (BBB) and neurovascular unit (NVU) models with discussions about the chip architecture, the ECM used, and how they relate to the in vivo human brain. With increased knowledge on how to make informed choices when selecting or designing BoC models, the scientific community will benefit from shorter development phases and platforms curated for their application.

APA, Harvard, Vancouver, ISO, and other styles

22

Kawakita, Satoru, Kalpana Mandal, Lei Mou, Marvin Magan Mecwan, Yangzhi Zhu, Shaopei Li, Saurabh Sharma, et al. "Organ‐On‐A‐Chip Models of the Blood–Brain Barrier: Recent Advances and Future Prospects (Small 39/2022)." Small 18, no. 39 (September 2022): 2270210. http://dx.doi.org/10.1002/smll.202270210.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

YANG, Pan-Hui, Feng-Yi ZHENG, Qiu-Shi LI, Tian TIAN, Guo-Yuan ZHANG, Lei WU, and Hong-Ju MAO. "An easy-repeat method to build a blood-brain barrier model on a chip with independent TEER detection module." Chinese Journal of Analytical Chemistry 50, no. 2 (February 2022): 97–101. http://dx.doi.org/10.1016/j.cjac.2021.11.003.

Full text

APA, Harvard, Vancouver, ISO, and other styles

24

Herland, Anna, Andries D. van der Meer, Edward A. FitzGerald, Tae-Eun Park, Jelle J. F. Sleeboom, and Donald E. Ingber. "Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip." PLOS ONE 11, no. 3 (March 1, 2016): e0150360. http://dx.doi.org/10.1371/journal.pone.0150360.

Full text

APA, Harvard, Vancouver, ISO, and other styles

25

Tu, Kai-Hong, Ling-Shan Yu, Zong-Han Sie, Han-Yi Hsu, Khuloud T. Al-Jamal, Julie Tzu-Wen Wang, and Ya-Yu Chiang. "Development of Real-Time Transendothelial Electrical Resistance Monitoring for an In Vitro Blood-Brain Barrier System." Micromachines 12, no. 1 (December 30, 2020): 37. http://dx.doi.org/10.3390/mi12010037.

Full text

Abstract:

Three-dimensional (3D) cell cultures and organs-on-a-chip have been developed to construct microenvironments that resemble the environment within the human body and to provide a platform that enables clear observation and accurate assessments of cell behavior. However, direct observation of transendothelial electrical resistance (TEER) has been challenging. To improve the efficiency in monitoring the cell development in organs-on-a-chip, in this study, we designed and integrated commercially available TEER measurement electrodes into an in vitro blood-brain barrier (BBB)-on-chip system to quantify TEER variation. Moreover, a flowing culture medium was added to the monolayered cells to simulate the promotion of continuous shear stress on cerebrovascular cells. Compared with static 3D cell culture, the proposed BBB-on-chip integrated with electrodes could measure TEER in a real-time manner over a long period. It also allowed cell growth angle measurement, providing instant reports of cell growth information online. Overall, the results demonstrated that the developed system can aid in the quantification of the continuous cell-pattern variations for future studies in drug testing.

APA, Harvard, Vancouver, ISO, and other styles

26

Koch, Eugen V., Verena Ledwig, Sebastian Bendas, Stephan Reichl, and Andreas Dietzel. "Tissue Barrier-on-Chip: A Technology for Reproducible Practice in Drug Testing." Pharmaceutics 14, no. 7 (July 12, 2022): 1451. http://dx.doi.org/10.3390/pharmaceutics14071451.

Full text

Abstract:

One key application of organ-on-chip systems is the examination of drug transport and absorption through native cell barriers such the blood–brain barrier. To overcome previous hurdles related to the transferability of existing static cell cultivation protocols and polydimethylsiloxane (PDMS) as the construction material, a chip platform with key innovations for practical use in drug-permeation testing is presented. First, the design allows for the transfer of barrier-forming tissue into the microfluidic system after cells have been seeded on porous polymer or Si3N4 membranes. From this, we can follow highly reproducible models and cultivation protocols established for static drug testing, from coating the membrane to seeding the cells and cell analysis. Second, the perfusion system is a microscopable glass chip with two fluid compartments with transparent embedded electrodes separated by the membrane. The reversible closure in a clamping adapter requires only a very thin PDMS sealing with negligible liquid contact, thereby eliminating well-known disadvantages of PDMS, such as its limited usability in the quantitative measurements of hydrophobic drug molecule concentrations. Equipped with tissue transfer capabilities, perfusion chamber inertness and air bubble trapping, and supplemented with automated fluid control, the presented system is a promising platform for studying established in vitro models of tissue barriers under reproducible microfluidic perfusion conditions.

APA, Harvard, Vancouver, ISO, and other styles

27

Wang, Peng, Yunsong Wu, Wenwen Chen, Min Zhang, and Jianhua Qin. "Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model." Biosensors 12, no. 2 (January 31, 2022): 89. http://dx.doi.org/10.3390/bios12020089.

Full text

Abstract:

Malignant melanoma is a type of highly aggressive tumor, which has a strong ability to metastasize to brain, and 60–70% of patients die from the spread of the tumor into the central nervous system. Exosomes are a type of nano-sized vesicle secreted by most living cells, and accumulated studies have reported that they play crucial roles in brain tumor metastasis, such as breast cancer and lung cancer. However, it is unclear whether exosomes also participate in the brain metastasis of malignant melanoma. Here, we established a human blood–brain barrier (BBB) model by co-culturing human brain microvascular endothelial cells, astrocytes and microglial cells under a biomimetic condition, and used this model to explore the potential roles of exosomes derived from malignant melanoma in modulating BBB integrity. Our findings showed that malignant melanoma-derived exosomes disrupted BBB integrity and induced glial activation on the BBB chip. Transcriptome analyses revealed dys-regulation of autophagy and immune responses following tumor exosome treatment. These studies indicated malignant melanoma cells might modulate BBB integrity via exosomes, and verified the feasibility of a BBB chip as an ideal platform for studies of brain metastasis of tumors in vitro.

APA, Harvard, Vancouver, ISO, and other styles

28

Miccoli, Beatrice, Dries Braeken, and Yi-Chen Ethan Li. "Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications." Current Pharmaceutical Design 24, no. 45 (April 16, 2019): 5419–36. http://dx.doi.org/10.2174/1381612825666190220161254.

Full text

Abstract:

:Neurodegenerative disorders are related to the progressive functional loss of the brain, often connected to emotional and physical disability and, ultimately, to death. These disorders, strongly connected to the aging process, are becoming increasingly more relevant due to the increase of life expectancy. Current pharmaceutical treatments poorly tackle these diseases, mainly acting only on their symptomology. One of the main reasons of this is the current drug development process, which is not only expensive and time-consuming but, also, still strongly relies on animal models at the preclinical stage.:Organ-on-a-chip platforms have the potential to strongly impact and improve the drug screening process by recreating in vitro the functionality of human organs. Patient-derived neurons from different regions of the brain can be directly grown and differentiated on a brain-on-a-chip device where the disease development, progression and pharmacological treatments can be studied and monitored in real time. The model reliability is strongly improved by using human-derived cells, more relevant than animal models for pharmacological screening and disease monitoring. The selected cells will be then capable of proliferating and organizing themselves in the in vivo environment thanks to the device architecture, materials selection and bio-chemical functionalization.:In this review, we start by presenting the fundamental strategies adopted for brain-on-a-chip devices fabrication including e.g., photolithography, micromachining and 3D printing technology. Then, we discuss the state-of-theart of brain-on-a-chip platforms including their role in the study of the functional architecture of the brain e.g., blood-brain barrier, or of the most diffuse neurodegenerative diseases like Alzheimer’s and Parkinson’s. At last, the current limitations and future perspectives of this approach for the development of new drugs and neurodegenerative diseases modeling will be discussed.

APA, Harvard, Vancouver, ISO, and other styles

29

Cameron, Tiffany C., Avineet Randhawa, Samantha M. Grist, Tanya Bennet, Jessica Hua, Luis G. Alde, Tara M. Caffrey, Cheryl L. Wellington, and Karen C. Cheung. "PDMS Organ-On-Chip Design and Fabrication: Strategies for Improving Fluidic Integration and Chip Robustness of Rapidly Prototyped Microfluidic In Vitro Models." Micromachines 13, no. 10 (September 22, 2022): 1573. http://dx.doi.org/10.3390/mi13101573.

Full text

Abstract:

The PDMS-based microfluidic organ-on-chip platform represents an exciting paradigm that has enjoyed a rapid rise in popularity and adoption. A particularly promising element of this platform is its amenability to rapid manufacturing strategies, which can enable quick adaptations through iterative prototyping. These strategies, however, come with challenges; fluid flow, for example, a core principle of organs-on-chip and the physiology they aim to model, necessitates robust, leak-free channels for potentially long (multi-week) culture durations. In this report, we describe microfluidic chip fabrication methods and strategies that are aimed at overcoming these difficulties; we employ a subset of these strategies to a blood–brain-barrier-on-chip, with others applied to a small-airway-on-chip. Design approaches are detailed with considerations presented for readers. Results pertaining to fabrication parameters we aimed to improve (e.g., the thickness uniformity of molded PDMS), as well as illustrative results pertaining to the establishment of cell cultures using these methods will also be presented.

APA, Harvard, Vancouver, ISO, and other styles

30

Andrews, Allison M., Evan M. Lutton, Lee A. Cannella, Nancy Reichenbach, Roshanak Razmpour, Matthew J. Seasock, Steven J. Kaspin, et al. "Characterization of human fetal brain endothelial cells reveals barrier properties suitable for in vitro modeling of the BBB with syngenic co-cultures." Journal of Cerebral Blood Flow & Metabolism 38, no. 5 (May 23, 2017): 888–903. http://dx.doi.org/10.1177/0271678x17708690.

Full text

Abstract:

Endothelial cells (ECs) form the basis of the blood–brain barrier (BBB), a physical barrier that selectively restricts transport into the brain. In vitro models can provide significant insight into BBB physiology, mechanisms of human disease pathology, toxicology, and drug delivery. Given the limited availability of primary human adult brain microvascular ECs ( aBMVECs), human fetal tissue offers a plausible alternative source for multiple donors and the opportunity to build syngenic tri-cultures from the same host. Previous efforts to culture fetal brain microvascular ECs ( fBMVECs) have not been successful in establishing mature barrier properties. Using optimal gestational age for isolation and flow cytometry cell sorting, we show for the first time that fBMVECs demonstrate mature barrier properties. fBMVECs exhibited similar functional phenotypes when compared to aBMVECs for barrier integrity, endothelial activation, and gene/protein expression of tight junction proteins and transporters. Importantly, we show that tissue used to culture fBMVECs can also be used to generate a syngenic co-culture, creating a microfluidic BBB on a chip. The findings presented provide a means to overcome previous challenges that limited successful barrier formation by fBMVECs. Furthermore, the source is advantageous for autologous reconstitution of the neurovascular unit for next generation in vitro BBB modeling.

APA, Harvard, Vancouver, ISO, and other styles

31

Chen, Xingchi, Chang Liu, Laureana Muok, Changchun Zeng, and Yan Li. "Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases." Cells 10, no. 11 (November 15, 2021): 3183. http://dx.doi.org/10.3390/cells10113183.

Full text

Abstract:

The blood–brain barrier (BBB) is a vital structure for maintaining homeostasis between the blood and the brain in the central nervous system (CNS). Biomolecule exchange, ion balance, nutrition delivery, and toxic molecule prevention rely on the normal function of the BBB. The dysfunction and the dysregulation of the BBB leads to the progression of neurological disorders and neurodegeneration. Therefore, in vitro BBB models can facilitate the investigation for proper therapies. As the demand increases, it is urgent to develop a more efficient and more physiologically relevant BBB model. In this review, the development of the microfluidics platform for the applications in neuroscience is summarized. This article focuses on the characterizations of in vitro BBB models derived from human stem cells and discusses the development of various types of in vitro models. The microfluidics-based system and BBB-on-chip models should provide a better platform for high-throughput drug-screening and targeted delivery.

APA, Harvard, Vancouver, ISO, and other styles

32

Miura, Shigenori, Yuya Morimoto, Tomomi Furihata, and Shoji Takeuchi. "Functional analysis of human brain endothelium using a microfluidic device integrating a cell culture insert." APL Bioengineering 6, no. 1 (March 1, 2022): 016103. http://dx.doi.org/10.1063/5.0085564.

Full text

Abstract:

The blood-brain barrier (BBB) is a specialized brain endothelial barrier structure that regulates the highly selective transport of molecules under continuous blood flow. Recently, various types of BBB-on-chip models have been developed to mimic the microenvironmental cues that regulate the human BBB drug transport. However, technical difficulties in complex microfluidic systems limit their accessibility. Here, we propose a simple and easy-to-handle microfluidic device integrated with a cell culture insert to investigate the functional regulation of the human BBB endothelium in response to fluid shear stress (FSS). Using currently established immortalized human brain microvascular endothelial cells (HBMEC/ci18), we formed a BBB endothelial barrier without the substantial loss of barrier tightness under the relatively low range of FSS (0.1–1 dyn/cm2). Expression levels of key BBB transporters and receptors in the HBMEC/ci18 cells were dynamically changed in response to the FSS, and the effect of FSS reached a plateau around 1 dyn/cm2. Similar responses were observed in the primary HBMECs. Taking advantage of the detachable cell culture insert from the device, the drug efflux activity of P-glycoprotein (P-gp) was analyzed by the bidirectional permeability assay after the perfusion culture of cells. The data revealed that the FSS-stimulated BBB endothelium exhibited the 1.9-fold higher P-gp activity than that of the static culture control. Our microfluidic system coupling with the transwell model provides a functional human BBB endothelium with secured transporter activity, which is useful to investigate the bidirectional transport of drugs and its regulation by FSS.

APA, Harvard, Vancouver, ISO, and other styles

33

Subramaniyan Parimalam, Subhathirai, Simona Badilescu, Nahum Sonenberg, Rama Bhat, and Muthukumaran Packirisamy. "Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases." International Journal of Molecular Sciences 20, no. 24 (December 5, 2019): 6126. http://dx.doi.org/10.3390/ijms20246126.

Full text

Abstract:

There is a huge demand for pro-/anti-angiogenic nanomedicines to treat conditions such as ischemic strokes, brain tumors, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Nanomedicines are therapeutic particles in the size range of 10–1000 nm, where the drug is encapsulated into nano-capsules or adsorbed onto nano-scaffolds. They have good blood–brain barrier permeability, stability and shelf life, and able to rapidly target different sites in the brain. However, the relationship between the nanomedicines’ physical and chemical properties and its ability to travel across the brain remains incompletely understood. The main challenge is the lack of a reliable drug testing model for brain angiogenesis. Recently, microfluidic platforms (known as “lab-on-a-chip” or LOCs) have been developed to mimic the brain micro-vasculature related events, such as vasculogenesis, angiogenesis, inflammation, etc. The LOCs are able to closely replicate the dynamic conditions of the human brain and could be reliable platforms for drug screening applications. There are still many technical difficulties in establishing uniform and reproducible conditions, mainly due to the extreme complexity of the human brain. In this paper, we review the prospective of LOCs in the development of nanomedicines for brain angiogenesis–related conditions.

APA, Harvard, Vancouver, ISO, and other styles

34

Boghdeh, Niloufar A., Kenneth H. Risner, Michael D. Barrera, Clayton M. Britt, David K. Schaffer, Farhang Alem, Jacquelyn A. Brown, John P. Wikswo, and Aarthi Narayanan. "Application of a Human Blood Brain Barrier Organ-on-a-Chip Model to Evaluate Small Molecule Effectiveness against Venezuelan Equine Encephalitis Virus." Viruses 14, no. 12 (December 15, 2022): 2799. http://dx.doi.org/10.3390/v14122799.

Full text

Abstract:

The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load.

APA, Harvard, Vancouver, ISO, and other styles

35

Singh, Ajay Vikram, Vaisali Chandrasekar, Peter Laux, Andreas Luch, Sarada Prasad Dakua, Paolo Zamboni, Amruta Shelar, et al. "Micropatterned Neurovascular Interface to Mimic the Blood–Brain Barrier’s Neurophysiology and Micromechanical Function: A BBB-on-CHIP Model." Cells 11, no. 18 (September 8, 2022): 2801. http://dx.doi.org/10.3390/cells11182801.

Full text

Abstract:

A hybrid blood–brain barrier (BBB)-on-chip cell culture device is proposed in this study by integrating microcontact printing and perfusion co-culture to facilitate the study of BBB function under high biological fidelity. This is achieved by crosslinking brain extracellular matrix (ECM) proteins to the transwell membrane at the luminal surface and adapting inlet–outlet perfusion on the porous transwell wall. While investigating the anatomical hallmarks of the BBB, tight junction proteins revealed tortuous zonula occludens (ZO-1), and claudin expressions with increased interdigitation in the presence of astrocytes were recorded. Enhanced adherent junctions were also observed. This junctional phenotype reflects in-vivo-like features related to the jamming of cell borders to prevent paracellular transport. Biochemical regulation of BBB function by astrocytes was noted by the transient intracellular calcium effluxes induced into endothelial cells. Geometry-force control of astrocyte–endothelial cell interactions was studied utilizing traction force microscopy (TFM) with fluorescent beads incorporated into a micropatterned polyacrylamide gel (PAG). We observed the directionality and enhanced magnitude in the traction forces in the presence of astrocytes. In the future, we envisage studying transendothelial electrical resistance (TEER) and the effect of chemomechanical stimulations on drug/ligand permeability and transport. The BBB-on-chip model presented in this proposal should serve as an in vitro surrogate to recapitulate the complexities of the native BBB cellular milieus.

APA, Harvard, Vancouver, ISO, and other styles

36

Iyer, Jayashree, Adam Akkad, Nanyun Tang, Michael Berens, Frederic Zenhausern, and Jian Gu. "EXTH-17. A FOCUSED ULTRASOUND BLOOD BRAIN BARRIER DISRUPTION MODEL TO TEST THE INFLUENCE OF TIGHT JUNCTION GENES TO TREAT BRAIN TUMORS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi167. http://dx.doi.org/10.1093/neuonc/noab196.656.

Full text

Abstract:

Abstract Treating primary or metastatic tumors in the brain (glioblastomas, melanoma, lung cancer, breast cancer) proves challenging by virtue of the protective function of the blood brain barrier (BBB). The tight junction proteins (TJPs) binding the specialized endothelial cells of the BBB largely contribute to the limited permeability of cancer-therapeutic drugs. In both preclinical and clinical models, low intensity focused ultrasound (LIFU) coupled with microbubbles has been proven to safely and transiently open the BBB. Despite this method being established, potential genetic influences on the durability and vulnerability of tight junctions to LIFU have not been elucidated, nor have the determinants of tight junction repair post LIFU been thoroughly investigated. We report the development of an ultrasound transparent organ-on-chip model populated by iPSC-derived endothelial cells (iPSC-EC) co-cultured with astrocytes. We aim to probe the contributions of various tight junction genes to barrier integrity along with the subsequent protein topology involved in reassembly post ultrasound. Thus, this model serves to determine parameters for ultrasound disruption for precision opening of the BBB. The BBB-On-Chip was successfully fabricated and assembled with an optimized technique that has an 80% yield of leak-free devices, with stable cavitation post nanobubble injection. Furthermore, Western blots show expression of claudin-5, a key TJP, in our iPSC-ECs. We have also demonstrated by confocal microscopy that another component of the TJP complex, ZO-1, can be visualized at iPSC-derived cell junctions. Further benchmarking of device-ultrasound interactions, successful iPSC differentiation, tight junction formation, and fabrication of nanobubbles and their assistance in ultrasound BBB disruption will be presented. Efforts are underway to characterize the contributions of tight junction genes and their variations to the integrity and disruption of the BBB.

APA, Harvard, Vancouver, ISO, and other styles

37

Oliver, Christopher Ryan, Trisha M. Westerhof, Benjamin A. Yang, Nathan M. Merrill, Joel A. Yates, Liam Russell, Anna J. Miller, et al. "Abstract 3189: Characterization of secretory cues that promote brain metastasis using a microfluidic blood brain niche (BBN) device." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3189. http://dx.doi.org/10.1158/1538-7445.am2022-3189.

Full text

Abstract:

Abstract Brain metastases occur in ~ 20% of cancers and are one of the most lethal progression events. The dynamic processes underpinning cancer/tumor microenvironment (TME) interactions are poorly understood. We examined the TME remodeling in response to secretory cues provided by the brain niche components that attract metastatic cancer cells. We identified individual secretions by cell type in the niche. Dkk1 was regulated in response to the brain niche cells exposure to cancer cells; thus, we delineated how Dkk1 modulates the remodeling of the niche and migratory behavior of the cancer cells. We utilized two in vitro microfluidic devices: 1) a blood brain niche (BBN) chip that recapitulates the BBB and brain TME; 2) a migration chip that assesses linear cell migration. The BBN chip consists of two-chambers separated by a porous membrane. The bottom is filled with human astrocytes or their secretions in collagen to recapitulate the pre-metastatic niche. Endothelial cells (hCMEC/D3) form a barrier on the membrane separating the two chambers. MDA-231-BR extravasate into BBN chips containing astrocytes within 2-Days, develop into micro-metastases after 9-Days, and establish cancer – astrocyte contacts. Providing astrocytic secretions in BBN chips produced similar results. Increased interaction was found between brain seeking clones of MDA-MB-231 and JIMT-1 cells and astrocytes compared to parental cells. Analysis of astrocytic and endothelial secretions detected, amongst others, Dkk-1, that is preferentially elevated in astrocytes when stimulated with MDA-231-BR compared to MDA-231. The migration chip was utilized to assess the impact of Dkk-1 on cancer cell migration. Dkk-1 gradients are established using passive diffusion, then migration is monitored. Neither 231-BR or 231 increase migration towards a Dkk-1 gradient. Instead, both increase migration when directly stimulated with Dkk-1 and then exposed to an external chemotactic gradient of FBS, indicating cancer exposure to Dkk-1 produced within the BBN may promote cancer cell migration. Strikingly, Dkk-1 neutralization in BBN chips with astrocytes reduces 231-BR extravasation across the BBB, decreases migration within the brain niche space, and disrupts cancer–astrocyte contacts, suggesting Dkk-1 is a critical cytokine that promotes brain metastasis. Thirty genes were significantly differentially expressed with Dkk-1 stimulation. The top 3, MDA-231-BR expressed genes FGF-13, PLCB1, and MYC are involved in important oncological pathways: Ras, PI3K, MAPK, Wnt suggesting the plasticity of metastatic cancer permits the cells to adapt to the brain TME. An FGF-13 knockdown of the cells showed Dkk1 effects are partially reduced migration in the brain tropic cells in Dkk1 stimulated conditions. We conclude that the cancer response to Dkk-1 is one critical interaction amenable to therapeutics. Citation Format: Christopher Ryan Oliver, Trisha M. Westerhof, Benjamin A. Yang, Nathan M. Merrill, Joel A. Yates, Liam Russell, Anna J. Miller, Peter J. Ulintz, Carlos A. Aguilar, Aki Morikawa, Maria G. Castro, Sofia M. Merajver. Characterization of secretory cues that promote brain metastasis using a microfluidic blood brain niche (BBN) device [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3189.

APA, Harvard, Vancouver, ISO, and other styles

38

Virlogeux, Amandine, Chiara Scaramuzzino, Sophie Lenoir, Rémi Carpentier, Morgane Louessard, Aurélie Genoux, Patricia Lino, et al. "Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice." Science Advances 7, no. 14 (March 2021): eabb0799. http://dx.doi.org/10.1126/sciadv.abb0799.

Full text

Abstract:

Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell–derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.

APA, Harvard, Vancouver, ISO, and other styles

39

Sahtoe, Danny D., Adrian Coscia, Nur Mustafaoglu, Lauren M. Miller, Daniel Olal, Ivan Vulovic, Ta-Yi Yu, et al. "Transferrin receptor targeting by de novo sheet extension." Proceedings of the National Academy of Sciences 118, no. 17 (April 20, 2021): e2021569118. http://dx.doi.org/10.1073/pnas.2021569118.

Full text

Abstract:

The de novo design of polar protein–protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood–brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM Kd, is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands.

APA, Harvard, Vancouver, ISO, and other styles

40

Hajal, Cynthia, Yoojin Shin, Leanne Li, Jean Carlos Serrano, Tyler Jacks, and Roger Kamm. "TAMI-08. THE CCL2-CCR2 ASTROCYTE-CANCER CELL AXIS IN TUMOR EXTRAVASATION AT THE BRAIN." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi199. http://dx.doi.org/10.1093/neuonc/noab196.792.

Full text

Abstract:

Abstract Although brain metastases are common in cancer patients, little is known about the mechanisms of extravasation across the blood-brain barrier (BBB), a key step in the metastatic cascade that regulates the entry of cancer cells into the brain parenchyma through its selective endothelial barrier. Progress in this area has been impeded by challenges in conducting high spatio-temporal resolution imaging in vivo and isolating factors and cellular interactions directly contributing to extravasation rather than cancer survival and proliferation in the brain tissue. To address these limitations, we engineered a three-dimensional in vitro BBB microvascular model with endothelial cells derived from induced pluripotent stem cells, brain pericytes, and astrocytes, into which we perfused cancer cells to recapitulate their circulation and extravasation at the BBB. With this platform, we revealed that astrocytes play a major role in promoting cancer cell transmigration via their secretion of C-C motif chemokine ligand 2 (CCL2). We found that this chemokine promoted the chemotaxis and chemokinesis of cancer cells via their C-C chemokine receptor type 2 (CCR2), with no significant changes in vascular permeability. These findings were validated in vivo, where CCR2-deficient cancer cells exhibited significantly reduced cancer cell arrest and transmigration in mouse brain capillaries. Our results attest to the translational value of our BBB-on-a-chip model and reveal that the CCL2-CCR2 astrocyte-cancer cell axis plays a fundamental role in extravasation and consequently metastasis to the brain.

APA, Harvard, Vancouver, ISO, and other styles

41

Pun, Sirjana, Li Cai Haney, and Riccardo Barrile. "Modelling Human Physiology on-Chip: Historical Perspectives and Future Directions." Micromachines 12, no. 10 (October 15, 2021): 1250. http://dx.doi.org/10.3390/mi12101250.

Full text

Abstract:

For centuries, animal experiments have contributed much to our understanding of mechanisms of human disease, but their value in predicting the effectiveness of drug treatments in the clinic has remained controversial. Animal models, including genetically modified ones and experimentally induced pathologies, often do not accurately reflect disease in humans, and therefore do not predict with sufficient certainty what will happen in humans. Organ-on-chip (OOC) technology and bioengineered tissues have emerged as promising alternatives to traditional animal testing for a wide range of applications in biological defence, drug discovery and development, and precision medicine, offering a potential alternative. Recent technological breakthroughs in stem cell and organoid biology, OOC technology, and 3D bioprinting have all contributed to a tremendous progress in our ability to design, assemble and manufacture living organ biomimetic systems that more accurately reflect the structural and functional characteristics of human tissue in vitro, and enable improved predictions of human responses to drugs and environmental stimuli. Here, we provide a historical perspective on the evolution of the field of bioengineering, focusing on the most salient milestones that enabled control of internal and external cell microenvironment. We introduce the concepts of OOCs and Microphysiological systems (MPSs), review various chip designs and microfabrication methods used to construct OOCs, focusing on blood-brain barrier as an example, and discuss existing challenges and limitations. Finally, we provide an overview on emerging strategies for 3D bioprinting of MPSs and comment on the potential role of these devices in precision medicine.

APA, Harvard, Vancouver, ISO, and other styles

42

Teixeira, Maria Inês, Maria Helena Amaral, Paulo C. Costa, Carla M. Lopes, and Dimitrios A. Lamprou. "Recent Developments in Microfluidic Technologies for Central Nervous System Targeted Studies." Pharmaceutics 12, no. 6 (June 11, 2020): 542. http://dx.doi.org/10.3390/pharmaceutics12060542.

Full text

Abstract:

Neurodegenerative diseases (NDs) bear a lot of weight in public health. By studying the properties of the blood-brain barrier (BBB) and its fundamental interactions with the central nervous system (CNS), it is possible to improve the understanding of the pathological mechanisms behind these disorders and create new and better strategies to improve bioavailability and therapeutic efficiency, such as nanocarriers. Microfluidics is an intersectional field with many applications. Microfluidic systems can be an invaluable tool to accurately simulate the BBB microenvironment, as well as develop, in a reproducible manner, drug delivery systems with well-defined physicochemical characteristics. This review provides an overview of the most recent advances on microfluidic devices for CNS-targeted studies. Firstly, the importance of the BBB will be addressed, and different experimental BBB models will be briefly discussed. Subsequently, microfluidic-integrated BBB models (BBB/brain-on-a-chip) are introduced and the state of the art reviewed, with special emphasis on their use to study NDs. Additionally, the microfluidic preparation of nanocarriers and other compounds for CNS delivery has been covered. The last section focuses on current challenges and future perspectives of microfluidic experimentation.

APA, Harvard, Vancouver, ISO, and other styles

43

Wang, Jiuhai, Yutian Gu, Xu Liu, Yadi Fan, Yu Zhang, Changqing Yi, Changming Cheng, and Mo Yang. "Near-Infrared Photothermally Enhanced Photo-Oxygenation for Inhibition of Amyloid-β Aggregation Based on RVG-Conjugated Porphyrinic Metal–Organic Framework and Indocyanine Green Nanoplatform." International Journal of Molecular Sciences 23, no. 18 (September 17, 2022): 10885. http://dx.doi.org/10.3390/ijms231810885.

Full text

Abstract:

Amyloid aggregation is associated with many neurodegenerative diseases such as Alzheimer’s disease (AD). The current technologies using phototherapy for amyloid inhibition are usually photodynamic approaches based on evidence that reactive oxygen species can inhibit Aβ aggregation. Herein, we report a novel combinational photothermally assisted photo-oxygenation treatment based on a nano-platform of the brain-targeting peptide RVG conjugated with the 2D porphyrinic PCN−222 metal–organic framework and indocyanine green (PCN−222@ICG@RVG) with enhanced photo-inhibition in Alzheimer’s Aβ aggregation. A photothermally assisted photo-oxygenation treatment based on PCN@ICG could largely enhance the photo-inhibition effect on Aβ42 aggregation and lead to much lower neurotoxicity upon near-infrared (NIR) irradiation at 808 nm compared with a single modality of photo-treatment in both cell-free and in vitro experiments. Generally, local photothermal heat increases the instability of Aβ aggregates and keeps Aβ in the status of monomers, which facilitates the photo-oxygenation process of generating oxidized Aβ monomers with low aggregation capability. In addition, combined with the brain-targeting peptide RVG, the PCN−222@ICG@RVG nanoprobe shows high permeability of the human blood–brain barrier (BBB) on a human brain-on-a-chip platform. The ex vivo study also demonstrates that NIR-activated PCN−222@ICG@RVG could efficiently dissemble Aβ plaques. Our work suggests that the combination of photothermal treatment with photo-oxygenation can synergistically enhance the inhibition of Aβ aggregation, which may boost NIR-based combinational phototherapy of AD in the future.

APA, Harvard, Vancouver, ISO, and other styles

44

Ganderton, Ros, Chantelle Monck, Tomasz Wojdacz, Mark Slevin, Nicola Meakin, and Paul Grundy. "A Feasibility Study Evaluating the Use of Cell-free DNA Analysis in Laboratory Brain Cancer Investigations." Neuro-Oncology 23, Supplement_4 (October 1, 2021): iv25. http://dx.doi.org/10.1093/neuonc/noab195.063.

Full text

Abstract:

Abstract Aims Circulating tumour DNA (ctDNA), shed from solid cancers in to the plasma, represents an exciting analyte for diagnosis and monitoring of disease in cancer patients. However, its use in glioma brain cancer patients represents a challenge, due to reduced permeability of the blood brain barrier. This pilot study sought to investigate the practical aspects and clinical utility of using cell-free DNA (cfDNA) in glioma tests in a NHS diagnostic laboratory. Firstly, we investigated the potential of ctDNA as a proxy for the brain cancer biopsy; where cfDNA analysis was compared to the paired FFPE brain specimen for relevant glioma genetic biomarkers. Secondly, ctDNA constitutes a portion of the overall cfDNA and there is evidence cfDNA metrics per se may also be of value as prognostic tools and surrogates of tumour burden. Additionally, we investigated a potential role for cfDNA metrics in prognostic impact; linking cfDNA concentrations to clinical outcome measures. Method 10ml peripheral blood was collected in specialist preservative tubes and cfDNA isolated using an extraction kit (Qiagen MinElute ccfDNA kit). cfDNA concentration and purity was assessed using chip-based automated electrophoresis. Where relevant (12/39 cases), cfDNA samples were run though laboratory tests of IDH variant detection, 1p19q co-deletion assessment and MGMT promoter methylation analysis. Results were compared with ‘standard of care’ brain biopsy tests. A potential correlate of cfDNA concentration and clinical outcomes data were assessed in a sub-cohort of glioblastoma patients (n=32). The cohort was divided in to 2 groups – high cfDNA vs. low cfDNA - based on whether a subject’s extracted sample cfDNA concentration fell above or below the mean. Comparison of overall survival in months between subjects was checked for normal distribution using the Shapiro-Wilk t-test. The test of equity of survival distributions for the high cfDNA vs. low cfDNA was then analysed as a Kaplan-Meier curve. Results The protocol delivered cfDNA of high purity, averaging 91%, within the plasma nucleic acid fraction, however the cfDNA concentrations (mean ≈1ng µl-1) fell below the conventional limit of detection of the laboratory tests. In spite of the low concentration, cfDNA samples did generate test PCR amplicon; however results reflected the germline DNA profile rather than the new somatic changes of the tumour. The cfDNA analysis did not pick up the tumour biomarkers seen in the paired tumour biopsy sample. In a second part of the study, cfDNA concentrations for the glioblastoma cohort were assessed in the context of their clinical outcomes data. The data showed a correlate where high cfDNA concentration in the extracted sample was independently associated with inferior outcome in terms of overall survival, with Log Rank significance p=0.014 (Figure 1). Conclusion The cfDNA yields from a 10ml blood sample were consistently too low to meet the limit of detection requirements of the standard laboratory neuropathology genetic tests and glioma tumour profile could not be picked up against the germline background. Thus, in spite of the considerable advantages to glioma plasma molecular testing, using cfDNA as a proxy for a brain biopsy would currently not be possible in our routine diagnostic environment. However, within the limitations of the pilot project testing strategy, the data showed an interesting correlate where high cfDNA concentration was independently associated with inferior outcome in terms of overall survival for glioblastoma patients. Given the simplicity of obtaining this quantifiable metric, there are grounds for further investigations as to its utility; not only with survival outcomes, but also potential correlation with the clinical assessment of tumour burden, blood brain barrier integrity and disease pseudoprogression.

APA, Harvard, Vancouver, ISO, and other styles

45

Mosiagina, A. I., A. V. Morgun, and A. B. Salmina. "Overview of existing in vitro BBB models: advantages and disadvantages, current state and future prospects." Complex Issues of Cardiovascular Diseases 10, no. 3 (September 25, 2021): 109–20. http://dx.doi.org/10.17802/2306-1278-2021-10-3-109-120.

Full text

Abstract:

There is growing research focusing on endothelial cells as separate units of the blood-brain barrier (BBB), and on the complex relationships between different types of cells within a neurovascular unit. To conduct this type of studies, researches use vastly different in vitro BBB models. The main objective of such models is to study the BBB permeability for different molecules, and to advance the current level of understanding the mechanisms of disease and to develop methods of targeted therapy for the central nervous system. The analysis of the existing Abstract in vitro BBB models and their advantages/disadvantages was conducted using the clinical trial data obtained in Russian/foreign countries. In this review, the authors highlight the most relevant assessment parameters and propose a unified classification of in vitro BBB models. According to the performed analysis, there is a tendency to move from 2D BBB models based on semipermeable inserts to 3D BBB spheroid and microfluidic organ-on-chip models. Moreover, the use of human induced pluripotent stem cells instead of animal primary cells will make it possible to reliably scale the results obtained in vitro to conditions in vivo.

APA, Harvard, Vancouver, ISO, and other styles

46

Ju, Dapeng, Wei Zhang, Jiawei Yan, Haijiao Zhao, Wei Li, Jiawen Wang, Meimei Liao, et al. "Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals." Science Translational Medicine 12, no. 542 (May 6, 2020): eaba0769. http://dx.doi.org/10.1126/scitranslmed.aba0769.

Full text

Abstract:

Transcriptional regulation lies at the core of the circadian clockwork, but how the clock-related transcription machinery controls the circadian phase is not understood. Here, we show both in human cells and in mice that RuvB-like ATPase 2 (RUVBL2) interacts with other known clock proteins on chromatin to regulate the circadian phase. Pharmacological perturbation of RUVBL2 with the adenosine analog compound cordycepin resulted in a rapid-onset 12-hour clock phase-shift phenotype at human cell, mouse tissue, and whole-animal live imaging levels. Using simple peripheral injection treatment, we found that cordycepin penetrated the blood-brain barrier and caused rapid entrainment of the circadian phase, facilitating reduced duration of recovery in a mouse jet-lag model. We solved a crystal structure for human RUVBL2 in complex with a physiological metabolite of cordycepin, and biochemical assays showed that cordycepin treatment caused disassembly of an interaction between RUVBL2 and the core clock component BMAL1. Moreover, we showed with spike-in ChIP-seq analysis and binding assays that cordycepin treatment caused disassembly of the circadian super-complex, which normally resides at E-box chromatin loci such as PER1, PER2, DBP, and NR1D1. Mathematical modeling supported that the observed type 0 phase shifts resulted from derepression of E-box clock gene transcription.

APA, Harvard, Vancouver, ISO, and other styles

47

Ma, Zhiyuan, Baicheng Li, Jie Peng, and Dan Gao. "Recent Development of Drug Delivery Systems through Microfluidics: From Synthesis to Evaluation." Pharmaceutics 14, no. 2 (February 17, 2022): 434. http://dx.doi.org/10.3390/pharmaceutics14020434.

Full text

Abstract:

Conventional drug administration usually faces the problems of degradation and rapid excretion when crossing many biological barriers, leading to only a small amount of drugs arriving at pathological sites. Therapeutic drugs delivered by drug delivery systems to the target sites in a controlled manner greatly enhance drug efficacy, bioavailability, and pharmacokinetics with minimal side effects. Due to the distinct advantages of microfluidic techniques, microfluidic setups provide a powerful tool for controlled synthesis of drug delivery systems, precisely controlled drug release, and real-time observation of drug delivery to the desired location at the desired rate. In this review, we present an overview of recent advances in the preparation of nano drug delivery systems and carrier-free drug delivery microfluidic systems, as well as the construction of in vitro models on-a-chip for drug efficiency evaluation of drug delivery systems. We firstly introduce the synthesis of nano drug delivery systems, including liposomes, polymers, and inorganic compounds, followed by detailed descriptions of the carrier-free drug delivery system, including micro-reservoir and microneedle drug delivery systems. Finally, we discuss in vitro models developed on microfluidic devices for the evaluation of drug delivery systems, such as the blood–brain barrier model, vascular model, small intestine model, and so on. The opportunities and challenges of the applications of microfluidic platforms in drug delivery systems, as well as their clinical applications, are also discussed.

APA, Harvard, Vancouver, ISO, and other styles

48

Lynch, Mark J., and Oliviero L. Gobbo. "Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders." Nanomaterials 11, no. 10 (October 7, 2021): 2632. http://dx.doi.org/10.3390/nano11102632.

Full text

Abstract:

Nanotheranostics constitute a novel drug delivery system approach to improving systemic, brain-targeted delivery of diagnostic imaging agents and pharmacological moieties in one rational carrier platform. While there have been notable successes in this field, currently, the clinical translation of such delivery systems for the treatment of neurological disorders has been limited by the inadequacy of correlating in vitro and in vivo data on blood–brain barrier (BBB) permeation and biocompatibility of nanomaterials. This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy and current non-animal-based models for assessing the safety and efficiency of such formulations. This review will also address current and future directions of select in vitro models for reducing the cumbersome and laborious mandate for testing exclusively in animals. It is hoped these non-animal-based modelling approaches will facilitate researchers in optimising promising multifunctional nanocarriers with a view to accelerating clinical testing and authorisation applications. By rational design and appropriate selection of characterised and validated models, ranging from monolayer cell cultures to organ-on-chip microfluidics, promising nanotheranostic particles with modular and rational design can be screened in high-throughput models with robust predictive power. Thus, this article serves to highlight abbreviated research and development possibilities with clinical translational relevance for developing novel nanomaterial-based neuropharmaceuticals for therapy in CNS disorders. By generating predictive data for prospective nanomedicines using validated in vitro models for supporting clinical applications in lieu of requiring extensive use of in vivo animal models that have notable limitations, it is hoped that there will be a burgeoning in the nanotherapy of CNS disorders by virtue of accelerated lead identification through screening, optimisation through rational design for brain-targeted delivery across the BBB and clinical testing and approval using fewer animals. Additionally, by using models with tissue of human origin, reproducible therapeutically relevant nanomedicine delivery and individualised therapy can be realised.

APA, Harvard, Vancouver, ISO, and other styles

49

Hou, Qinghong, Lina Zhu, Le Wang, Xiaoyan Liu, Feng Xiao, Yangzhouyun Xie, Wenfu Zheng, and Xingyu Jiang. "Screening on-chip fabricated nanoparticles for penetrating the blood–brain barrier." Nanoscale 14, no. 8 (2022): 3234–41. http://dx.doi.org/10.1039/d1nr05825h.

Full text

Abstract:

We synthesized a series of brain-targeting drug nanocarriers on multi-channel syringe pump-integrated microfluidic chips, and evaluated their performance in penetrating the blood–brain barrier by in vitro and in vivo experiments.

APA, Harvard, Vancouver, ISO, and other styles

50

Watson, David E., Rosemarie Hunziker, and John P. Wikswo. "Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology." Experimental Biology and Medicine 242, no. 16 (October 2017): 1559–72. http://dx.doi.org/10.1177/1535370217732765.

Full text

Abstract:

Microphysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children’s health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood–brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the development of MPS disease models to aid in the discovery of disease mechanisms; novel compounds including probes, leads, and clinical candidates; and mechanism of action of drug candidates. Impact statement Microphysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic – a well-perfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Blood-brain-barrier-on-a-chip'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles