Periodic Reporting for period 1 - NVU-Chip (An in vitro 3D microfluidic human NeuroVascular Unit model for identifying the cell-type-specific responses to diverse inflammatory stimuli in the brain capillaries)
Reporting period: 2021-06-01 to 2023-05-31
The NVU-Chip project addresses a limited problem is that the limited understanding and treatment options for neurological disorders, which are a significant cause of death and disability worldwide. The biggest challenge lies in the blood-brain barrier (BBB), a complex interface that separates the brain from the circulatory system. While the BBB protects the brain from toxins and pathogens, it also impedes the delivery of drugs to the central nervous system (CNS) to treat brain diseases. The lack of effective human models that can replicate the complexity and functionality of the BBB hinders research efforts to study neurological diseases and develop better treatments.
The importance of the research project to society lies in the potential to improve our understanding of neurological diseases and increase treatment outcomes. Neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD) have a significant impact on millions of people worldwide, resulting in high mortality and morbidity rates. By developing a 3D model of the neurovascular unit (NVU) that closely resembles human physiology, researchers can identify cellular responses to inflammatory stimuli and gain insight into disease mechanisms. This knowledge may lead to the discovery of key inflammatory factors associated with CNS-related diseases and facilitate the development of more effective therapeutic interventions. Ultimately, research has the potential to improve the quality of life of people affected by neurological diseases and reduce the burden on healthcare systems.
The overall objectives of the research project are as follows:
•Objective 1: Development of stem cell-derived brain endothelial cells and parenchymal brain cells
•Objective 2: Development of NVU-Chip
•Objective 3: Development of neurodegenerative NVU-Chip model
Consequently, the project created an advanced human in vitro NVU chip model that closely resembles the human neurovascular unit and will allow researchers to study cellular interactions and neurodegenerative processes. The NVU-Chip project reached to its goal is generate unique, physiologically relevant microfluidic devices that improves our understanding of neurological diseases and develop better treatments for them.
The importance of the research project to society lies in the potential to improve our understanding of neurological diseases and increase treatment outcomes. Neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD) have a significant impact on millions of people worldwide, resulting in high mortality and morbidity rates. By developing a 3D model of the neurovascular unit (NVU) that closely resembles human physiology, researchers can identify cellular responses to inflammatory stimuli and gain insight into disease mechanisms. This knowledge may lead to the discovery of key inflammatory factors associated with CNS-related diseases and facilitate the development of more effective therapeutic interventions. Ultimately, research has the potential to improve the quality of life of people affected by neurological diseases and reduce the burden on healthcare systems.
The overall objectives of the research project are as follows:
•Objective 1: Development of stem cell-derived brain endothelial cells and parenchymal brain cells
•Objective 2: Development of NVU-Chip
•Objective 3: Development of neurodegenerative NVU-Chip model
Consequently, the project created an advanced human in vitro NVU chip model that closely resembles the human neurovascular unit and will allow researchers to study cellular interactions and neurodegenerative processes. The NVU-Chip project reached to its goal is generate unique, physiologically relevant microfluidic devices that improves our understanding of neurological diseases and develop better treatments for them.
The NVU Chip project served as the catalyst for establishing a dynamic and interdisciplinary research group that focused on bioengineering approaches to construct a neurovascular unit (NVU) model. Each member of the group was assigned to different project objectives, fostering collaboration and the exchange of knowledge to achieve successful outcomes.
During the course of the NVU Chip project, we embarked on the design and fabrication of innovative microfluidic devices tailored to cultivate cells under physiologically relevant flow and shear conditions. Leveraging 3D printing technologies, we generated molds to cascade microfluidic chips with diverse channel sizes and shapes. These devices were then subjected to comprehensive investigations involving cell-culturing at varying flow rates and shear forces. Moreover, we integrated additional modules into our chip system to monitor crucial cellular activities, such as transendothelial electrical resistance and oxygen sensing. The culmination of our efforts resulted in the coculturing of brain endothelial cells and peripheral cells within our custom-designed chip models, yielding vascularized brain models. A significant aspect of the project involved the development of unique differentiation protocols, enabling us to obtain neurons and brain endothelial cells from mesenchymal stem cells. Furthermore, ongoing work focuses on refining differentiation protocols for endothelial cells derived from induced pluripotent stem cells. As a testament to the project's impact, two master's students conducted their theses on the differentiation of neurons and endothelial cells, respectively.
We have undertaken an array of research endeavors in the field of microfluidic chips, which have resulted in several significant publications. These include a review article detailing the design of microfluidic chips, a conference paper outlining the successful implementation of pH sensors for organ crisps, and a book chapter focusing on epilepsy chip models integrated with blood-brain barrier components. Furthermore, we have collaborated on two additional review articles. Moreover, our contributions extend to the domain of vascular chip models, where a master's thesis was dedicated to the design and fabrication of such models.
Presently, we are actively engaged in a patent application for our unique chip design and concurrently working on three scientific publications centered around vascular chip models and endothelial cell differentiation protocols. The NVU chip project, in particular, has served as a foundational cornerstone for our research group, leading to the initiation of various other projects. These subsequent endeavors have received funding from esteemed local and European sources.
During the course of the NVU Chip project, we embarked on the design and fabrication of innovative microfluidic devices tailored to cultivate cells under physiologically relevant flow and shear conditions. Leveraging 3D printing technologies, we generated molds to cascade microfluidic chips with diverse channel sizes and shapes. These devices were then subjected to comprehensive investigations involving cell-culturing at varying flow rates and shear forces. Moreover, we integrated additional modules into our chip system to monitor crucial cellular activities, such as transendothelial electrical resistance and oxygen sensing. The culmination of our efforts resulted in the coculturing of brain endothelial cells and peripheral cells within our custom-designed chip models, yielding vascularized brain models. A significant aspect of the project involved the development of unique differentiation protocols, enabling us to obtain neurons and brain endothelial cells from mesenchymal stem cells. Furthermore, ongoing work focuses on refining differentiation protocols for endothelial cells derived from induced pluripotent stem cells. As a testament to the project's impact, two master's students conducted their theses on the differentiation of neurons and endothelial cells, respectively.
We have undertaken an array of research endeavors in the field of microfluidic chips, which have resulted in several significant publications. These include a review article detailing the design of microfluidic chips, a conference paper outlining the successful implementation of pH sensors for organ crisps, and a book chapter focusing on epilepsy chip models integrated with blood-brain barrier components. Furthermore, we have collaborated on two additional review articles. Moreover, our contributions extend to the domain of vascular chip models, where a master's thesis was dedicated to the design and fabrication of such models.
Presently, we are actively engaged in a patent application for our unique chip design and concurrently working on three scientific publications centered around vascular chip models and endothelial cell differentiation protocols. The NVU chip project, in particular, has served as a foundational cornerstone for our research group, leading to the initiation of various other projects. These subsequent endeavors have received funding from esteemed local and European sources.
The NVU Chip project represents a significant leap beyond the current state of the art. We have achieved remarkable success by developing novel microfluidic systems equipped with diverse sensing capabilities. These advanced systems allow us to create physiologically relevant neurovascular unit models and closely monitor dynamic changes that take place during both healthy and disease conditions. Looking ahead, these developments hold the promise of directly impacting patients' lives, particularly when these technologies are employed as drug development tools in the long run. The ability to simulate complex physiological conditions and closely study disease mechanisms using our microfluidic systems can significantly accelerate the discovery and development of novel therapeutic interventions and ultimately improve the lives of patients worldwide.
Over the course of the 2-year fellowship, my research outcomes have been disseminated widely through over 10 invited talks in Turkey and Europe, as well as engagements with student club activities where I shared my experiences as a young academician. These efforts have been recognized, leading to appearances on acclaimed academic platforms like BolBilim, a prominent academic YouTube channel in Turkey (https://www.youtube.com/watch?v=IyseDT9Pn5E&t=617s).
This research will prove beneficial to researchers working in academia and biotechnological industries, as well as benefiting society as a whole. As a woman scientist, I have actively encouraged and recruited women students and researchers to join my laboratory, fostering a diverse team with varied backgrounds, irrespective of gender or ethnicity. This commitment to inclusivity and multidisciplinary collaboration has proven successful, as evidenced by the significantly higher representation of female researchers in the team compared to male researchers.
As the NVU-Chip project progresses, we will continue to establish and foster national and international collaborations. These collaborations will serve to strengthen the project's impact and facilitate the dissemination of knowledge and research advancements even beyond the project's duration. The ultimate aim is to leverage the power of multidisciplinary and collaborative work to drive meaningful contributions to the field of Molecular Biology, Genetics, and Bioengineering while serving as role models for young women scientists and researchers.
Over the course of the 2-year fellowship, my research outcomes have been disseminated widely through over 10 invited talks in Turkey and Europe, as well as engagements with student club activities where I shared my experiences as a young academician. These efforts have been recognized, leading to appearances on acclaimed academic platforms like BolBilim, a prominent academic YouTube channel in Turkey (https://www.youtube.com/watch?v=IyseDT9Pn5E&t=617s).
This research will prove beneficial to researchers working in academia and biotechnological industries, as well as benefiting society as a whole. As a woman scientist, I have actively encouraged and recruited women students and researchers to join my laboratory, fostering a diverse team with varied backgrounds, irrespective of gender or ethnicity. This commitment to inclusivity and multidisciplinary collaboration has proven successful, as evidenced by the significantly higher representation of female researchers in the team compared to male researchers.
As the NVU-Chip project progresses, we will continue to establish and foster national and international collaborations. These collaborations will serve to strengthen the project's impact and facilitate the dissemination of knowledge and research advancements even beyond the project's duration. The ultimate aim is to leverage the power of multidisciplinary and collaborative work to drive meaningful contributions to the field of Molecular Biology, Genetics, and Bioengineering while serving as role models for young women scientists and researchers.