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Art Imitates Life: The Brain Vasculature as a Muse for Designing Novel Bioelectronics

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by Jerry (Yuhsiang) Cheng

Over the past decade, scientific strides have been made in both treating and monitoring brain diseases to facilitate neural regeneration for diseases like peripheral neuropathy and multiple sclerosis. However, scientific progress has been met with challenges such as recruiting neural stem cells (NSC), necessary for recovery, to sites of injury and choosing between exogenous stem cells and endogenous NSCs for driving repair of brain tissue. While endogenous NSCs circumvent many complications of exogenous cell transplantation therapy such as cellular rejection, NSCs are largely constrained to specific anatomical niches, such as the subventricular zone (SVZ) and subgranular zone (SGZ). Potential solutions such as designer, injectable gels have been developed to promote NSC recruitment (Marquardt et al., 2020), but there is still a need for approaches that simultaneously treat disease and track disease progression. In an effort to address these pain points, Xiao Yang, currently a postdoctoral scholar in the Department of Chemistry and Department of Psychiatry and Behavioral Sciences at Stanford University, and team in the lab of Prof. Charles M. Lieber (currently retired from Harvard U.) and in the Hong Lab led by Prof. Guosong Hong of the Materials Science and Engineering Department at Stanford U. have developed a novel, minimally invasive device that simultaneously facilitates neuronal migration to sites of injury and performs single-cell resolution recording of electrophysiological dynamics in the brain.

Vasculature-like electronic scaffolds
Vasculature-like electronic scaffolds for promoting and tracking neuronal migration, Image credit: Xiao Yang.

Alongside advancements in translational science, understanding of basic brain vasculature biology has grown substantially from blood-brain barrier-crossing therapies to the pivotal role of blood vessels in cell migration. When she was a Ph.D. student, Xiao Yang working in the lab of Prof. Charles M. Lieber drew inspiration from past learnings about the neural microenvironment to develop an alternative approach for her Ph.D. research. “Unfortunately, many people suffer from brain diseases and disorders including traumatic brain injuries, strokes, and neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases,” explains Yang. “These disorders usually lead to a significant loss of neurons, affecting various neural functions.” This prompted Yang to view implantable brain-machine interfaces as more than monitoring devices; she envisions them as innovative ‘electronic medicine’ that can actively intervene, repair, and treat a range of brain diseases and injuries. Drawing inspiration from studies that demonstrate the migration of newly generated neurons along blood vessels, Yang and Lieber asked, “Is it possible to design brain-machine interfaces that emulate blood vessels, thereby facilitating neural regeneration and migration?”

In a recent report in Nature Biomedical Engineering, Yang, Lieber, Hong, and their co-authors design vasculature-like bioelectronic scaffolds (VasES) that recapitulate properties of blood vessels. VasES are coated with laminin, which is a major basement membrane protein that facilitates many functional properties of blood vessels such as structural integrity, cell adhesion, cell signaling, angiogenesis, and importantly tissue repair. Moreover, 32 platinum electrodes are embedded within the VasES scaffold structure to enable single-unit recordings for confirming the functionality of migrating neurons at the single-cell and circuit levels.

VasES implanted into mouse brain
Schematic of VasES implanted with Matrigel into a cortical resection of a mouse brain, Image credit: Xiao Yang

The team assessed the efficacy of VasES in replicating vascular-like properties, promoting neuronal migration, and restoring both single-unit functionality and circuit level neural plasticity. To this end, the authors first injected the Matrigel matrix into the resection of a brain resection mouse model. Then, VasES were stereotaxically positioned across the Matrigel matrix, remaining cortical tissue, and the subventricular zone directly underneath. Notably, when compared to adjacent vessels, the device clearly recapitulated both the topography and dimensions of endogenous vasculature. Yang recounts, “I was immensely excited the first time I observed newborn neurons with distinct and characteristic morphology closely adhering to and aligning along the vasculature-like electronic scaffold in the brain resection.” Relative to Matrigel matrix controls without VasES implantation, VasES greatly enhanced the migration of doublecortin (DCX) -positive newborn neurons into the Matrigel-filled resection. Astrocytes, microglia, and endothelial cells, which are all crucial in supporting neural function, were also observed to enter the resected area.

Importantly, elevated neuronal migration into the resection was accompanied by an increase in NeuN-positive mature neurons. Through principal component analysis, the group found that activity in single neurons, which was absent 12 hours after surgery, emerged after 1 week. The team also sought to understand if and when the regenerated neural circuit begins interacting with the host brain, as well as whether those connections are direct or remote.

In conclusion, the team have developed a novel and minimally invasive bioelectronic capable of promoting neuronal recruitment while performing single-cell resolution recordings of electrophysiological dynamics.

Headshot of Xiao Yang
Lead author Dr. Xiao Yang, Stanford U.

VasES demonstrates the possibility of combining strengths across bioelectronic solutions to give the multifaceted functionality of promoting neuronal recruitment crucial for brain repair while performing single-cell resolution recordings of electrophysiological dynamics. This technology will allow for unprecedented access in not only medicine, but also in basic neuroscience research. The granularity and depth offered by traditional electrodes often create non-physiological conditions in which data is collected. VasES will allow neuroscientists to attain a much more accurate understanding of in vivo electrophysiological dynamics in the brain. Yang believes, “This platform offers an intriguing method for manipulating and monitoring neural migration and holds promise as a treatment platform strategy for addressing neuron loss and exploring recovery pathways.” And by mirroring endogenous biology, the team has begun paving a path forward in unlocking endogenous therapies.

Xiao Yang is the lead author and conducted this research as a Ph.D. student at Harvard U and a postdoctoral scholar at Stanford U. Stanford University co-authors include Nicholas J. Rommelfanger in the Department of Applied Physics and Guosong Hong, assistant professor in the Department of Materials Science and Engineering. Other co-authors include Yue Qi, Chonghe Wang, and Theodore J. Zwang from Harvard University, and Charles M. Lieber, retired Harvard Professor of Chemistry and Chemical Biology.

The authors acknowledge support for the research described in this study from the National Institute on Drug Abuse and the Director’s Pioneer Award of the National Institutes of Health. N.J.R. received support from a Stanford Bio-X Honorary Graduate Student Fellowship and the National Science Foundation Graduate Research Fellowship Program. This work was performed in part at the Harvard Center for Biological Imaging and Harvard University Center for Nanoscale Systems, a member of the National Nanotechnology Coordinated Infrastructure Network supported by the National Science Foundation.

The eWEAR-TCCI awards for science writing is a project commissioned by the Wearable Electronics Initiative (eWEAR) at Stanford University and made possible by funding through eWEAR industrial affiliates program member Shanda Group and the Tianqiao and Chrissy Chen Institute (TCCI®).