Pathophysiology, Management, and Therapeutics in Subarachnoid Hemorrhage and Delayed Cerebral Ischemia: An Overview.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke resulting from the rupture of an arterial vessel within the brain. Unlike other stroke types, SAH affects both young adults (mid-40s) and the geriatric population. Patients with SAH often experience significant neurological deficits, leading to a substantial societal burden in terms of lost potential years of life. This review provides a comprehensive overview of SAH, examining its development across different stages (early, intermediate, and late) and highlighting the pathophysiological and pathohistological processes specific to each phase. The clinical management of SAH is also explored, focusing on tailored treatments and interventions to address the unique pathological changes that occur during each stage. Additionally, the paper reviews current treatment modalities and pharmacological interventions based on the evolving guidelines provided by the American Heart Association (AHA). Recent advances in our understanding of SAH will facilitate clinicians' improved management of SAH to reduce the incidence of delayed cerebral ischemia in patients.

PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury.

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI.

A role for protein arginine methyltransferase 7 in repetitive and mild traumatic brain injury.

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

Guidelines for establishing a 3-D printing biofabrication laboratory.

Advanced manufacturing and 3D printing are transformative technologies currently undergoing rapid adoption in healthcare, a traditionally non-manufacturing sector. Recent development in this field, largely enabled by merging different disciplines, has led to important clinical applications from anatomical models to regenerative bioscaffolding and devices. Although much research to-date has focussed on materials, designs, processes, and products, little attention has been given to the design and requirements of facilities for enabling clinically relevant biofabrication solutions. These facilities are critical to overcoming the major hurdles to clinical translation, including solving important issues such as reproducibility, quality control, regulations, and commercialization. To improve process uniformity and ensure consistent development and production, large-scale manufacturing of engineered tissues and organs will require standardized facilities, equipment, qualification processes, automation, and information systems. This review presents current and forward-thinking guidelines to help design biofabrication laboratories engaged in engineering model and tissue constructs for therapeutic and non-therapeutic applications.

Machine intelligence for nerve conduit design and production.

Nerve guidance conduits (NGCs) have emerged from recent advances within tissue engineering as a promising alternative to autografts for peripheral nerve repair. NGCs are tubular structures with engineered biomaterials, which guide axonal regeneration from the injured proximal nerve to the distal stump. NGC design can synergistically combine multiple properties to enhance proliferation of stem and neuronal cells, improve nerve migration, attenuate inflammation and reduce scar tissue formation. The aim of most laboratories fabricating NGCs is the development of an automated process that incorporates patient-specific features and complex tissue blueprints (e.g. neurovascular conduit) that serve as the basis for more complicated muscular and skin grafts. One of the major limitations for tissue engineering is lack of guidance for generating tissue blueprints and the absence of streamlined manufacturing processes. With the rapid expansion of machine intelligence, high dimensional image analysis, and computational scaffold design, optimized tissue templates for 3D bioprinting (3DBP) are feasible. In this review, we examine the translational challenges to peripheral nerve regeneration and where machine intelligence can innovate bottlenecks in neural tissue engineering.