Aquaporin 4 (AQP4) is a cerebral glial marker that labels ependymal cells and astrocytes’ endfeet and is the main water channel responsible for the parenchymal fluid balance. However, in brain development, AQP4 is a marker of glial stem cells and plays a crucial role in the pathophysiology of pediatric hydrocephalus. Gliogenesis characterization has been hampered by a lack of biomarkers for precursor and intermediate stages and a deeper understanding of hydrocephalus etiology is needed. This manuscript is a focused review of the current research landscape on AQP4 as a possible biomarker for gliogenesis and its influence in pediatric hydrocephalus, emphasizing reactive astrogliosis. The goal is to understand brain development under hydrocephalic and normal physiologic conditions.

Hydrocephalus (HCP) is a chronic neurological brain disorder caused by a malfunction of the cerebrospinal fluid (CSF) drainage mechanism in the brain. The current standard method to treat HCP is a shunt system. Unfortunately, the shunt system suffers from complications including mechanical malfunctions, obstructions, infections, blockage, breakage, overdrainage, and/or underdrainage. Some of these complications may be attributed to the shunts’ physically large and lengthy course making them susceptible to external forces, siphoning effects, and risks of infection. Additionally, intracranial catheters artificially traverse the brain and drain the ventricle rather than the subarachnoid space. We report a 3D-printed microelectromechanical system-based implantable valve to improve HCP treatment. This device provides an alternative approach targeting restoration of near-natural CSF dynamics by artificial arachnoid granulations (AGs), natural components for CSF drainage in the brain. The valve, made of hydrogel, aims to regulate the CSF flow between the subarachnoid space and the superior sagittal sinus, in essence, substituting for the obstructed arachnoid granulations. The valve, operating in a fully passive manner, utilizes the hydrogel swelling feature to create nonzero cracking pressure, P T ≈ 47.4 ± 6.8 mmH2O, as well as minimize reverse flow leakage, Q O ≈ 0.7 μL/min on benchtop experiments. The additional measurements performed in realistic experimental setups using a fixed sheep brain also deliver comparable results, P T ≈ 113.0 ± 9.8 mmH2O and Q O ≈ 3.7 μL/min. In automated loop functional tests, the valve maintains functionality for a maximum of 1536 cycles with the P T variance of 44.5 mmH2O < P T < 61.1 mmH2O and negligible average reverse flow leakage rates of ∼0.3 μL/min.

The leading cause of ventricular shunt failure in pediatric patients is proximal catheter occlusion. Here, we evaluate various types of shunt catheters to assess in vitro cellular adhesion and obstruction. The following four types of catheters were tested: (1) antibiotic- and barium-impregnated, (2) polyvinylpyrrolidone, (3) barium stripe, and (4) barium impregnated. Catheters were either seeded superficially with astrocyte cells to test cellular adhesion or inoculated with cultured astrocytes into the catheters to test catheter performance under obstruction conditions. Ventricular catheters were placed into a three-dimensional printed phantom ventricular replicating system through which artificial CSF was pumped. Differential pressure sensors were used to measure catheter performance. Polyvinylpyrrolidone catheters had the lowest median cell attachment compared to antibiotic-impregnated (18 cells), barium stripe (17 cells), and barium-impregnated (21.5 cells) catheters after culture (p < 0.01). In addition, polyvinylpyrrolidone catheters had significantly higher flow in the phantom ventricular system (0.12 mL/min) compared to the antibiotic coated (0.10 mL/min), barium stripe (0.02 mL/min) and barium-impregnated (0.08 mL/min; p < 0.01) catheters. Polyvinylpyrrolidone catheters showed less cellular adhesion and were least likely to be occluded by astrocyte cells. Our findings can help suggest patient-appropriate proximal ventricular catheters for clinical use.

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Hydrocephalus (HCP) is a neurological disease resulting from the disruption of the cerebrospinal fluid (CSF) drainage mechanism in the brain. Reliable draining of CSF is necessary to treat hydrocephalus. The current standard of care is an implantable shunt system. However, shunts have a high failure rate caused by mechanical malfunctions, obstructions, infection, blockage, breakage, and over or under drainage. Such shunt failures can be difficult to diagnose due to nonspecific systems and the lack of long-term implantable pressure sensors. Herein, we present the evaluation of a fully realized and passive implantable valve made of hydrogel to restore CSF draining operations within the cranium. The valves are designed to achieve a non-zero cracking pressure and no reverse flow leakage by using hydrogel swelling. The valves were evaluated in a realistic fluidic environment with ex vivo CSF and brain tissue. They display a successful operation across a range of conditions, with negligible reverse flow leakage. Additionally, a novel wireless pressure sensor was incorporated alongside the valve for in situ intracranial pressure measurement. The wireless pressure sensor successfully replicated standard measurements. Those evaluations show the reproducibility of the valve and sensor functions and support the system’s potential as a chronic implant to replace standard shunt systems.