Fabrication of three-dimensional hydrogel scaffolds for modeling shunt failure by tissue obstruction in hydrocephalus

Abstract

BackgroundShunt obstruction in the treatment of hydrocephalus is poorly understood, is multi-factorial, and in many cases is modeled ineffectively. Several mechanisms may be responsible, one of which involves shunt infiltration by reactive cells from the brain parenchyma. This has not been modeled in culture and cannot be consistently examined in vivo without a large sample size.MethodsWe have developed and tested a three-dimensional in vitro model of astrocyte migration and proliferation around clinical grade ventricular catheters and into catheter holes that mimics the development of cellular outgrowth from the parenchyma that may contribute to shunt obstruction.ResultsCell attachment and growth was observed on shunt catheters for as long as 80 days with at least 77 % viability until 51 days. The model can be used to study cellular attachment to ventricular catheters under both static and pulsatile flow conditions, which better mimic physiological cerebrospinal fluid dynamics and shunt system flow rates (0.25 mL/min, 100 pulses/min). Pulsatile flow through the ventricular catheter decreased cell attachment/growth by 63 % after 18 h. Under both conditions it was possible to observe cells accumulating around and in shunt catheter holes.ConclusionsAlone or in combination with previously-published culture models of shunt obstruction, this model serves as a relevant test bed to analyze mechanisms of shunt failure and to test catheter modifications that will prevent cell attachment and growth.

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure

“…Recent long-term in vivo data collected in our lab indicate that inflammatory astrocytes are ubiquitous on all shunts; they make up more than 21% of cells bound to obstructed shunts, and of the occluded masses blocking ventricular catheter holes, a vast majority of the cells are astrocytes, and their number and reactivity peak on failed shunts. Our data corroborate other reports suggesting that inflammatory astrocyte activation on shunts is correlated to a change in flow rate through the shunt holes and indirectly, the shear rate through these holes 10 , 15 – 17 . Astrocytes have an increased attachment propensity in vitro with increasing flow-induced shear stress.…”

Response of Astrocytes to Blood Exposure due to Shunt Insertion in vitro

“…This fluid buildup can be caused by an imbalance between the production and absorption of the CSF within the brain with the root variable etiology, including precursors such as hemorrhage, congenital malformations, and tumors (1),(2), (5) . Treatment typically involves the insertion of a shunt system, including a shunt catheter into the brain's ventricular space to drain excess CSF (6) . Shunt failure is one of the highest among all neurological devices with 40-50% requiring revision within the first two years and 80% within 10 years (7), (8) .…”

“…Shunt failure is one of the highest among all neurological devices with 40-50% requiring revision within the first two years and 80% within 10 years (7), (8) . Obstruction of the ventricular catheter accounts for 70% of shunt failures, which makes it the most prevalent failure modality compared to infection, over-drainage, and loculated ventricles (6) . The dominant cell types involved in the blocking of these holes are astrocytes and cells of the monocyte-macrophage lineage, suspected to be due to inflammatory stimuli (6),( 9), (10) .…”

“…An inflammatory response occurs within the ventricles following the infiltration of blood, which stimulates the activation of astrocytes and microglia (10), (19) . This astrocyte and microglia activation is maintained for up to 28 days post shunt insertion (20) .…”

“…Glial activation is a result of various cytokines and growth factors produced by the activated microglia and leads to the rapid proliferation of astrocytes (20)- (22) . In response to this activation, an astrocyte layer is created to cover the denuded areas, from loss of ependymal cells, which was shown to increase cellular migration and attachment to the shunt surface (19), (23) . Blood within the CSF has been shown, in vivo , to cause an increase in shunt obstruction causing failure making up 34.8% of shunt revisions (24) .…”