Complement Drives Chronic Inflammation and Progressive Hydrocephalus in Murine Neonatal Germinal Matrix Hemorrhage.

Germinal matrix hemorrhage (GMH) is a pathology that occurs in infancy, with often devastating long-term consequences. Posthemorrhagic hydrocephalus (PHH) can develop acutely, while periventricular leukomalacia (PVL) is a chronic sequala. There are no pharmacological therapies to treat PHH and PVL. We investigated different aspects of the complement pathway in acute and chronic outcomes after murine neonatal GMH induced at postnatal day 4 (P4). Following GMH-induction, the cytolytic complement membrane attack complex (MAC) colocalized with infiltrating red blood cells (RBCs) acutely but not in animals treated with the complement inhibitor CR2-Crry. Acute MAC deposition on RBCs was associated with heme oxygenase-1 expression and heme and iron deposition, which was reduced with CR2-Crry treatment. Complement inhibition also reduced hydrocephalus and improved survival. Following GMH, there were structural alterations in specific brain regions linked to motor and cognitive functions, and these changes were ameliorated by CR2-Crry, as measured at various timepoints through P90. Astrocytosis was reduced in CR2-Crry-treated animals at chronic, but not acute, timepoints. At P90, myelin basic protein and LAMP-1 colocalized, indicating chronic ongoing phagocytosis of white matter, which was reduced by CR2-Crry treatment. Data indicate acute MAC-mediated iron-related toxicity and inflammation exacerbated the chronic effects of GMH.

A Role of Complement in the Pathogenic Sequelae of Mouse Neonatal Germinal Matrix Hemorrhage.

Germinal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia, and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed and characterized a mouse model of GMH based on the injection of collagenase into the subventricular zone of post-natal pups and utilized the model to investigate the role of complement in PHH development. The site-targeted complement inhibitor CR2Crry, which binds deposited C3 complement activation products, localized specifically in the brain following its systemic administration after GMH. Compared to vehicle, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Complement inhibition also improved survival and weight gain, and it improved motor performance and cognitive outcomes measured in adolescence. The progression to PHH, neuronal loss, and associated behavioral deficits was linked to the microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Thus, complement plays an important role in the pathological sequelae of GMH, and complement inhibition represents a novel therapeutic approach to reduce the disease progression of a condition for which there is currently no treatment outside of surgical intervention.

Pediatric Cranioplasty Using Hydroxyapatite Cement: A Retrospective Review and Preliminary Computational Model.

INTRODUCTION: Cranioplasty is a standard technique for skull defect repair. Restoration of cranial defects is imperative for brain protection and allowing for homeostasis of cerebral spinal fluid within the cranial vault. Calcium phosphate hydroxyapatite (HA) is a synthetic-organic material that is commonly used in cranioplasty. We evaluate a patient series undergoing HA cement cranioplasty with underlying bioresorbable mesh for various cranial defects and propose a preliminary computational model for understanding skull osteointegration. METHODS: A retrospective review was performed at the institution for all pediatric patients who underwent HA cement cranioplasty. Seventeen patients were identified, and success of cranioplasty was determined based on clinical and radiographic follow-up. A preliminary computational model was developed using bone growth and scaffold decay equations from previously published literature. The model was dependent on defect size and shape. Patient data were used to optimize the computational model. RESULTS: Seventeen patients were identified with an average age of 6 ± 5.6 years. Average defect size was 11.7 ± 16.8 cm2. Average time to last follow-up computer tomography scan was 10 ± 6 months. Three patients had failure of cranioplasty, all with a defect size above 15 cm2. The computational model developed shows a constant decay rate of the scaffold, regardless of size or shape. The bone growth rate was dependent on the shape and number of edges within the defect. Thus, a star-shaped defect obtained a higher rate of growth than a circular defect because of faster growth rates at the edges. The computational simulations suggest that shape and size of defects may alter success of osteointegration. CONCLUSION: Pediatric cranioplasty is a necessary procedure for cranial defects with a relatively higher rate of failure than adults. Here, we use HA cement to perform the procedure while creating a preliminary computational model to understand osteointegration. Based on the findings, cranioplasty shape may alter the rate of integration and lead to higher success rates.