Intracisternal BioGlue injection in the fetal lamb: a novel model for creation of obstructive congenital hydrocephalus without additional chemically induced neuroinflammation

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>The authors hypothesized that new agents such as BioGlue would be as efficacious as kaolin in the induction of hydrocephalus in fetal sheep.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>This study was performed in 34 fetal lambs randomly divided into 2 studies. In the first study, fetuses received kaolin, BioGlue (2.0 mL), or Onyx injected into the cisterna magna, or no injection (control group) between E85 and E90. In the second study, fetuses received 2.0-mL or 2.5-mL injections of BioGlue into the cisterna magna between E85 and E90. Fetuses were monitored using ultrasound to assess lateral ventricle size and progression of hydrocephalus. The fetuses were delivered (E120–E125) and euthanized for histological analysis. Selected brain sections were stained for ionized calcium binding adaptor 1 (Iba1) and glial fibrillary acidic protein (GFAP) to assess the presence and activation of microglia and astroglia, respectively. Statistical comparisons were performed with Student’s t-test for 2 determinations and ANOVA 1-way and 2-way repeated measures for multiple determinations.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>At 30 days after injection, the lateral ventricles were larger in all 3 groups that had undergone injection than in controls (mean diameter in controls 3.76 ± 0.05 mm, n = 5). However, dilatation was greater in the fetuses injected with 2 mL of BioGlue (11.34 ± 4.76 mm, n = 11) than in those injected with kaolin (6.4 ± 0.98 mm, n = 7) or Onyx (5.7 ± 0.31 mm, n = 6) (ANOVA, *p ≤ 0.0001). Fetuses injected with 2.0 mL or 2.5 mL of BioGlue showed the same ventricle dilatation but it appeared earlier (at 10 days postinjection) in those injected with 2.5 mL. The critical threshold of ventricle dilatation was 0.1 for all the groups, and only the BioGlue 2.0 mL and BioGlue 2.5 mL groups exceeded this critical value (at 30 days and 18 days after injection, respectively) (ANOVA, *p ≤ 0.0001)<jats:italic>.</jats:italic> Moderate to severe hydrocephalus with corpus callosum disruption was observed in all experimental groups. All experimental groups showed ventriculomegaly with significant microgliosis and astrogliosis in the subventricular zone around the lateral ventricles. Only kaolin resulted in significant microgliosis in the fourth ventricle area (ANOVA, *p ≤ 0.005).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The results of these studies demonstrate that BioGlue is more effective than Onyx or kaolin for inducing hydrocephalus in the fetal lamb and results in a volume-related response by obstructive space-occupancy without local neuroinflammatory reaction. This novel use of BioGlue generates a model with potential for new insights into hydrocephalus pathology and the development of therapeutics in obstructive hydrocephalus. In addition, this model allows for the study of acute and chronic obstructive hydrocephalus by using different BioGlue volumes for intracisternal injection.</jats:p></jats:sec>

In vitro and in vivo assessment of a novel ultra-flexible ventriculoamniotic shunt for treating fetal hydrocephalus

“…1.25 mL of BioGlue (CryoLife, Kwennesay GA) is injected over 20 s since BioGlue has an advantage that it does not travel retrograde into the ventricular system. 26,27 The needle is withdrawn. If twins, the left or right ear is tagged with 2-0 silk suture to maintain identity.…”

Fetal Endoscopic Third Ventriculostomy Is Technically Feasible in Prenatally Induced Hydrocephalus Ovine Model

“…Measurements were performed in the true axial plane in the atria of the lateral ventricle and the glomus of the choroid plexus (CP), as previously described. 16 The lateral ventricular diameter was measured from the inner margin of the medial ventricular wall to the inner margin of the lateral wall, the biparietal diameter was measured from the more external parietal bone point in one side to the contralateral one, and finally, the ratio between the lateral ventricular diameter and the biparietal diameter was calculated based on observed measurements.…”

“…HCP severity was calculated using the Cincinnati Hydrocephalus Severity Scale, recently described by our group 16 (Supplementary-data 1, http://links.lww.com/NEU/D580).…”

“…13 Isolated HCP without associated genetic anomalies includes congenital aqueduct stenosis, Chiari II malformation with myelomeningocele, and Dandy-Walker syndrome. 15 The aim of this study, using this HCP-induced fetal lamb model that we recently described and validated, 16 was to test the feasibility of fetal ETV and optimize this technique as an initial way for future translation to human clinic.…”

The Sheep as a Comprehensive Animal Model to Investigate Interdependent Physiological Pressure Propagation and Multiparameter Influence on Cerebrospinal Fluid Dynamics

“…Sheep have also previously been used to study hydrocephalus and CSF physiology ( Di Rocco et al, 1977 , 1978 ; Cambria et al, 1984 ; Di Trapani et al, 1990 ; De Keersmaecker et al, 2005 ; Johnston et al, 2013 ; Duru et al, 2019 ; Oria et al, 2019 ; Emery et al, 2020 ). However, little can be found in current literature describing physiologic values for the CSF space and the adjacent compartments in sheep.…”