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J Neurosurg Pediatr. 2019 Sep 27:1-11. doi: 10.3171/2019.6.PEDS19141. [Epub ahead of print]

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

Author information

1Center for Fetal and Placental Research, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio.
3Department of Pediatric Surgery, Hospital Bambino Gesu, Rome, Italy.
4Department of Pediatric Surgery, Pontificia Universidad Católica de Chile, Santiago, Chile; and.
5Department of Pediatric Surgery, Hospital La Paz, Madrid, Spain.
2Jesus Usón Minimally Invasive Surgery Centre (JUMISC), Caceres, Spain.



The authors hypothesized that new agents such as BioGlue would be as efficacious as kaolin in the induction of hydrocephalus in fetal sheep.


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.


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). 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).


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.


BPD = biparietal diameter; BSA = bovine serum albumin; BioGlue; CHSS = Cincinnati Hydrocephalus Severity Scale; GFAP = glial fibrillary acidic protein; HC = head circumference; Iba1 = ionized calcium binding adaptor 1; JUMISC = Jesus Usón Minimally Invasive Surgery Centre; LVD = lateral ventricle diameter; Onyx; SVZ = subventricular zone; congenital hydrocephalus; experimental model; fetal lamb; kaolin; neuroinflammation; ventriculomegaly


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