Faculty Bibliography

OBJECTIVE/UNASSIGNED:Prior clinical findings have demonstrated that maternal laparotomy with trans-amniotic trans-uterine suturing of the fetoscopic port site during in utero myelomeningocele repair reduces the risk of membrane rupture. However, due to laparotomy-associated morbidity, we aimed to explore the feasibility of using a vascular closure device for percutaneous trans-amniotic trans-uterine suturing. METHODS/UNASSIGNED:cannula over the same guidewire. Samples of the sutured uterine wall were sent to pathology and H&E staining was performed to assess uterine hole closure and amnion-to-uterus fixation. RESULTS/UNASSIGNED:device effectively sutured the amnion to the uterus in both the pre- and post-close approach. The pre-close technique achieved better amnion-to-uterus approximation and more appropriate uterine hole closure. H&E staining revealed that without suturing, amnion separation from the chorion layer occurred, and the uterine hole persisted. The post-close technique showed partial connection between the amnion and chorion, but inadequate uterine hole closure with amnion shift into the defect. Optimal closure, with secure amnion-to-chorion fixation and uterine closure, was achieved through the pre-close technique. CONCLUSION/UNASSIGNED:Device seems to be a feasible device for use of uterine port closure in maternal-fetal surgery, larger animal studies with mid-pregnancy application are needed to further validate or refute these findings.

INTRODUCTION/BACKGROUND:Perinatal management of gastroschisis remains a subject of substantial research. Current models, including teratogenic, genetic, and surgical approaches, often fail to accurately replicate gastroschisis, exhibiting limitations such as inaccurate phenotyping, low success rates, high mortality, lack of scientific validation, and significant technical challenges. Refined disease models are essential for improving the understanding of GS. This study seeks to develop and validate a minimally invasive transuterine experimental model of GS that overcomes these existing constraints to advance gastroschisis research. METHODS:A gastroschisis model was surgically created in rat fetuses at E17 (n = 51 fetuses from n = 13 dams). Intestines were harvested at term and divided into herniated gastroschisis (GS-H), intra-abdominal gastroschisis (GS-I), and control (Co) groups. Morphometric analysis, histopathological examination, immunohistochemistry for interstitial cells of Cajal (ICC), double immunofluorescence for ICC and mast cells, TUNEL assay for apoptotic cells, and multiplex cytokine assay were performed to assess intestinal architecture, inflammation, ICC network, apoptosis, and cytokine levels across studied groups. RESULTS:Histology from GS intestines revealed subchronic inflammation, peel formation, and architectural disruption. Herniated intestines exhibited a significantly increased weight/length ratio and thicker outer layers (p < 0.001) compared with control intestines. Herniated intestines had elevated inflammatory cytokine levels (GS-H vs GS-I and Co, p < 0.05 for G-CSF, GM-CSF, IL-12p70, IL-1beta) and increased apoptotic activity. CONCLUSIONS:We developed and validated a new surgical model of GS that offers improved survival and feasibility. The key morphological changes and molecular markers observed in this experimental model resemble human gastroschisis.

INTRODUCTION/BACKGROUND:This study evaluated whether comorbidities such as genetic conditions, other congenital anomalies, infection, and other exposures impact the mortality rate and/or neurologic outcomes of patients with congenital ventriculomegaly. METHODS:This was a retrospective cohort study that assessed the mortality rate and developmental delay of 91 patients diagnosed with congenital ventriculomegaly followed at Cincinnati Children's Hospital Medical Center between January 1, 2010, and December 31, 2020. RESULTS:Of the 91 patients included in the study, 20 (22.0%) had a genetic diagnosis. The mortality rate was higher for patients with a genetic diagnosis compared to those without a genetic diagnosis (p = 0.022), as was the rate of developmental delay (p = 0.026). The presence of comorbidities (confirmed genetic condition, confirmed maternal exposures or infections, and/or additional anomalies) was not associated with an increased risk of mortality nor developmental delay. CONCLUSIONS:Patients diagnosed with congenital ventriculomegaly and a genetic condition have a significantly higher risk of early mortality and developmental delay compared to those without a genetic diagnosis. Therefore, diagnostic genetic testing should be considered after identification of congenital ventriculomegaly to facilitate counseling about prognosis and care management.

OBJECTIVE:The objective of this study was to describe the technical aspects and postnatal neurosurgical outcomes of a prenatal, 3-miniport fetoscopic myelomeningocele (MMC) repair technique providing a multilayered closure using cryopreserved decellularized human umbilical cord (HUC) matrix allograft for duraplasty. METHODS:The authors conducted a subanalysis of an ongoing prospective cohort study analyzing the neurosurgical outcomes of 57 of 92 consecutive patients who underwent multilayered fetoscopic surgical MMC repair using HUC matrix allograft for duraplasty at their institution from December 2016 to March 2022, including more than 24 months of postnatal follow-up. RESULTS:Of 92 patients who underwent fetoscopic MMC repair, 88 had duraplasty using cryopreserved HUC matrix allograft. Fifty-seven patients had at least 24 months of follow-up data. The mean gestational age at the time of surgical repair was 24.8 ± 0.7 weeks. The average operative time from skin incision to closure was 260 ± 43.4 minutes, in which 79% of this time was used for the fetoscopic portion. No patient required intraoperative emergency delivery. At birth, there were no cases of CSF leak or complete wound dehiscence. Six (11.5%) of 52 patients experienced superficial wound dehiscence, and only 2 (3.5%) required surgical revision. At 30 months, 54.8% of patients were noted to be independent ambulators, 35.5% were therapeutic ambulators, and 9.7% remained wheelchair users in this subset of patients. The rate of hydrocephalus requiring CSF diversion was 35.3%, and 84.3% of patients had complete reversal of hindbrain herniation at birth. Eight (15.7%) of 51 patients had spinal inclusion cysts noted on routine follow-up spinal imaging, but only 2 (3.9%) required surgical intervention due to radiological progression without neurological symptoms. CONCLUSIONS:A laparotomy-assisted, 3-miniport fetoscopic approach for prenatal MMC multilayered repair offers excellent access and visualization for an effective watertight closure. The use of HUC matrix allograft as a dural substitute was shown to be effective with a low rate of neurosurgical postnatal complications.

BACKGROUND:Congenital hydrocephalus (HCP) is a prevalent condition, that leads to fetal cerebral ventricle dilation and increased intracranial pressure. It is associated with significant neurological impairments, partly due to the disruption of neurogenesis and gliogenesis. This study aims to investigate alterations in the proliferation and differentiation of neural progenitor cells (NPCs) in a fetal lamb model of obstructive HCP induced by intracisternal BioGlue injection, to identify the potential optimal intervention time for prenatal surgery. METHODS:This study involved 22 fetal lambs, divided into control (n = 10) and HCP (n = 12) groups with hydrocephalus induced at approximately 85-90 gestational days. Histological and molecular techniques, including hematoxylin and eosin staining, triple immunofluorescence, Western blot analysis, and RT-qPCR, were utilized to assess changes in NPCs, astrocytes, and oligodendrocytes across three different gestational stages (E105, E125, and E140). The analysis of data was done by using multiple (unpaired) two-sample t-test and was represented as mean and standard deviation. RESULTS:HCP led to significant disruptions in the ventricular zone (VZ), with the translocation of NPCs into the intraventricular CSF and formation of periventricular heterotopias. This study revealed an initial surge in the expression of NPC markers (Pax6 and Sox2), which decreased as HCP progressed. Astroglia reaction intensified, as indicated by increased expression of GFAP, vimentin, and aquaporin 4, particularly at later stages of pregnancy (p < 0.001, p < 0.001 and p < 0.001, control and HCP E140, respectively). Myelin formation was also adversely affected, with reduced expression of oligodendrocyte markers (Olig2 and Sox10, p = 0.01 and p = 0.009, control and HCP E140, respectively) and myelin proteins (MOBP, MOG and MBP, p = 0.02, p = 0.049 and p = 0.02 control and HCP E140, respectively). CONCLUSIONS:This study contributed to clarify the profound impact of congenital HCP on neurogenesis and gliogenesis in an experimental fetal lamb model. The VZ disruption and altered expression of key neurogenic and glial markers suggested a significant pathological process underlying neurodevelopmental abnormalities. The findings suggested a potential window for prenatal surgical intervention between E105 and E125 in the sheep model, offering new avenues for prenatal therapeutic approaches and improving surgical outcomes in affected fetuses and neonates.

Congenital aqueduct stenosis AS is a significant cause of fetal obstructive hydrocephalus, characterized by the obliteration of the cerebral aqueduct, leading to cerebrospinal fluid (CSF) accumulation in the ventricular system and secondary brain damage and cerebral maldevelopment. This review explores the progression from basic science to clinical applications of antenatal surgical interventions for AS, emphasizing historical efforts, current research, and translational studies. Despite advances in prenatal imaging and genetic screening, challenges remain in achieving appropriate fetal candidates, consistent ventricular decompression, and standardized surgical protocols. This review highlights the need for further research and innovation to improve prenatal treatment and outcomes for AS-affected fetuses.

OBJECTIVE:Normal Saline (NS) and Lactated Ringer's (LR) damage human amniotic epithelium in vitro when compared with a synthetic amniotic fluid (Amnio-well, AW). We sought to evaluate the effect of amnio-exchange with NS, LR, and AW in vivo. METHODS:On day E17.5, pregnant rats underwent amnio-exchange with NS, LR, or AW. Fetuses in each pregnant rat that did not undergo amnio-exchange acted as controls. Amnions were harvested at E20.5 and ultrastructure evaluated via electron microscopy. Protein levels of cleaved matrix metalloproteinase 9 (MMP9) and collagen 1 (Col1a) were evaluated via Western Blot. Connexin-43 expression was evaluated via immunofluorescence (IF). RESULTS:There was an increase in amnion microfractures and epithelial cellular shrinkage with NS and LR compared with control and AW. The cleaved MMP9/Col1 ratio was increased 3.9-fold in NS (p < 0.001) and 4.5-fold LR (p = 0.0201) relative to control, whereas AW expression was similar to control (p = 0.636). Connexin-43 was also increased on IF in NS and LR relative to AW (mean gray intensity 26.5 ± 4.5, 26.5 ± 6.7, 19.2 ± 3.4, p < 0.001). CONCLUSION:Amnio-exchange with NS and LR led to increased amniotic microfractures and collagen degradation compared with synthetic amniotic fluid. Larger models are warranted to validate or refute these findings.

Myelomeningocele (MMC) is a congenital birth defect of the spine and spinal cord, commonly treated clinically through prenatal or postnatal surgery by repairing the unclosed spinal canal. Having previously developed a PLA/PCL polymer smart patch for this condition, we aim to further expand the potential therapeutic options by providing additional cellular and biochemical support in addition to its mechanical properties. Bone morphogenetic proteins (BMPs) are a large class of secreted factors that serve as modulators of development in multiple organ systems, including the CNS. We hypothesize that our smart patch mitigates the astrogenesis induced, at least partly, by increased BMP activity during MMC. To test this hypothesis, neural stem or precursor cells were isolated from rat fetuses and cultured in the presence of Noggin, an endogenous antagonist of BMP action, with recombinant BMPs. We found that the developed PLA/PCL patch not only serves as a biocompatible material for developing neural stem cells but was also able to act as a carrier for BMP-Notch pathway inhibitor Noggin, effectively minimizing the effect of BMP2 or BMP4 on NPCs cultured with the Noggin-loaded patch.