Fetal ventriculomegaly (VM) is a defect of the central nervous system, typically diagnosed during the second-trimester ultrasound in fetuses with an atrial diameter (AD) of >10 mm. Non-isolated ventriculomegaly (NIVM) is heterogeneous in nature, coexisting with additional intracranial and/or extracranial malformations and genetic syndromes, resulting in an unfavorable prognosis for the further development of the child. Both the pregnancy management and counseling are dependent on the findings of combined ultrasound/MRI, genetic testing, and gestational age at diagnosis. The purpose of this review is to propose a hypothesis that diagnostic advancements allow to define the process of identification of the isolated forms of VM (IVM). Based on the evidence presented in the literature, we consider whether prenatal decompression for severe isolated VM (ISVM) is supported by the experimental trials and whether it might be implemented in clinical practice. Also, we describe the evolution of the diagnostic methods and expert opinions about the previously used prenatal decompression techniques for ISVM. In conclusion, we introduce the idea that fetal surgery centers have either reached or nearly reached the necessary level of expertise to perform such procedures. Endoscopic cystoventriculostomy (ETV) appears to be the most promising, as it is associated with minimal perinatal complications and favorable neurological outcomes in the neonatal period. Randomized trials with long-term neurodevelopmental follow-up of children who underwent prenatal decompression due to ISVM are necessary.

Maternal-fetal surgery is fraught with inherent controversy from within the medical community and general public. Despite these challenges, the field of maternal-fetal surgery evolved into an international enterprise. Carefully nurtured by pioneers with foresight and resilience, the field navigated ethical dilemmas with rigorous scientific methodology, collaboration, transparency, and accordance. These central pillars are consistent throughout the brief but momentous history of maternal-fetal surgery, serving as the catalyst for its success. The maturation of fetal intervention is an exemplar of technological innovation propelling clinical innovation, as well as a celebration of mastering the delicate balance between caution and optimism.

Spina bifida aperta (SBA) is one of the most common neural tube defects. Neural injury in SBA occurs in two stages involving failed neural tube closure and progressive degeneration through contact with the amniotic fluid. We previously suggested that intra-amniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for fetal rat SBA could achieve beneficial functional recovery through lesion-specific differentiation. The aim of this study is to examine whether the amniotic fluid microenvironment can be improved by intra-amniotic BMSC transplantation.

The intra-amniotic BMSC injection was performed using in vivo rat fetal SBA models. The various cytokine expressions in rat amniotic fluid were screened by protein microassays. Intervention experiments were used to study the function of differentially expressed cytokines.

A total of 32 cytokines showed significant upregulated expression in the BMSC-injected amniotic fluid. We focused on Activin A, NGF, BDNF, CNTF, and CXCR4. Intervention experiments showed that the upregulated Activin A, NGF, BDNF, and CNTF could inhibit apoptosis and promote synaptic development in fetal spinal cords. Inhibiting the activity of these factors weakened the anti-apoptotic and pro-differentiation effects of transplanted BMSCs. Inhibition of CXCR4 activity reduced the engraftment rate of BMSCs in SBA fetuses.

BMSC transplantation can improve the amniotic fluid environment, and this is beneficial for SBA repair.

While fetal surgery-and pregnancy termination as a possible therapeutic alternative-have been examined in a number of studies, very few have addressed the issues and tensions that arise when prenatal surgery is considered from the standpoint of Disability Studies. This article will expose these concerns by tracing the medical development of fetal surgery; the arguments for and against prenatal surgery; and the connections between fetal surgery, abortion, and disability rights. Like other dimensions of the life cycle that involve reproduction, prenatal surgery has become highly politicized in the United States which has, to a certain extent, stalled critical discussion. However, the skepticism with which many disability rights advocates and policymakers approach prenatal medical intervention in general has opened a new space for active debate concerning fetal surgery in terms of how it medicalizes pregnancy, pathologizes diversity, contributes to the valuation of life, and emphasizes 'perfect babies' at any cost.

Fetal surgery is a relatively new field of medicine. The purpose of this narrative review is to present the history of how fetal surgery became the standard of care for myelomeningocele (MMC), the current controversies of this treatment, and active areas of research that may change how MMC is treated. Fetal surgery for MMC emerged out of the University of California, San Francisco in the 1980s in the laboratory of Dr. Michael Harrison. Initial research focused on testing the hypothesis that the in utero repair of MMC could improve outcomes in the ovine model. Evidence from this model suggested that in utero repair decreases the secondary damage to the exposed neural tissue and improves post-natal neurologic outcomes, opening the door for human intervention. This was followed by the Management of Myelomeningocele Study (MOMS), which was a multicenter randomized controlled trial comparing the prenatal versus postnatal MMC repair. The MOMS trial was stopped early due to the improved outcomes of the prenatal repair, establishing the open fetal MMC repair as the standard of care. Since the MOMS trial, two primary areas of controversy have arisen: the operative approach and criteria for the repair. The three operative approaches include open, endoscopic and a hybrid approach combining open and endoscopic. Several of the inclusion and exclusion criteria from the MOMS trial have been challenged, to include body mass index, gestational diabetes, other fetal abnormalities, maternal infections and Rh alloimmunization. New areas of research have also emerged, exploring cell based therapies to improve fetal outcomes, alternatives to fetal surgery and alternatives to primary skin closure of the fetus.

The history of fetal surgery is one of constant evolution. Over the last 50 years, fetal surgery has progressed from a mere idea to an internationally respected innovative field of surgery. This article aims to provide a historical review of how the enterprise of maternal-fetal surgery came to be its modern version. This review is less focused on the history of specific therapies for a relatively small number of conditions, and more on how the whole field of maternal-fetal surgery evolved. The various internal and external influences that steered the field's evolution are discussed in chronologic order. Since the start of modern fetal surgery in the 1980s, large paradigm shifts have characterized the growth of the field as a whole. Innovative interventions are now based on physiologic manipulation as opposed to simple anatomic repair, fetoscopy has become the more frequently preferred surgical approach, and rigorous scientific evaluation with randomized controlled trials is now the standard expected by the community. In a very similar fashion to when the field first began in the early 1980s, recently community's leaders have risen to protect the integrity of maternal-fetal surgery by publishing ethical guidelines for innovation and clinical practice. This incredible history of innovation, rigorous science and ethical contemplation is the foundation on which modern maternal-fetal surgery rests.

Endothelial colony-forming cells (ECFCs) have been implicated in the process of vascularization, which includes vasculogenesis and angiogenesis. Vasculogenesis is a de novo formation of blood vessels, and is an essential physiological process that occurs during embryonic development and tissue regeneration. Angiogenesis is the growth of new capillaries from pre-existing blood vessels, which is observed both prenatally and postnatally. The placenta is an organ composed of a variety of fetal-derived cells, including ECFCs, and therefore has significant potential as a source of fetal ECFCs for tissue engineering.

To investigate the possibility of isolating clonal ECFCs from human early gestation chorionic villi (CV-ECFCs) of the placenta, and assess their potential for tissue engineering.

The early gestation chorionic villus tissue was dissociated by enzyme digestion. Cells expressing CD31 were selected using magnetic-activated cell sorting, and plated in endothelial-specific growth medium. After 2-3 wks in culture, colonies displaying cobblestone-like morphology were manually picked using cloning cylinders. We characterized CV-ECFCs by flow cytometry, immunophenotyping, tube formation assay, and Dil-Ac-LDL uptake assay. Viral transduction of CV-ECFCs was performed using a Luciferase/tdTomato-containing lentiviral vector, and transduction efficiency was tested by fluorescent microscopy and flow cytometry. Compatibility of CV-ECFCs with a delivery vehicle was determined using an FDA approved, small intestinal submucosa extracellular matrix scaffold.

After four passages in 6-8 wks of culture, we obtained a total number of 1.8 × 107 CV-ECFCs using 100 mg of early gestational chorionic villus tissue. Immunophenotypic analyses by flow cytometry demonstrated that CV-ECFCs highly expressed the endothelial markers CD31, CD144, CD146, CD105, CD309, only partially expressed CD34, and did not express CD45 and CD90. CV-ECFCs were capable of acetylated low-density lipoprotein uptake and tube formation, similar to cord blood-derived ECFCs (CB-ECFCs). CV-ECFCs can be transduced with a Luciferase/tdTomato-containing lentiviral vector at a transduction efficiency of 85.1%. Seeding CV-ECFCs on a small intestinal submucosa extracellular matrix scaffold confirmed that CV-ECFCs were compatible with the biomaterial scaffold.

In summary, we established a magnetic sorting-assisted clonal isolation approach to derive CV-ECFCs. A substantial number of CV-ECFCs can be obtained within a short time frame, representing a promising novel source of ECFCs for fetal treatments.

Cell-biomaterial interactions are primarily governed by cell adhesion, which arises from the binding of cellular integrins to the extracellular matrix (ECM). Integrins drive the assembly of focal contacts that serve as mechanotransducers and signaling nexuses for stem cells, for example integrin α4β1 plays pivotal roles in regulating mesenchymal stem cell (MSC) homing, adhesion, migration and differentiation. The strategy to control the integrin-mediated cell adhesion to bioinspired, ECM-mimicking materials is essential to regulate cell functions and tissue regeneration. Previously, using one-bead one-compound (OBOC) combinatorial technology, we discovered that LLP2A was a high-affinity peptidomimetic ligand (IC50 = 2 pM) against integrin α4β1. In this study, we identified that LLP2A had a strong binding to human early gestation chorionic villi-derived MSCs (CV-MSCs) via integrin α4β1. To improve CV-MSC seeding, expansion and delivery for regenerative applications, we constructed artificial scaffolds simulating the structure of the native ECM by immobilizing LLP2A onto the scaffold surface as cell adhesion sites. LLP2A modification significantly enhanced CV-MSC adhesion, spreading and viability on the polymeric scaffolds via regulating signaling pathways including phosphorylation of focal adhesion kinase (FAK), and AKT, NF-kB and Caspase 9. In addition, we also demonstrated that LLP2A had strong binding to MSCs of other sources, such as bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs). Therefore, LLP2A and its derivatives not only hold great promise for improving CV-MSC-mediated treatment of fetal diseases, but they can also be widely applied to functionalize various biological and medical materials, which are in need of MSC recruitment, enrichment and survival, for regenerative medicine applications.

Prenatal stem cell-based regenerative therapies have progressed substantially and have been demonstrated as effective treatment options for fetal diseases that were previously deemed untreatable. Due to immunoregulatory properties, self-renewal capacity, and multilineage potential, autologous human placental chorionic villus-derived mesenchymal stromal cells (CV-MSCs) are an attractive cell source for fetal regenerative therapies. However, as a general issue for MSC transplantation, the poor survival and engraftment is a major challenge of the application of MSCs. Particularly for the fetal transplantation of CV-MSCs in the naturally hypoxic fetal environment, improving the survival and engraftment of CV-MSCs is critically important. Hypoxic preconditioning (HP) is an effective priming approach to protect stem cells from ischemic damage. In this study, we developed an optimal HP protocol to enhance the survival and proangiogenic capacity of CV-MSCs for improving clinical outcomes in fetal applications. Total cell number, DNA quantification, nuclear area test, and cell viability test showed HP significantly protected CV-MSCs from ischemic damage. Flow cytometry analysis confirmed HP did not alter the immunophenotype of CV-MSCs. Caspase-3, MTS, and Western blot analysis showed HP significantly reduced the apoptosis of CV-MSCs under ischemic stimulus via the activation of the AKT signaling pathway that was related to cell survival. ELISA results showed HP significantly enhanced the secretion of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by CV-MSCs under an ischemic stimulus. We also found that the environmental nutrition level was critical for the release of brain-derived neurotrophic factor (BDNF). The angiogenesis assay results showed HP-primed CV-MSCs could significantly enhance endothelial cell (EC) proliferation, migration, and tube formation. Consequently, HP is a promising strategy to increase the tolerance of CV-MSCs to ischemia and improve their therapeutic efficacy in fetal clinical applications.

To investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering.

PMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis.

We determined that an average of 2.09 × 10(6) (SD ± 8.59 × 10(5)) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 10(3). Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation.

Our findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.

Congenital diaphragmatic hernia (CDH) retains high mortality and morbidity due to lung hypoplasia, pulmonary hypertension and severe co-existent anomalies. This article offers a comprehensive state-of-the-art review for the paediatric surgeon whilst also describing key contributions from the basic sciences in the search to uncover the cause of the birth defect together with efforts to develop new and better therapies for CDH.

Fetal diagnosis prompts the question for fetal therapy in highly selected cases. Some conditions are suitable for in utero surgical intervention. This paper reviews historically important steps in the development of fetal surgery. The first invasive fetal intervention in 1963 was an intra-uterine blood transfusion. It took another 20 years to understand the pathophysiology of other candidate fetal conditions and to develop safe anaesthetic and surgical techniques before the team at the University of California at San Francisco performed its first urinary diversion through hysterotomy. This procedure would be abandoned as renal and pulmonary function could be just as effectively salvaged by ultrasound-guided insertion of a bladder shunt. Fetoscopy is another method for direct access to the feto-placental unit. It was historically used for fetal visualisation to guide biopsies or for vascular access but was also abandoned following the introduction of high-resolution ultrasound. Miniaturisation revived fetoscopy in the 1990 s, since when it has been successfully used to operate on the placenta and umbilical cord. Today, it is also used in fetuses with congenital diaphragmatic hernia (CDH), in whom lung growth is triggered by percutaneous tracheal occlusion. It can also be used to diagnose and treat urinary obstruction. Many fetal interventions remain investigational but for a number of conditions randomised trials have established the role of in utero surgery, making fetal surgery a clinical reality in a number of fetal therapy programmes. The safety of fetal surgery is such that even non-lethal conditions, such as myelomeningocoele repair, are at this moment considered a potential indication. This, as well as fetal intervention for CDH, is currently being investigated in randomised trials.

Recent surgical advances have resulted in fetal surgery becoming an option for children with myelomeningocele (MMC). However, there is little information about the parents' attitudes towards such therapy.

Following a lecture on the current status and problems of fetal surgery for MMC, a 12-item questionnaire was administered to 58 parents of children with MMC. Questionnaire topics included knowledge of the disease and treatment options, as well as attitudes and concerns towards fetal surgery or termination of pregnancy.

Following the lecture, 14 (out of 58) parents felt that knowledge of the disease would allow for abortion to be an option, while 18 were uncertain. Once informed of potential risks and benefits of fetal surgery, 34 parents had a positive or rather positive attitude towards this procedure.

On the basis of these results, it was concluded that this population is potentially interested in the use of fetal surgery.

The clinical course of primary fetal hydrothorax is unpredictable. Whereas smaller unilateral effusions might remain stable or even regress, this is rarely the case with larger collections. Bilateral effusions, hydrops, preterm delivery and the lack of antenatal therapy are all associated with poor outcome. Once structural and chromosomal anomalies have been excluded, optimal management depends on gestational age, rate of progression, the development of hydrops and associated maternal symptoms. For very large effusions with mediastinal shift, hydrops and/or hydramnios, or when there is rapid enlargement of the effusion, fetal intervention is warranted. Survival can be maximized by pleuroamniotic shunting, which can reverse hydrops and hydramnios and prevent pulmonary hypoplasia. Pleuroamniotic shunting can also be used for the treatment of other large cystic lung lesions, such as a macrocystic congenital cystic adenomatoid malformation or bronchopulmonary sequestration, especially when associated with hydrops.