Biomedical subjects
Publications and source records attributed to A W Flake.
Development of fetal animal models for congenital anomalies helps elucidate the pathophysiological consequences of the disease process as well as the efficiency of prenatal intervention in ameliorating the disease. The experimental work that supports the pathophysiological rationale for in-utero correction of diaphragmatic hernia and urinary tract obstruction is reviewed in this article.
The aim of this study was to determine the accuracy of a new computer-assisted stereological technique in obtaining structural information of the lung. We compared the point fraction of lung parenchyma (Pp) and alveolar surface density (Sv) obtained by established manual point/intercept counting methods and compared them with those obtained using a computer-assisted method. Lung tissues obtained from normally grown fetal sheep (n = 6) and from newborn lambs with severe lung hypoplasia (n = 5) were inflation fixed via the trachea and processed for light microscopy. In verification-of-technique experiments, Pp and Sv correlated well with known values. There was a significant linear correlation between manual and computer-assisted stereological measurements for values of Pp (r2 = 0.92) and Sv (r2 = 0.98). Our data lead us to believe that the computer-assisted stereological technique described in this study provides accurate estimates of Pp and Sv and hence may be a valuable tool for evaluating the effects of factors upon structural development of the lung.
Prenatal transplantation of stem cells is an exciting frontier for the treatment of many congenital diseases. The fetus may be an ideal recipient for stem cells, as it is immunologically immature and has rapidly proliferating cellular compartments that may support the engraftment of transplanted cells. Mesenchymal stem cells (MSC), given their ability to differentiate into multiple cell types, could potentially be used to treat diseases such as osteogenesis imperfecta, muscular dystrophy, and other mesenchymal disorders that can be diagnosed in utero. We have shown, using a human-sheep in utero xenotransplantation model, that human MSC have the ability to engraft, undergo site-specific differentiation into multiple cell types, and survive for more than 1 year in fetal lamb recipients. In addition, in this model MSC-derived cells appear to be present in increased numbers in wounded or regenerating tissues. This observation warrants further studies of the biology of MSCs following systemic or site-directed transplantation.
Fetal imaging is integral to the past, present, and future of fetal intervention. In the early history of fetal intervention, the role of prenatal ultrasound was primarily to identify a fetal lesion, provide a correct anatomic diagnosis, and exclude other anatomic defects. We now depend on ultrasound, and other imaging studies, not only to provide anatomic information, but to provide prognostic, physiologic and functional information prior to, during, and after surgery for optimal selection and management of fetal surgery patients. In the future improvements in imaging and non-invasive technology will drive further expansion of indications and therapeutic options for fetal intervention.
A fetus with congenital high airway obstruction syndrome (CHAOS) due to complete tracheal atresia was referred at 31 weeks of gestation after 12 weeks of massive hydrops. The fetus was delivered by the ex utero intrapartum treatment procedure allowing sufficient time while on placental support for bronchoscopy to confirm tracheal atresia and tracheostomy to secure the airway. His postnatal course was complicated by severe capillary leak syndrome secondary to hydrops, diaphragmatic paralysis, tracheobronchial malacia, and the need for chronic ventilatory support. The infant's tracheobronchial malacia resolved by 5 months of age and normal diaphragmatic function was restored at 9 months allowing him to be weaned from mechanical ventilation. He underwent tracheal reconstruction at 17 months of age. At follow up at 32 months of age he has a patent airway and is the first long-term survivor with CHAOS.
Transplantation of fetal hematopoietic stem cells is a new therapy for fetuses diagnosed in utero with inherited disorders. However, prior to transplantation of fetal stem cells, the cells must be free of microbial contamination. In order to investigate the contamination of human fetal liver tissue, we determined the rate and types of bacterial and fungal contamination of human fetal liver tissue collected transvaginally for use in stem cell transplantation by using the US Pharmacopoiea Assay. We found a high rate of contamination with bacteria or fungi (12 of the 14 fetal livers, or 85%). Non-fermenting gram-negative rods were the predominant contaminants. The high rate of microbial contamination of fetal tissue suggests that techniques for tissue collection need to be improved before fetal stem cells are used for clinical transplantation.