About

Alan W. Flake is a Professor of Surgery in the Department of Surgery at the Children’s Hospital of Philadelphia, affiliated with the Perelman School of Medicine at the University of Pennsylvania. His educational background includes a B.S. from the University of Arkansas at Fayetteville in 1977 and an M.D. from the University of Arkansas for Medical Sciences in 1981. His professional work involves research and clinical practice related to fetal and maternal health, with a focus on prenatal therapies, maternal-fetal surgery, and congenital malformations. His contributions include developing animal models for prenatal gene therapy, exploring gene transfer techniques for fetal lung and skin conditions, and advancing surgical interventions for congenital anomalies such as diaphragmatic hernia and sacrococcygeal teratomas.

Research topics

• Engineering
• Medicine
• Engineering ethics
• Gynecology
• Pediatrics
• Psychology
• Internal medicine
• Obstetrics
• Surgery
• Biology
• Genetics

Selected publications

• Ex Utero Artificial Womb Support

  Clinics in Perinatology · 2026-04-01

  articleSenior author
  PublisherDOI

• Evaluation of an Oxygenator in the EXTra-Uterine Environment for Neonatal Development (EXTEND) System Without Systemic Anticoagulation

  ASAIO Journal · 2025-12-18 · 2 citations

  articleOpen accessSenior authorCorresponding

  An important goal in the development of an artificial womb is the avoidance of the use of heparin, due to the presumed risk of intracranial hemorrhage in premature infants. We developed the Experimental Oxygenator (Exp-Ox), featuring a small surface area and low priming volume, as an oxygenator to support the clinical application of the EXTra-uterine Environment for Neonatal Development (EXTEND) system. This study evaluated the durability and hemocompatibility of the Exp-Ox during prolonged use (exceeding 14 days) in premature lambs in the EXTEND system without systemic anticoagulation (heparin-free study) compared to the standard heparin-based EXTEND system (heparin study). Twelve animals (91-93 days gestational age) completed the study: six in the heparin and six in the heparin-free study. Oxygen and CO2 transfer per weight remained stable overall in both studies, with no significant differences observed in oxygen transfer efficiency between the studies (p = 0.61). The quantitative clot burden of the Exp-Ox on computed tomography scan images ranged from 3.91-29.94% to 1.28-11.77% in the heparin and heparin-free studies, respectively (p = 0.15, nonsignificant difference), with no correlation to study duration or oxygen transfer efficiency. The Exp-Ox sustained function and hemocompatibility for over 14 days in the EXTEND system without systemic anticoagulation.

  PublisherDOI

• Evaluation of Gas Exchange and Hemocompatibility of an Experimental Oxygenator at Anticipated Human Fetal Flow Rates in Fetal Lambs Using a Dual Oxygenator Platform in the <scp>EXTra</scp> ‐Uterine Environment for Neonatal Development ( <scp>EXTEND</scp> ) System

  Artificial Organs · 2025-07-01 · 4 citations

  articleOpen accessSenior authorCorresponding

  BACKGROUND: We previously reported the EXTEND (EXTra-uterine Environment for Neonatal Development) system provides physiologic support of fetal lambs (105-111 days gestational age; GA) via a pumpless arteriovenous circuit using a commercially available oxygenator (Maquet-Ox). However, for anticipated human subjects at 23-28 weeks of GA, a smaller oxygenator is required. To meet this requirement, a proprietary oxygenator (Experimental Oxygenator: Exp-Ox) was developed. METHODS: Fourteen lambs (mean GA 99 days, mean weight at cannulation 1.36 kg) were placed on the EXTEND system. Thereafter, Exp-Ox was connected in parallel with the Maquet-Ox, and its durability and hemocompatibility were assessed over a prolonged use of up to 21 days, utilizing a dual oxygenator platform. Blood flow to Exp-Ox was increased over time using a tubing clamp to maintain the anticipated human fetal flow rates (50-165 mL/min). RESULTS: exchange function. The pressure drop in the Exp-Ox remained unchanged over time, with no statistically significant difference, whereas the calculated Exp-Ox resistance (pressure drop/blood flow) decreased since the change in pressure drop increased at a slower rate than the increase in blood flow. The quantitative clot burden in the Exp-Ox following completion of the study ranged from 0.03% to 2.55%, with no correlation to study duration. CONCLUSIONS: The study demonstrated the Exp-Ox maintained its ability to transfer oxygen and CO2 and sustained hemocompatibility for up to 21 days at anticipated fetal flow rates on the EXTEND system.

  PublisherOA PDFDOI

• Development and validation of an ultra-low-cost, open source normothermic <i>ex vivo</i> organ perfusion platform

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-28

  preprintOpen access

  ABSTRACT Background Normothermic ex vivo organ perfusion (NEVOP) promises to catalyze organ preservation, therapeutic discovery, and organ-specific disease modeling. Existing technology platforms remain inaccessible for research due to restricted access to commercial organ perfusion devices, high costs of both devices and proprietary consumables, and steep technical learning curves. Additionally, the available technology is not optimized to perfuse smaller organs such as the kidney. Methods To overcome these barriers, a custom NEVOP circuit was developed using recycled, repurposed, and low-cost components. Porcine kidneys and autologous blood were used to iteratively optimize circuit design. A porcine kidney autotransplantation protocol was adapted to evaluate in vivo kidney function after ex vivo perfusion. To pilot the flexibility of this system as a multi-organ platform for ex vivo human biology, non-transplantable human donor kidney, spleen, and pancreas specimens were stably perfused using human blood products and analyzed. Results An ultra low-cost NEVOP system engineered to perfuse porcine kidneys and diverse human organs (kidney, pancreas, and spleen) sustained viable organs for up to 24 hours with evidence of both function and viability. Key innovations included a parallel flow resistor to facilitate low-flow perfusion in non-heparinized organs and a containment bag with adjustable magnets to provide vascular stability and recycling of venous overflow. The circuit costs less than 1,500USD to construct, and porcine kidneys perfused for 24 hours on this platform demonstrated healthy in vivo function upon autotransplantation. Conclusions Custom NEVOP platforms constitute novel and potentially transformative research platforms which use low-cost and readily available materials. Paired with access to non-transplantable research organs from altruistic donors, this model provides a road map for investigators to advance biomedical discovery and human ex vivo biology.

  PublisherOA PDFDOI

• Fetal heart and surroundings: umbilical cord traction triggers sympathetic heart rate surge in fetal lambs in the artificial womb

  Frontiers in Medicine · 2025-11-04

  articleOpen accessSenior author

  Objective: To investigate whether umbilical cord traction triggers a unique umbilico-neuro-cardio reflex via sympathetic autonomic nervous system (ANS) activation, potentially explaining fetal heart rate (FHR) increases such as the double mountain peak sign and unexplained tachycardia outside labor. Design: Experimental physiological study using the EXTrauterine Environment for Neonatal Development (EXTEND) system. Setting: Controlled laboratory environment at The Children's Hospital of Philadelphia with fetal lambs supported by the EXTEND system. Population or sample: Twenty-nine experiments were performed on three fetal lambs: 5 ANS-immature (<110 days gestational age) and 24 ANS-mature (>110 days GA), including subgroups for pharmacological intervention. Methods: Umbilical cord traction was performed in 20 experiments (5 ANS-immature, 15 ANS-mature). To investigate autonomic modulation, nine ANS-mature experiments included administration of either periumbilical capsaicin or intravenous propranolol. FHR changes were measured, and norepinephrine levels were sampled before and after interventions. Main outcome measures: Change in FHR (bpm) and circulating norepinephrine concentrations in response to umbilical cord traction and pharmacologic modulation. Results: = 0.770). Capsaicin also elevated FHR and norepinephrine, while propranolol inhibited both responses. Conclusion: Umbilical cord traction appears to activate an umbilico-neuro-cardiac reflex through sympathetic ANS pathways in ANS-mature fetuses. This mechanism may underlie clinical CTG features such as the double mountain peak sign and fetal tachycardia outside of labor.

  PublisherOA PDFDOI

• IP17-02 KIDNEY IN A BAG: A LOW-COST STRATEGY FOR ESTABLISHING PROFICIENCY IN NORMOTHERMIC EX VIVO ORGAN PERFUSION

  The Journal of Urology · 2025-04-08

  article
  PublisherDOI

• Experimental Impact of Increasing Circuit Resistance in the Artificial Womb

  Prenatal Diagnosis · 2025-04-22 · 2 citations

  articleOpen access

  OBJECTIVE: To determine the impact of controlled incremental changes in circuit blood flow resistance to the oxygenator on hemodynamics in the fetal lamb supported by the EXTrauterine Environment for Neonatal Development (EXTEND) system. METHODS: A prospective study of oxygenator circuit clamping was conducted on 7 lambs on EXTEND. Echocardiography was performed at four levels of circuit flow (250, 225, 200 and 300 mL/kg/min). Hemodynamic parameters including cardiac output, velocities and pulsatility indexes (PI) were measured, and physiological parameters were documented. RESULTS: As circuit resistance increases, combined cardiac output (CCO) declines significantly, with reduction most profoundly evident in the right ventricle with left ventricle flow preserved until reaching the lowest circuit flow level of 200 mL/kg/min. Umbilical artery (UA), umbilical vein (UV), and inferior vena cava (IVC) velocities decrease while middle cerebral artery (MCA) velocities increase. UA PI values change commensurately with changes in circuit resistance; however, MCA PI values did not change. Blood pressure and oxygen extraction elevate with increased circuit resistance, while heart rate and oxygen consumption remain unchanged. CONCLUSIONS: Fetal sheep supported by the EXTEND system undergo hemodynamic and physiological changes in response to alterations in circuit flow, reflecting physiological adaptations to maintain circulatory homeostasis.

  PublisherOA PDFDOI

• Extracorporeal Circuit for Evaluating Pharmacological Interventions in Umbilical Venous Spasm Using Porcine Umbilical Cords

  ASAIO Journal · 2025-11-14

  articleSenior authorCorresponding
  PublisherDOI

• Chronic Hypoxia in an EXTrauterine Environment for Neonatal Development Impairs Lung Development

  American Journal of Respiratory Cell and Molecular Biology · 2024-10-25 · 2 citations

  articleOpen access

  Severe fetal hypoxia poses a significant risk to lung development, resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development, we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 d gestational age) delivered by cesarean section was reduced, and animals were supported using the Extrauterine Environment for Neonatal Development through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared with their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions, with decreased macrovessel numbers and microvascular endothelial cell numbers and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB (surfactant protein B) and processed SFTPC protein expression concomitant with a decrease in alveolar type 2 cell number. These findings demonstrate that maternally independent fetal hypoxia predominantly affects distal airway development, alveolar type 2 cell number, and surfactant production, with mild effects on the vasculature.

  PublisherOA PDFDOI

• Assessment of extremely premature lambs supported by the Extrauterine Environment for Neonatal Development (EXTEND)

  Pediatric Research · 2024-06-04 · 8 citations

  articleOpen accessSenior author

  BACKGROUND: Our team has previously reported physiologic support by the EXTra-uterine Environment for Neonatal Development (EXTEND) of 105 to 117 days gestational age (GA) lambs for up to 28 days with normal organ maturation. However, the fetal lamb brain matures more rapidly, requiring the study of 90-105 day GA fetal lambs to assess more neurodevelopmentally equivalent lambs to the 23-25 week GA extreme premature infant. METHODS: Extremely preterm lambs (90-95 days of GA) were delivered by C-section and supported by EXTEND. Estimated circuit flows were maintained at around 325 ml/kg/min. After support on EXTEND, MRI and histopathologic analysis were performed and compared to 105-112 days GA control lambs. RESULTS: The extremely preterm group includes 10 animals with a mean GA of 91.6 days, a mean weight at cannulation of 0.98 kg and a mean length of stay on EXTEND of 13.5 days (10-21 days). Hemodynamics and oxygenation showed stable parameters. Animals showed growth and physiologic cardiac function. MRI volumetric and diffusion analysis was comparable to controls. Histologic brain analysis revealed no difference between study groups. CONCLUSION: EXTEND appears to support brain and cardiac development in an earlier gestation, less mature, lamb model. IMPACT: Prolonged (up to 21 days) physiological support of extremely preterm lambs of closer neurodevelopmental equivalence to the 24-28 gestational week human was achieved using the EXTEND system. EXTEND treatment supported brain growth and development in extremely preterm fetal lambs and was not associated with intraventricular hemorrhage or white matter injury. Daily echocardiography demonstrated physiologic heart function, absence of cardiac afterload, and normal developmental increase in cardiac chamber dimensions. This study demonstrates hemodynamic and metabolic support by the EXTEND system in the extremely preterm ovine model.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL064715

  NIH · $2.7M · 2011

• NIH Grant R01HL063434

  NIH · $1.4M · 2003

• NIH Grant T32HD046402

  NIH · $999k · 2010

• NIH Grant R01HL053998

  NIH · $690k · 1999

• NIH Grant R01HL073253

  NIH · $1.7M · 2007

Frequent coauthors

• N. Scott Adzick

  University of Pennsylvania

  432 shared

• Holly L. Hedrick

  Children's Hospital of Philadelphia

  276 shared

• William H. Peranteau

  Children's Hospital of Philadelphia

  219 shared

• Mark P. Johnson

  Rolls-Royce (United Kingdom)

  219 shared

• Enrico Danzer

  Stanford University

  154 shared

• Timothy M. Crombleholme

  Connecticut Children's Medical Center

  149 shared

• R. Douglas Wilson

  University of Calgary

  120 shared

• Lori J. Howell

  Children's Hospital of Philadelphia

  111 shared

Education

• B.S.

  University of Arkansas, Fayetteville

  1977

• M.D.

  University of Arkansas for Medical Sciences, Little Rock

  1981