About this work package
In this work package we assess our technical achievements in a preclinical and eventually clinical environment. We follow a sequence of initial testing in mock-up models of animals, continue in dedicated animal experiments, for the study of feasibility, efficacy and safety before moving into the clinic. In order to adhere to the 3Rs and to responsibly limit the use of animals, we have created in-silico models as well as virtual reality simulators for testing of novel surgical instruments for clinical applications such as spina bifida and twin-to-twin transfusion syndrome. We are also making use of human ex-vivo tissue to test our photoacoustic imaging probes. Animal models are utilised for trialling a novel needle tracking system for ultrasound-guided procedures and optimal protocols for fetoscopic spina bifida repair.
Successful therapy of twin‐to‐twin transfusion syndrome requires accurate imaging to guide laser photocoagulation of the anastomosing placental vessels. Photoacoustic (PA) imaging is an alternative imaging method that provides contrast for hemoglobin, and in this study, it was used to visualize chorionic superficial and subsurface vasculature in human placentas. The strong potential of PA imaging to guide minimally invasive fetal therapies was demonstrated.
Professor Jan Deprest
Work package tasks
Minimally invasive fetal interventions require accurate imaging from inside the uterine cavity. Twin-to-twin transfusion syndrome (TTTS) occurs from abnormal vascular anastomoses in the placenta that allow blood to flow unevenly between the fetuses. Currently, TTTS is treated fetoscopically by identifying the anastomosing vessels, and then performing laser photocoagulation. However, white light fetoscopy provides limited visibility of placental vasculature, which can lead to missed anastomoses or incomplete photocoagulation. Photoacoustic (PA) imaging is an alternative imaging method that provides contrast for hemoglobin, and we have developed two PA systems to visualize chorionic (fetal) superficial and subsurface vasculature in human placentas. The first system comprises an optical parametric oscillator for PA excitation and a 2D Fabry-Pérot cavity ultrasound sensor; the second, light emitting diode arrays and a 1D clinical linear-array ultrasound imaging probe. Volumetric photoacoustic images have been acquired from ex vivo normal term and TTTS-treated placentas. Superficial and subsurface branching blood vessels could be visualized to depths of approximately 7 mm, and ablated tissue yielded negative image contrast, demonstrating the strong potential of PA imaging to guide minimally invasive fetal therapies.
Ultrasonic tracking and navigation
Ultrasonic tracking is a solution that has recently been the focus of intense development. With this method, there is ultrasonic communication between the external ultrasound probe and a miniature transducer (either an ultrasound transmitter or a receiver) integrated within the medical device. The medical device can be localised from measurements of the transmission times between the transducer and different elements of the probe.
We have pioneered the development of ultrasonic tracking with a novel fibre-optic ultrasound transducer (receiver or transmitter). Compared to conventional piezoelectric ultrasound transducers, the fibre-optic counterpart has a number of distinct advantages including broad bandwidth, omnidirectionality, high level of miniaturisation, and low cost. The feasibility of the technological platform has been validated with preclinical studies and we are now preparing for a first-in-human study in 2021.
Virtual Reality Simulator for Twin to Twin Transfusion Syndrome: a Training and Virtual Prototyping tool
Smaller incisions and reduced surgical trauma made minimally invasive surgery (MIS) grow in popularity even though long training is required to master the instrument manipulation constraints. While numerous training systems have been developed in the past, very few of them tackled fetal surgery and more specifically the treatment of twin-to-twin transfusion syndrome (TTTS). To address this lack of training resources, this research presents a novel mixed-reality surgical trainer equipped with comprehensive sensing for TTTS procedures. Our trainer combines the benefits of box trainer technology and virtual reality systems. Face and content validity of the developed setup was assessed by asking surgeons from the field of fetal MIS to accomplish specific tasks on the trainer.
The trainer was deemed sufficiently realistic and its proposed tasks relevant for practicing the required motor skills. The user experiments demonstrated that the motion and force sensing capabilities of the trainer were able to analyse surgical skill.
Low Fidelity In-silico Spina Bifida Repair training model with Embedded Sensing
Considering the complexity of fetoscopic spina bifida repair and the severe consequences in case of failure, a surgeon must undergo intensive training. Good training models are scarce and driven by the principle of the three Rs (replace, reduce, refine) to minimise the amount of animal trials in biomedical research. Hence, we aim to develop a synthetic training model with embedded sensing. This training model can be used to practice the minimally invasive Spina Bifida repair procedure repeatedly. After every training session, the synthetic defect site that was used can be easily replaced to prepare the model for a new intervention. Embedded sensing allows crucial performance parameters to be measured, which can be used to optimise the surgeon’s technique and review over multiple surgeries allows a learning curve of the surgeon to be established.
In this task, a spina bifida defect site has been made using silicon material and placed inside a uterus model for single port fetoscopic repair. The defect site is replaceable after each practice session. The model will be used to start a new study to train novice and expert surgeons and also to compare use of 2D versus 3D fetoscope.
Validation of a high-fidelity training model for fetoscopic spina bifida surgery
3D vs. 2D Fetoscopy for Spina Bifida Repair: a Quantitative Motion Analysis in a High Fidelity Training Model
Today’s maturation of 3D imaging technology allows also application in prenatal minimally invasive surgery techniques. In this task, we aimed to assess if 3D vision via 3-port access benefits expert surgeons in performing fetoscopic spina bifida aperta (SBA) repair.
We designed a superiority study in the high-fidelity rabbit model powered on operation time as primary outcome. 149±15 min was required to achieve a fetoscopic repair under 2D vision and a 30-min time reduction was expected for 3D fetoscopy, equivalent to a duration of 119 min (n=6 animals per group, power 90%; 5% significance). Secondary outcomes were time for patch running suture, watertightness of the repair, CO2 insufflation volume, OSATS score and surgical motions. One expert laparoscopic fetal surgeon performed twelve (n=12) simulated fetoscopic surgeries. Animals were assigned chronologically to 2D and then 3D fetoscopy to mimic clinical reality. During surgery, a six degree of freedom (DOF) electromagnetic tracking system recorded the position, orientation and motions of instruments hold by the surgeon. 39 motion metrics such as path length, smoothness, maximum speed, modified Spectral Arc Length (SPARC) and Log Dimensionless Jerk (LDLJ) were calculated. Data were processed using Matlab R2019b and the results were analysed with the unpaired t-test and Wilcoxon rank sum test using GraphPad Prism 8.4.2.
The operation time under 3D vision was significantly shorter than under 2D vision (113±11 min vs. 149±24; p=0.026). This materialized in a substantial reduction of 36 minutes on average. Time for patch running suture, watertightness of the repair, CO2 insufflation volume, and OSATS scores were comparable. Some motion metrics during patch running suture such LDLJ were improved (-29.6±0.7 vs. -28.4±0.7; 0.007).
In the high-fidelity rabbit model for fetoscopic SBA repair, 3D vision via 3-port access shorten operation time and improves some motion metrics when performing a running suture by an expert fetal surgeon. These results should be confirmed in a subsequent study using an adapted motion tracking set-up, LDLJ motion metric being the primary outcome and involving two group of novices and experts.
Feasibility of single, dual and triple port fetoscopic SBA repair under amniotic insufflation of humidified and heated CO2 in the fetal lamb model
Fetoscopic spina bifida aperta (SBA) repair under humidified-heated Partial Amniotic CO2 Insufflation (hPACI) is clinically performed both through a two- as well as three-port approach, with promising early results, neither with proper preclinical validation. As in other fetal conditions, single-port fetoscopy could be a less invasive alternative. Herein we aimed to experimentally assess the feasibility of single-, two- and three-port approaches for fetoscopic SBA repair.
We used the standardized skin-defect fetal lamb model simulating SBA (100 days; term 145 days). We first catheterized the fetuses through a hysterotomy with two catheters, one in the fetal carotid artery, for metabolic surveillance, and one under a SBA-like skin defect, for watertightness testing. Then we performed a fetoscopic layered repair of the defect through an exteriorized uterus under hPACI. A team of two fetal surgeons, previously trained in the high-fidelity SBA rabbit model and did initial pilot surgeries (n=3) to standardize the procedures. 12 fetuses were chronologically assigned to single- (n=4), three- (n=4) and then two-port (n=4) fetoscopy. The reference fetoscopic approach was three-port access like in laparoscopic surgery. Based on a meta-analysis of clinical fetal SBA repairs, to determine the learning curve of open and fetoscopic SBA repair, each approach was considered feasible, i.e. obtaining a clinically acceptable successful repair, under the condition that (1) the repair was watertight in ≥70% of the cases and within (2) an operation and insufflation duration ≤180 min, (3) with an OSATS score ≥18/25, (4) and fetus blood gas parameters and heart rate at the end of the procedure comparable to baseline.
All fetuses were alive at the end of the procedure and had their pH, pCO2, pO2, bicarbonate, lactate and heart rate at the end of the procedure comparable to baseline. Using single-port fetoscopy, a watertight repair was achieved in 50% of cases, with times of fetal repair and hPACI of 140±17 and 176±23 min respectively, and an OSATS score of 14±6. When performing three-port fetoscopy, a watertight repair was achieved in 100% of cases with a duration of fetal repair and hPACI of 138±27 and 174±34 min respectively, and an OSATS score of 19 ±3. Using two-port fetoscopy, a watertight repair was achieved in 100% of the cases with times of fetal repair and hPACI of 182 ±41 and 216 ±54 min respectively, and an OSATS score of 20 ±5. Taking all outcome measures together (composite outcome), a successful fetal repair was reached in 0%, 75% and 50% via single-, three- or two-port approach respectively.
With the current instrumentation, experience and skills, it seems that a clinically acceptable repair is only achieved when using a three-port fetoscopic approach.
Added value of 3-dimensional fetoscopy for spina bifida repair in the fetal lamb model
This task aimed to assess the added value of fetoscopic spina bifida aperta (SBA) repair under 3D, rather than 2D vision.
We used the standardised skin-defect fetal lamb model simulating SBA (100 days; term 145d). We first catheterized the fetuses through a hysterotomy with two catheters, one in the fetal carotid artery and one under the skin defect. Then we performed a three-port fetoscopic layered repair of the defect through an exteriorized uterus under humidified and heated partial carbon dioxide insufflation (hPACI). A team of two fetal surgeons, previously trained on high-fidelity SBA rabbit as well as fetal lamb models for three-port fetoscopy, performed the surgeries. To replicate what is the clinical scenario, first 6 consecutive fetuses were operated with 2D-fetoscopy whereafter another six by 3D-fetoscopy. We designed a superiority study powered on fetal repair time as primary outcome (n=6, power 90%). Secondary outcomes was surgical performance including the watertightness of the repair, OSATS score of recorded videos, hPACI time and volume, successful fetal repair (defined by a watertight repair in ≤180min with an OSATS score ≥18/25); and fetal blood gas parameters and heart rate at the end of the procedure.
Fetal repair time under 3D vision was significantly shorter than under 2D vision (151 ± 28 vs. 113 ± 7; p=0.009). This materialized in a substantial reduction of 38 minutes on average. Total volume of hPACI was also smaller in the 3D-fetoscopy group (529 ± 131 vs. 324 ± 155; p=0.033). A successful watertight fetal repair was reached in all fetuses of the 3D-fetoscopy group as opposed to three (50%) of the 2D-fetoscopy group (p=0.181). The OSATS score and hPACI time were comparable and a watertight skin repair was achieved in all fetuses. Fetal pH, pCO2, pO2, bicarbonate, lactate and heart rate at the end of the surgery were also not different in both groups.
Three-port fetoscopic repair under 3D vision, as compared to 2D vision, was associated with a substantial reduction in operation time and CO2 insufflation volume. This was not associated with a significantly improved surgical performance.
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We have tested our photoacoustic imaging technique in the human placenta after birth to study how it visualises the fine placental vessels in identical twin pregnancies. This study is recruiting women who have fetoscopic laser treatment of twin-to-twin transfusion syndrome.
Motion-based skill analysis in a fetoscopic spina-bifida repair training model. Javaux, A., Joyeux, L., Deprest, J., Denis, K., Vander Poorten, E. 2018-09. CRAS. Date: 2018/09/10 – 2018/09/11. Location: London, UK. Open Access.
Feasibility and safety of three- and single-port fetoscopy for spina bifida in the fetal lamb. Joyeux L., Basurto D., Van der Veeken L., Kunpalin Y., Corno E., Pla LY., Inversetti A., De Vleeschauwer S., Van Calenbergh F., Deprest J. (2019). American Journal of Obstetrics and Gynecology: vol. 220 (1) S158-S159. Presented at the 39th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM), Las Vegas, NV, 11-16 Feb 2019. doi: 10.1016/j.ajog.2018.11.240
Safety and feasibility of humidified-warmed PACI (partial-amniotic-carbon-dioxide-insufflation) for fetoscopic spina bifida repair. Joyeux, D. Basurto, T. Bleeser, L. Van der Veeken, Y. Kunpalin, E. Corno, A. Inversetti, S. De Vleeschauwer, P. De Coppi, F. Van Calenbergh, J. Deprest. (2020). American Journal of Obstetrics and Gynecology: vol. 222(1) S680-S681. Presented at the 40th Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM), Grapevine, TX, 3-8 Feb 2020. doi: 10.1016/j.ajog.2019.11.1117
3D vs. 2D Fetoscopy for Spina Bifida Repair: a Quantitative Motion Analysis in a High Fidelity Training Model. Weiler, L. Joyeux, A. M. Ahmad , J. Deprest, E. Vander Poorten. (master thesis, Yolan Weiler, Master of Science in Biomedical Engineering, Katholieke Universiteit Leuven).
Looking beyond the imaging plane: 3D needle tracking with a linear array ultrasound probe. Xia, W., West, S. J., Finlay, M. C., Mari, J. M., Ourselin, S., David, A. L., Desjardins, A. E. (2017). Scientific reports. doi: 10.1038/s41598-017-03886-4