Sally M Winkler, BS1, Vamsi K Aribindi, MD2, Veeshal H Patel, MD3, Michael R Harrison, MD4, Philip B Messersmith, PhD1. 1University of California, Berkeley, 2University of California, San Francisco; Baylor College of Medicine, 3University of California, San Francisco; University of Washington, 4University of California, San Francisco
Fetal surgery has the potential to correct or ameliorate developmental defects such as spina bifida, twin twin transfusion syndrome, congenital diaphragmatic hernia, sacrococcygeal teratomas, and urinary tract obstructions in utero. However, even in minimally invasive fetal surgery, puncturing the amniotic sac (fetal membranes) to access the fetus carries a large risk of amniotic fluid leakage, chorioamniotic separation, and sac rupture with subsequent pre-term birth; around 30% of patients who undergo fetal surgery deliver prematurely. These risks are present, though to a much lesser degree, after amniocentesis. Recent bench-top evidence suggested that applying an adhesive to the space between the membranes and the uterus prior to puncture would reduce defect size, decrease amniotic fluid leakage, and prevent sac rupture, all of which contribute to pre-term birth. Thus far, no sealant has proven effective enough and safe for fetal exposure for use in this application.
Here, we present initial data from our pilot studies of fetal membrane pre-sealing in pregnant rabbits. As a sealant, we used a two-component mixture of multi-arm poly(ethylene glycol) that, upon mixing, crosslinks to form a gel since each sealant component has a different reactive end-functionalization (n-hydroxysuccinimide or cysteine). The material forms a gel in under 2 minutes and gelation time is tunable. In some materials, mussel-inspired peptides are incorporated to provide additional wet adhesion. These peptides are found in the adhesive plaques of marine mussels, who secrete adhesive protein threads to adhere to rocks underwater.
In our rabbit model, a laparotomy is performed to partially expose the uterus. Then, the two components of the sealant are mixed and a 23g needle is used to apply a bolus of ~1mL of sealant to between the membranes and uterus. Sealant is allowed to gelate in situ for ~1 minute and, after puncture, sealed membranes exhibited far less leakage than unsealed membranes. We also present our optimized gel injection strategies near the fragile amniotic sac. Preliminary results in an acute study showed that, when the uterus is opened to fully expose the amniotic sac in a non-survival surgery, sacs that are sealed with the sealant and then punctured with an 18g needle or with a scalpel exhibit almost no leakage, while sacs without the sealant that are punctured leak excessively.
In conclusion, a novel glue to seal fetal membranes after fetal interventions was developed and deployed in an acute rabbit model, which was efficacious in preventing fluid leakage. Future directions include confirming lack of long-term fetal toxicity with longer term survival studies in rabbits, confirming efficacy in a model more closely resembling human uterine anatomy (e.g. pregnant swine), and further developing delivery techniques to apply the substance under ultrasound or laparoscopic guidance. In the future, this substance, possibly used in conjunction with a pre-sealing technique, may have other applications beyond fetal surgery- including for minimally invasive endoscopic and laproscopic bleeding control prior to resections.
Presented at the SAGES 2017 Annual Meeting in Houston, TX.
Abstract ID: 98904
Program Number: ETP757
Presentation Session: Emerging Technology Poster Session (Non CME)
Presentation Type: Poster