Successful Postnatal Tracheobronchoplasty for Unilateral Congenital High Airway Obstruction Syndrome (CHAOS) due to Mainstem Bronchial Atresia.

INTRODUCTION: Unilateral congenital high airway obstruction syndrome (CHAOS) is caused by a complete obstruction of a mainstem bronchus with resulting hyperinflation and accelerated growth of one lung, severe mediastinal shift and hydrops. Spontaneous perforation of the atresia has been observed in CHAOS which allows hydrops to resolve but hyperinflation, mediastinal shift and a critical airway obstruction persists as the perforation is usually pinhole-sized. CASE PRESENTATION: We present a case of unilateral CHAOS presenting at 26 2/7 weeks' with observed-to-expected total lung volume (O/E TLV) of 203% with spontaneous perforation occurring at 28 weeks' with resolution of hydrops but persistence of hyperinflation and mediastinal shift with an O/E TLV of 60.5% on 34 5/7 weeks' magnetic resonance imaging (MRI), successfully managed in a 35 5/7 weeks', 1670 gm, growth restricted baby, by veno-arterial extracorporeal membrane oxygenation (VA ECMO) and resection of the tracheobronchial atresia and tracheobronchoplasty on day of life 5. The baby was separated from ECMO on post-op day 12, required tracheostomy for positive end expiratory pressure (PEEP) for tracheomalacia at 4 months. CONCLUSION: At two years of age, she has met all developmental milestones, has been weaned to room air tracheostomy collar, and is anticipating tracheal decannulation. There is persistent bronchiectasis in the hyperinflated right lung but no malacia. This is the first reported survivor of mainstem bronchial atresia suggesting the importance of preservation of the hyperplastic lung and airway reconstruction to normal long-term outcome.

Fetoscopic Endoluminal Tracheal Occlusion for Severe, Left-Sided Congenital Diaphragmatic Hernia: The North American Fetal Therapy Network Fetoscopic Endoluminal Tracheal Occlusion Consortium Experience.

OBJECTIVE: To report the outcomes of fetoscopic endoluminal tracheal occlusion in a multicenter North American cohort of patients with isolated, left-sided congenital diaphragmatic hernia (CDH) and to compare neonatal mortality and morbidity in patients with severe left-sided congenital diaphragmatic hernia who underwent fetoscopic endoluminal tracheal occlusion with those expectantly managed. METHODS: We analyzed data from 10 centers in the NAFTNet (North American Fetal Therapy Network) FETO (Fetoscopic Endoluminal Tracheal Occlusion) Consortium registry, collected between November 1, 2008, and December 31, 2020. In addition to reporting procedure-related surgical outcomes of fetoscopic endoluminal tracheal occlusion, we performed a comparative analysis of fetoscopic endoluminal tracheal occlusion compared with contemporaneous expectantly managed patients. RESULTS: Fetoscopic endoluminal tracheal occlusion was successfully performed in 87 of 89 patients (97.8%). Six-month survival in patients with severe left-sided congenital diaphragmatic hernia did not differ significantly between patients who underwent fetoscopic endoluminal tracheal occlusion and those managed expectantly (69.8% vs 58.1%, P =.30). Patients who underwent fetoscopic endoluminal tracheal occlusion had higher rates of preterm prelabor rupture of membranes (54.0% vs 14.3%, P <.001), earlier gestational age at delivery (median 35.0 weeks vs 38.3 weeks, P <.001), and lower birth weights (mean 2,487 g vs 2,857 g, P =.001). On subanalysis, in patients for whom all recorded observed-to-expected lung/head ratio measurements were below 25%, patients with fetoscopic endoluminal tracheal occlusion required fewer days of extracorporeal membrane oxygenation (ECMO) (median 9.0 days vs 17.0 days, P =.014). CONCLUSION: In this cohort, fetoscopic endoluminal tracheal occlusion was successfully implemented across several North American fetal therapy centers. Although survival was similar among patients undergoing fetoscopic endoluminal tracheal occlusion and those expectantly managed, fetoscopic endoluminal tracheal occlusion in North American centers may reduce morbidity, as suggested by fewer days of ECMO in those patients with persistently reduced lung volumes (observed-to-expected lung/head ratio below 25%).

IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.

Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL-10 in dermal wounds promotes regenerative tissue repair via STAT3-dependent regulation of fibroblast-specific hyaluronan synthesis. However, IL-10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin-specific STAT3 knockdown mice were studied to determine IL-10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3-dependent. We show that IL-10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re-epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C-X-C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL-10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL-10-conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL-10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re-epithelialization.

Pediatric mediastinal mass algorithm: A quality improvement initiative to reduce time from presentation to biopsy.

BACKGROUND: Mediastinal masses in children may present with compression of the great vessels and airway. An interdisciplinary plan for rapid diagnosis, acute management, and treatment prevents devastating outcomes and optimizes care. Emergency pretreatment with steroids or radiation is more likely to be administered when care is variable, which may delay and complicate diagnosis and treatment. Strategies to standardize care and expedite diagnosis may improve acute patient safety and long-term outcomes. AIMS: The aim of this quality improvement project was to decrease time from presentation to diagnostic biopsy for children with an anterior mediastinal mass by 50% over 3 years within a tertiary healthcare system. METHODS: This quality improvement project involved a single center with data collected and analyzed retrospectively and prospectively for 71 patients presenting with anterior mediastinal mass between February 2008 and January 2018. The Model for Improvement was utilized for project design and development of a driver diagram and smart aim. An algorithm was implemented to facilitate communication between teams and standardize initial care of patients with mediastinal masses. The algorithm underwent multiple Plan-Do-Study-Act (PDSA) cycles. Data were collected before and after algorithm implementation and between each PDSA cycle. The primary outcome measure included time from presentation to biopsy, which was monitored with a statistical process control chart. Several process measures were evaluated with Student's t-tests including administration of emergency pretreatment. RESULTS: Nineteen patients preintervention and 52 patients postintervention were included in the analysis. Time from presentation to biopsy significantly decreased from 48 h at baseline to 24 h postimplementation. Although not statistically significant, emergency pretreatment decreased from a baseline of 26.3% to 6.7% postimplementation. CONCLUSION: Implementation of a diagnostic and management algorithm coordinating care among multidisciplinary teams significantly reduced time to biopsy for children presenting with mediastinal mass and may result in decreased use of emergent pretreatment.

Error traps in fetal surgery.

The growth of the field of fetal surgery over the last two decades driven by new indications and data from prospective randomized trials supporting prenatal intervention has resulted in techniques protocols and methodologies that have gained confidence by insuring good outcomes. Error traps are methods or techniques that usually work well in most of the cases, but which are apt to fail under certain specific circumstances. The very confidence the surgeon develops in these techniques or methodologies makes them a trap for the unwary surgeon. The purpose of this article is to discuss common error traps in fetal interventions, including ultrasound guided procedures, fetoscopic surgery, open fetal surgery and EXIT procedures. Awareness of these error traps and approaches to avoid them may enhance fetal surgical outcomes and reduce complications rates.

Indomethacin Dosing and Constriction of the Ductus Arteriosus During Open Fetal Surgery for Myelomeningocele Repair.

INTRODUCTION: The use of perioperative tocolytic agents in fetal surgery is imperative to prevent preterm labor. Indomethacin, a well-known tocolytic agent, can cause ductus arteriosus (DA) constriction. We sought to determine whether a relationship exists between preoperative indomethacin dosing and fetal DA constriction. MATERIALS AND METHODS: This is an IRB-approved, single-center retrospective observational case series of 42 pregnant mothers who underwent open fetal myelomeningocele repair. Preoperatively, mothers received either 1 (QD) or 2 (BID) indomethacin doses. Maternal anesthetic drug exposures and fetal cardiac dysfunction measures were collected from surgical and anesthesia records and intraoperative fetal echocardiography. Pulsatility Index was used to calculate DA constriction severity. Comparative testing between groups was performed using t- and chi-square testing. RESULTS: DA constriction was observed in all fetuses receiving BID indomethacin and in 71.4% of those receiving QD dosing (p = 0.0002). Severe DA constriction was observed only in the BID group (35.7%). QD indomethacin group received more intraoperative magnesium sulfate (p < 0.0001). Minimal fetal cardiac dysfunction (9.5%) and bradycardia (9.5%) were observed in all groups independent of indomethacin dosing. CONCLUSIONS: DA constriction was the most frequent and severe in the BID indomethacin group. QD indomethacin and greater magnesium sulfate dosing was associated with reduced DA constriction.

Intrauterine growth restriction decreases NF-κB signaling in fetal pulmonary artery endothelial cells of fetal sheep.

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

Modified Hysterotomy Closure Technique for Open Fetal Surgery.

OBJECTIVE: We reviewed our experience with open fetal surgical myelomeningocele repair to assess the efficacy of a new modification of the hysterotomy closure technique regarding hysterotomy complication rates at the time of cesarean delivery. METHODS: A modification of the standard hysterotomy closure was performed on all patients undergoing prenatal myelomeningocele repair. The closure consisted of an interrupted full-thickness #0 polydioxanone (PDS) retention suture as well as a running #0 PDS suture to re-approximate the myometrial edges, and the modification was a third imbricating layer resulting in serosal-to-serosal apposition. A standard omental patch was placed per our routine. Both operative reports and verbal descriptions of hysterotomy from delivering obstetricians were reviewed. RESULTS: A total of 49 patients underwent prenatal repair of myelomeningocele, 43 having adequate follow-up for evaluation. Of those, 95.4% had completely intact hysterotomy closures, with only 1 partial dehiscence (2.3%) and 1 thinned scar (2.3%). There were no instances of uterine rupture. DISCUSSION: In patients undergoing this modified hysterotomy closure technique, a much lower than expected complication rate was observed. This simple modified closure technique may improve hysterotomy healing and reduce obstetric morbidity.

Impact of Objective Echocardiographic Criteria for Timing of Congenital Diaphragmatic Hernia Repair.

OBJECTIVE: To assess the impact of specific echocardiographic criteria for timing of congenital diaphragmatic hernia repair on the incidence of acute postoperative clinical decompensation from pulmonary hypertensive crisis and/or acute respiratory decompensation, with secondary outcomes including survival to discharge, duration of ventilator support, and length of hospitalization. STUDY DESIGN: The multidisciplinary congenital diaphragmatic hernia management team instituted a protocol in 2012 requiring the specific criterion of echocardiogram-estimated pulmonary artery pressure ≤80% systemic blood pressure before repairing congenital diaphragmatic hernias. A retrospective review of 77 neonatal patients with Bochdalek hernias repaired between 2008 and 2015 were reviewed: group 1 included patients repaired before protocol implementation (n = 25) and group 2 included patients repaired after implementation (n = 52). RESULTS: The groups had similar baseline characteristics. Postoperative decompensation occurred less often in group 2 compared with group 1 (17% vs 48%, P = .01). Adjusted analysis accounting for repair type, liver herniation, and prematurity yielded similar results (15% vs 37%, P = .04). Group 2 displayed a trend toward improved survival to 30 days postoperatively, though this did not reach statistical significance (94% vs 80%, P = .06). Patient survival to discharge, duration of ventilator support, and length of hospitalization were not different between groups. CONCLUSIONS: The implementation of a protocol requiring echocardiogram-estimated pulmonary arterial pressure ≤80% of systemic pressure before congenital diaphragmatic hernia repair may reduce the incidence of acute postoperative decompensation, although there was no difference in longer-term secondary outcomes, including survival to discharge.

Ex utero Intrapartum Treatment to Ventricular Pacing: A Novel Delivery Strategy for Complete Atrioventricular Block with Severe Bradycardia.

Fetuses with anti-SSA-mediated complete atrioventricular block (CAVB) are at high risk for perinatal death if they present at <20 weeks of gestation and develop ventricular rates of <55 beats per minute (bpm), cardiac dysfunction, or hydrops [Izmirly et al.: Circulation 2011;124:1927-1935; Jaeggi et al.: J Am Coll Cardiol 2002;39:130-137; Eliasson et al.: Circulation 2011;124:1919-1926]. After our experience with two such fetuses who died with pulseless electrical activity despite being paced within 30 min of birth, we performed an ex utero intrapartum treatment procedure to ventricular pacing on a 36-week CAVB fetus with cardiac dysfunction, mild hydrops, and a ventricular rate of 46 bpm. While still on placental bypass, temporary epicardial ventricular pacing leads were successfully placed; the infant was delivered and made a successful transition to postnatal life. This approach can improve the 11-fold increase in mortality for the preterm fetus with long-standing CAVB, severe bradycardia, and heart failure.

Case report of myometrial window following fetoscopic treatment of twin-twin transfusion syndrome: indications of underlying collagen vascular disease?

Intraperitoneal amniotic fluid leak is a known complication of fetoscopic procedures that usually resolves spontaneously with expectant management. Intraperitoneal amniotic fluid leak may persist after fetoscopic procedures due to a myometrial window as well as to persistent chorioamniotic membrane disruption, which may be amenable to surgical repair.

Pediatric Intraocular Immature Teratoma Associated With Sacrococcygeal Teratoma.

Intraocular teratomas are rare neoplasms with only three previously reported cases. We present the fourth case of intraocular teratoma and the second associated with sacrococcygeal teratoma. While the nature of the association between intraocular teratomas and sacrococcygeal teratomas is unclear, it suggests a need for careful ophthalmologic follow-up of infants with congenital sacrococcygeal teratomas.

Fetal Treatment 2017: The Evolution of Fetal Therapy Centers - A Joint Opinion from the International Fetal Medicine and Surgical Society (IFMSS) and the North American Fetal Therapy Network (NAFTNet).

More than 3 decades ago, a small group of physicians and other practitioners active in what they called "fetal treatment" authored an opinion piece outlining the current status and future challenges anticipated in the field. Many advances in maternal, neonatal, and perinatal care and diagnostic and therapeutic modalities have been made in the intervening years, yet a thoughtful reassessment of the basic tenets put forth in 1982 has not been published. The present effort will aim to provide a framework for contemporary redefinition of the field of fetal treatment, with a brief discussion of the necessary minimum expertise and systems base for the provision of different types of interventions for both the mother and fetus. Our goal will be to present an opinion that encourages the advancement of thoughtful practice, ensuring that current and future patients have realistic access to centers with a range of fetal therapies with appropriate expertise, experience, and subspecialty and institutional support while remaining focused on excellence in care, collaborative scientific discovery, and maternal autonomy and safety.

Twin pregnancy complicated by esophageal atresia, duodenal atresia, gastric perforation, and hypoplastic left heart structures in one twin: a case report and review of the literature.

BACKGROUND: The antenatal diagnosis of a combined esophageal atresia without tracheoesophageal fistula and duodenal atresia with or without gastric perforation is a rare occurrence. These diagnoses are difficult and can be suspected on ultrasound by nonspecific findings including a small stomach and polyhydramnios. Fetal magnetic resonance imaging adds significant anatomical detail and can aid in the diagnosis of these complicated cases. Upon an extensive literature review, there are no reports documenting these combined findings in a twin pregnancy. Therefore we believe this is the first case report of an antenatal diagnosis of combined pure esophageal and duodenal atresia in a twin gestation. CASE PRESENTATION: We present a case of a 30-year-old G1P0 white woman at 22-week gestation with a monochorionic-diamniotic twin pregnancy discordant for esophageal atresia, duodenal atresia with gastric perforation, hypoplastic left heart structures, and significant early gestation maternal polyhydramnios. In this case, fetal magnetic resonance imaging was able to depict additional findings including area of gastric wall rupture, hiatal hernia, dilation of the distal esophagus, and area of duodenal obstruction and thus facilitated the proper diagnosis. After extensive counseling at our multidisciplinary team meeting, the parents elected to proceed with radiofrequency ablation of the anomalous twin to maximize the survival of the normal co-twin. The procedure was performed successfully with complete cessation of flow in the umbilical artery and complete cardiac standstill in the anomalous twin with no detrimental effects on the healthy co-twin. CONCLUSIONS: Prenatal diagnosis of complex anomalies in twin pregnancies constitutes a multitude of ethical, religious, and cultural factors that come into play in the management of these cases. Fetal magnetic resonance imaging provides detailed valuable information that can assist in management options including possible prenatal intervention. The combination of a cystic structure with peristalsis-like movement above the diaphragm (for example, "the upper thoracic pouch sign"), polyhydramnios, and progressive distention of the stomach and duodenum should increase suspicion for a combined pure esophageal and duodenal atresia.

Fetal origins of adult cardiac disease: a novel approach to prevent fetal growth restriction induced cardiac dysfunction using insulin like growth factor.

BACKGROUND: Fetal growth restriction (FGR) is a risk factor for adult cardiovascular disease. Intraplacental gene transfer of human insulin-like growth factor-1 (IGF-1) corrects birth weight in our mouse model of FGR. This study addresses long term effects of FGR on cardiac function and the potential preventive effect of IGF-1. STUDY DESIGN: Laparotomy was performed on pregnant C57BL/6J mice at embryonic day 18 and pups were divided into three groups: Sham operated; FGR (induced by mesenteric uterine artery ligation); treatment (intraplacental injection of IGF-1 after uterine artery ligation). Pups were followed until 32 wk of life. Transthoracic echocardiography was performed starting at 12 wk. RESULTS: Systolic cardiac function was significantly impaired in the FGR group with reduced fractional shortening compared with sham and treatment group starting at week 12 of life (20 ± 4 vs. 31 ± 5 vs. 32 ± 5, respectively, n = 12 for each group; P < 0.001) with no difference between the sham and treatment groups. CONCLUSION: Intraplacental gene transfer of IGF-1 prevents FGR induced cardiac dysfunction. This suggests that in utero therapy may positively impact cardiac remodeling and prevent adult cardiovascular disease.

Use of an Amnioport to Maintain Amniotic Fluid Volume in Fetuses with Oligohydramnios Secondary to Lower Urinary Tract Obstruction or Fetal Renal Anomalies.

OBJECTIVE: We describe a technique to maintain amniotic fluid in fetuses with severe oligo-/anhydramnios secondary to lower urinary tract obstruction or fetal renal disease when urine production is inadequate to maintain a normal amniotic fluid volume (AFV). METHODS: An amnioport was inserted into the amniotic space. The catheter was secured to prevent dislodgment and tunneled to a subcutaneous reservoir. The reservoir was accessed as necessary, infusing normal saline to maintain AFV. Pregnancy continued until term or indicated delivery. RESULTS: Since 2010, 15 patients in this category were considered for an amnioport. Six chose comfort care and one elected percutaneous amnioinfusions. Nine amnioport procedures were performed in eight patients. There were no fetal deaths. All eight had successful restoration and maintenance of amniotic fluid. Delivery ranged from 9 to 96 days after placement (mean 63.7 days). One died due to unrecognized laryngeal web and another one died of pulmonary hypoplasia after preterm premature rupture of membranes. None of the remaining six had pulmonary hypoplasia. Three remain alive. DISCUSSION: Severe oligo-/anhydramnios in the second trimester secondary to fetal anomalies is almost uniformly lethal due to pulmonary hypoplasia without restoration of amniotic fluid. The amnioport procedure may allow pulmonary survival but commits families to postnatal care decisions regarding pulmonary and renal complications.

Ultrasound versus MRI: is there a difference in measurements of the fetal lateral ventricles?

OBJECTIVE: To evaluate whether fetal brain lateral ventricle measurements differ between ultrasound (US) and MRI. METHODS: We evaluated 115 fetuses with US and MRI performed within 24 h of each other. Ventricular measurements were performed in the axial plane at the level of the atria for both modalities and the right and left ventricles were evaluated separately. We compared mean measurements; mean differences, association with gestational age (GA), association with the presence of a brain anomaly, and agreement between MRI and US. RESULTS: The LV and RV were measured in 65 and 64 cases, respectively. LV and RV size estimates were significantly greater when measured by MRI compared with US (p < 0.001). Therefore, LV and RV were 0.87 mm and 0.89 mm larger in MRI versus US, respectively. Neither GA at measurement or presence/absence of a brain anomaly was significantly associated with differences in measurements. When comparing the agreement between the US and MRI measurements for ventriculomegaly; the kappa level of agreement for the LV and RV was 0.74 for each. CONCLUSION: MRI measurements of ventricles are significantly larger than the measurements by US by ∼1 mm. There is a good level of agreement when categorizing by normal, mild and severe ventriculomegaly.

Effects of Maternal Valium Administration on Fetal MRI Motion Artifact: A Comparison Study at High Altitude.

PURPOSE: Fetal MRI is performed without sedation. In cases of maternal claustrophobia or when reduction of fetal motion is critical, benzodiazepines may help. The purpose of this study was to evaluate the effects of low-dose benzodiazepine on fetal motion MRI and its effect on maternal oxygen levels at higher elevation. METHODS: A total of 131 fetal MRI scans performed from March 2012 through December 2013 were studied. Nineteen of the cases were performed following Valium administration. Images were graded with a 5-point Likert scale. Using pulse oximetry, maternal oxygen levels were recorded. RESULTS: Results were analyzed for each category combining 3 readers' interpretations. Using a 2-sample t test model, the average imaging scores were better for the control than the Valium group (p = 0.0139). Maternal oxygen levels at different times and positions were compared using independent 2-sample t test between the Valium and control groups showing no change in O2 saturation, except when controlling for altitude and gestational age (p = 0.0326). CONCLUSION: Administration of low-dose Valium did not decrease fetal motion on MRI. Valium did not pose any risk of maternal hypoxemia, except when controlling for altitude and gestational age on supine position. Thus, caution should be exercised to prevent the risk of fetal hypoxemia.

Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.

The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice-plus syngeneic fibroblast cell-transplant models-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.-Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.