Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury.

Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti-inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.

Wharton's Jelly for Augmented Cleft Palate Repair in a Rat Critical-Size Alveolar Bone Defect Model.

Secondary alveolar bone grafts (ABGs) are the standard treatment for the alveolar defect in patients with cleft lip and palate (CLP), but remain invasive and have several disadvantages such as delayed timing of alveolar repair, donor-site complications, graft resorption, and need for multiple surgeries. Earlier management of the alveolar defect (primary ABG) would be ideal, but is limited by the minimal bony donor sites available in the infant. In this study we used a critical-size alveolar bone defect model in the rat to investigate the use of Wharton's Jelly (WJ), the stem cell-rich connective tissue matrix of the umbilical cord, to generate bone within the alveolar cleft. Human WJ was isolated and implanted into a critical-size alveolar bone defect model representative of secondary cleft ABG surgery in 10-11-week-old male Sprague-Dawley rats. The defects were monitored with CT imaging of living animals to evaluate bone regrowth and healing over 24 weeks, followed by histomorphometric evaluation at 24 weeks, after the last CT scan. CT data confirmed that the defect size was critical and did not lead to the union of the bones in the control animals (n = 12) for the entire duration of the study. New bone growth was stimulated leading to partial-to-full closure of the defect in the animals treated with WJ (n = 12). Twenty four weeks postoperatively, the percent increase in new bone formation in the WJ-treated group (156.58% ± 20.67%) was markedly higher than that in the control group (50.36% ± 21.07%) (p < 0.05). Histomorphometric data also revealed significantly greater new bone formation in WJ-treated versus control animals, confirming CT findings. qPCR analysis of human Alu elements was unable to detect any appreciable long-term persistence of human cells in the new bone, indicating that WJ may enhance bone growth by mediating osteoinduction in the host tissue, rather than through osteogenic differentiation of WJ-embedded cells. Impact statement In this study, Wharton's Jelly enhanced bone growth in a preclinical alveolar defect model, indicating its potential use as a natural adjunct in the repair of the alveolar cleft defect in patients with cleft lip and palate (CLP). The clinical success of this approach would represent a paradigm shift in the treatment of patients with CLP by reducing or eliminating the need for subsequent secondary alveolar bone graft and reducing their number of lifetime surgeries.

Morphometric and Physiologic Modeling Study for Endovascular Occlusion in Pediatric Trauma Patients.

The use of the resuscitative endovascular balloon occlusion of the aorta (REBOA) device is expanding in adult trauma. Reports of its use in pediatric patients have been published, but no guidelines currently exist nor has it been Food and Drug Administration approved in pediatrics. This project develops a model to determine appropriate balloon inflation volumes in pediatric patients to guide potential use. Artificial aortas were three-dimensional (3D) printed using synthetic polymers. Segments were created based on aortic diameters from 289 pediatric trauma patients' computer tomography (CT) scans. These aortic segments were inserted into a circulatory system model featuring two branches to simulate abdominal and upper body perfusion (cerebral, cardiac, and upper extremities). Sonographic flow meters and pressure transducers were placed along the circuit, and measurements were recorded as a REBOA device was inflated in the aortic segment. A negative sigmoidal relationship was observed between device inflation and aortic flow occlusion, with the initial 50% of inflation causing a 10% reduction in flow, followed by a steep decline. With increasing inflation, distal aortic flow and pressure were found to have an inverse relationship with the upper body branch metrics. In conclusion, pediatric patients present with a range of vessel diameters that occlude at various REBOA balloon inflation volumes. This study provides a basis to establish initial inflation volumes for safe REBOA deployment in appropriate pediatric trauma patients.

A Morphometric Model for Endovascular Occlusion of The Retrohepatic Vena Cava in Pediatric Trauma.

BACKGROUND: The resuscitative endovascular balloon occlusion of the aorta (REBOA) device has been adapted for inferior vena cava (IVC) use in both animal models and adult case reports. The aim of this study is to examine the feasibility for use of the REBOA device for pediatric IVC injuries and create a potential framework for implementation. MATERIALS AND METHODS: A simulated venous system was designed with modeled IVC components based on 290 abdominal computed tomography scans of pediatric trauma patients. These patients were randomly selected to represent the ten Broselow categories. These IVC segments were selected to represent the posthepatic and prehepatic diameters for the five largest Broselow categories. A closed circulatory model was created with steady-state flow designed to model the venous system. The REBOA device was inserted into the system with the balloon in the IVC segment. Pressure monitors were placed distally and in the closed system, replicating the capacitance of the venous system. A flow meter was placed distally to the segment and balloon. Flow and pressure readings were recorded as the REBOA device was inflated and total occlusion was achieved. RESULTS: Suprahepatic IVC diameters ranged from 1.14 to 2.71 cm, while infrahepatic IVC diameters ranged from 0.76 to 2.39 cm. There was significant overlap in the measurements of the IVC, allowing five modeled segments to represent ten different IVCs. The venous model demonstrated a significant delay between balloon inflation and vessel occlusion. Approximately 80%-90% of the REBOA inflation volume results in approximately an initial 10% reduction in flow. Flow was completely obstructed which corresponded with a small increase in pressure difference between the proximal and distal pressure monitors, reflecting the capacitance in the venous system with inflation. CONCLUSIONS: Pediatric IVC injuries with significant hemorrhage should be amenable to endovascular occlusion as an adjunct to resuscitation and operative management.

Venous thromboembolism risk factors in a pediatric trauma population.

PURPOSE: New guidelines have been proposed for venous thromboembolism (VTE) prophylaxis in pediatric trauma patients. This paper seeks to evaluate risk factors associated with VTE that might further guide patient selection for prophylaxis. METHODS: Review of a tertiary children's academic hospital's trauma database for VTE events and associated risk factors from 2005 to 2016. RESULTS: 15,306 pediatric trauma patients were identified and reviewed. During this time period there were 6191 admissions (40.4%), of which 20 developed a VTE (0.3%) including two pulmonary emboli. Primary outcome was comparison of risk factors for developing a VTE that were identified in the literature. Age stratification revealed the highest incidence of VTE in children under the age of 2 (0.7%), which increased with CVC placement when compared to children aged 2-12 and 13-15 (0.036 Fisher's exact test). CONCLUSIONS: VTE after pediatric trauma is rare, and may be more uncommon than previously reported. CVC placement was the strongest predictor of VTE, particularly in infant and toddler patients which can explain their higher overall incidence compared to other pediatric age groups. Identifying high-risk patients is important to optimize screening and prophylaxis of VTE in pediatric trauma patients while minimizing risks of anticoagulation.