Experimental and theoretical model of microvascular network remodeling and blood flow redistribution following minimally invasive microvessel laser ablation.

Overly dense microvascular networks are treated by selective reduction of vascular elements. Inappropriate manipulation of microvessels could result in loss of host tissue function or a worsening of the clinical problem. Here, experimental, and computational models were developed to induce blood flow changes via selective artery and vein laser ablation and study the compensatory collateral flow redistribution and vessel diameter remodeling. The microvasculature was imaged non-invasively by bright-field and multi-photon laser microscopy, and optical coherence tomography pre-ablation and up to 30 days post-ablation. A theoretical model of network remodeling was developed to compute blood flow and intravascular pressure and identify vessels most susceptible to changes in flow direction. The skin microvascular remodeling patterns were consistent among the five specimens studied. Significant remodeling occurred at various time points, beginning as early as days 1-3 and continuing beyond day 20. The remodeling patterns included collateral development, venous and arterial reopening, and both outward and inward remodeling, with variations in the time frames for each mouse. In a representative specimen, immediately post-ablation, the average artery and vein diameters increased by 14% and 23%, respectively. At day 20 post-ablation, the maximum increases in arterial and venous diameters were 2.5× and 3.3×, respectively. By day 30, the average artery diameter remained 11% increased whereas the vein diameters returned to near pre-ablation values. Some arteries regenerated across the ablation sites via endothelial cell migration, while veins either reconnected or rerouted flow around the ablation site, likely depending on local pressure driving forces. In the intact network, the theoretical model predicts that the vessels that act as collaterals after flow disruption are those most sensitive to distant changes in pressure. The model results correlate with the post-ablation microvascular remodeling patterns.

Experimental and Theoretical Model of Single Vessel Minimally Invasive Micro-Laser Ablation: Inducing Microvascular Network Remodeling and Blood Flow Redistribution Without Compromising Host Tissue Function.

Overly dense microvascular networks are treated by selective reduction of vascular elements. Inappropriate manipulation of microvessels could result in loss of host tissue function or a worsening of the clinical problem. Here, experimental, and computational models were developed to induce blood flow changes via selective artery and vein laser ablation and study the compensatory collateral flow redistribution and vessel diameter remodeling. The microvasculature was imaged non-invasively by bright-field and multi-photon laser microscopy, and Optical Coherence Tomography pre-ablation and up to 30 days post-ablation. A theoretical model of network remodeling was developed to compute blood flow and intravascular pressure and identify vessels most susceptible to changes in flow direction. The skin microvascular remodeling patterns were consistent among the five specimens studied. Significant remodeling occurred at various time points, beginning as early as days 1-3 and continuing beyond day 20. The remodeling patterns included collateral development, venous and arterial reopening, and both outward and inward remodeling, with variations in the time frames for each mouse. In a representative specimen, immediately post-ablation, the average artery and vein diameters increased by 14% and 23%, respectively. At day 20 post-ablation, the maximum increases in arterial and venous diameters were 2.5x and 3.3x, respectively. By day 30, the average artery diameter remained 11% increased whereas the vein diameters returned to near pre-ablation values. Some arteries regenerated across the ablation sites via endothelial cell migration, while veins either reconnected or rerouted flow around the ablation site, likely depending on local pressure driving forces. In the intact network, the theoretical model predicts that the vessels that act as collaterals after flow disruption are those most sensitive to distant changes in pressure. The model results match the post-ablation microvascular remodeling patterns.

Silicon membranes for extracorporeal life support: a comparison of design and fabrication methodologies.

Extracorporeal life support is an advanced therapy that circulates blood through an extracorporeal oxygenator, performing gas exchange outside the body. However, its use is limited by severe complications, including bleeding, clotting, and hemolysis. Semiconductor silicon-based membranes have emerged as an alternative to traditional hollow-fiber semipermeable membranes. These membranes offer excellent gas exchange efficiency and the potential to increase hemocompatibility by improving flow dynamics. In this work, we evaluate two next-generation silicon membrane designs, which are intended to be mechanically robust and efficient in gas exchange, while simultaneously reducing fabrication complexity. The "window" design features 10 µm pores on one side and large windows on the back side. The "cavern" design also uses 10 µm pores but contains a network of interconnected buried caverns to distribute the sweep gas from smaller inlet holes. Both designs were shown to be technically viable and able to be reproducibly fabricated. In addition, they both were mechanically robust and withstood 30 psi of transmembrane pressure without breakage or bubbling. At low sweep gas pressures, gas transfer efficiency was similar, with the partial pressure of oxygen in water increasing by 10.7 ± 2.3 mmHg (mean ± standard deviation) and 13.6 ± 1.9 mmHg for the window and cavern membranes, respectively. Gas transfer efficiency was also similar at higher pressures. At 10 psi, oxygen tension increased by 16.8 ± 5.7 mmHg (window) and 18.9 ± 1.3 mmHg (cavern). We conclude that silicon membranes featuring a 10 µm pore size can simplify the fabrication process and improve mechanical robustness while maintaining excellent efficiency.

Association of Ventilator Settings With Mortality in Pediatric Patients Treated With Extracorporeal Life Support for Respiratory Failure.

Extracorporeal life support (ECLS) is a treatment for acute respiratory failure that can provide extracorporeal gas exchange, allowing lung rest. However, while most patients remain mechanically ventilated during ECLS, there is a paucity of evidence to guide the choice of ventilator settings. We studied the associations between ventilator settings 24 hours after ECLS initiation and mortality in pediatric patients using a retrospective analysis of data from the Extracorporeal Life Support Organization Registry. 3497 patients, 29 days to 18 years of age, treated with ECLS for respiratory failure between 2015 and 2021, were included for analysis. 93.3% of patients on ECLS were ventilated with conventional mechanical ventilation. Common settings included positive end-expiratory pressure (PEEP) of 10 cm H 2 O (45.7%), delta pressure (ΔP) of 10 cm H 2 O (28.3%), rate of 10-14 breaths per minute (55.9%), and fraction of inspired oxygen (FiO 2 ) of 0.31-0.4 (30.3%). In a multivariate model, PEEP >10 cm H 2 O ( versus PEEP < 8 cm H 2 O, odds ratio [OR]: 1.53, 95% CI: 1.20-1.96) and FiO 2 ≥0.45 ( versus FiO 2 < 0.4; 0.45 ≤ FiO 2 < 0.6, OR: 1.31, 95% CI: 1.03-1.67 and FiO 2 ≥ 0.6, OR: 2.30; 95% CI: 1.81-2.93) were associated with higher odds of mortality. In a secondary analysis of survivors, PEEP 8-10 cm H 2 O was associated with shorter ECLS run times ( versus PEEP < 8 cm H 2 O, coefficient: -1.64, 95% CI: -3.17 to -0.11), as was ΔP >16 cm H 2 O ( versus ΔP < 10 cm H 2 O, coefficient: -2.72, 95% CI: -4.30 to -1.15). Our results identified several categories of ventilator settings as associated with mortality or ECLS run-time. Further studies are necessary to understand whether these results represent a causal relationship.

Advances in extracorporeal membrane oxygenator design for artificial placenta technology.

Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and morbidity, in large part due to the immaturity of the lungs at this stage of development. The standard of care for these patients includes support with mechanical ventilation, which exacerbates lung pathology. Extracorporeal life support (ECLS), also called artificial placenta technology when applied to extremely preterm (EPT) infants, offers an intriguing solution. ECLS involves providing gas exchange via an extracorporeal device, thereby doing the work of the lungs and allowing them to develop without being subjected to injurious mechanical ventilation. While ECLS has been successfully used in respiratory failure in full-term neonates, children, and adults, it has not been applied effectively to the EPT patient population. In this review, we discuss the unique aspects of EPT infants and the challenges of applying ECLS to these patients. In addition, we review recent progress in artificial placenta technology development. We then offer analysis on design considerations for successful engineering of a membrane oxygenator for an artificial placenta circuit. Finally, we examine next-generation oxygenators that might advance the development of artificial placenta devices.

Necrotising pneumonia and bronchiectasis in a previously healthy 30-year-old man.

We present a case of a previously healthy 30-year-old man who presented with a necrotising pneumonia and bronchiectasis. His infectious workup revealed a Staphylococcus aureus pneumonia. Since bronchiectasis and necrotising pneumonia are unusual findings in an otherwise healthy person, further investigation was pursued. His workup revealed non-classic cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis (ABPA). This case discusses the differential diagnosis of bronchiectasis, the diagnosis and treatment of ABPA, and the role of CF mutations in the pathogenesis of ABPA.

Distinct spatiotemporal activity in principal neurons of the mouse olfactory bulb in anesthetized and awake states.

The acquisition of olfactory information and its early processing in mammals are modulated by brain states through sniffing behavior and neural feedback. We imaged the spatiotemporal pattern of odor-evoked activity in a population of output neurons (mitral/tufted cells, MTCs) in the olfactory bulb (OB) of head-restrained mice expressing a genetically-encoded calcium indicator. The temporal dynamics of MTC population activity were relatively simple in anesthetized animals, but were highly variable in awake animals. However, the apparently irregular activity in awake animals could be predicted well using sniff timing measured externally, or inferred through fluctuations in the global responses of MTC population even without explicit knowledge of sniff times. The overall spatial pattern of activity was conserved across states, but odor responses had a diffuse spatial component in anesthetized mice that was less prominent during wakefulness. Multi-photon microscopy indicated that MTC lateral dendrites were the likely source of spatially disperse responses in the anesthetized animal. Our data demonstrate that the temporal and spatial dynamics of MTCs can be significantly modulated by behavioral state, and that the ensemble activity of MTCs can provide information about sniff timing to downstream circuits to help decode odor responses.