Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes

An important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages

Progressive Hypoxia-on-a-chip: An In Vitro Oxygen Gradient Model for Capturing the Effects of Hypoxia on Primary Hepatocytes in Health and Disease

Oxygen is vital to the function of all tissues including the liver and lack of oxygen, that is, hypoxia can result in both acute and chronic injuries to the liver in vivo and ex vivo. Furthermore, a permanent oxygen gradient is naturally present along the liver sinusoid, which plays a role in the metabolic zonation and the pathophysiology of liver diseases. Accordingly, here, we introduce an in vitro microfluidic platform capable of actively creating a series of oxygen concentrations on a single continuous microtissue, ranging from normoxia to severe hypoxia. This range approximately captures both the physiologically relevant oxygen gradient generated from the portal vein to the central vein in the liver, and the severe hypoxia occurring in ischemia and liver diseases. Primary rat hepatocytes cultured in this microfluidic platform were exposed to an oxygen gradient of 0.3–6.9%. The establishment of an ascending hypoxia gradient in hepatocytes was confirmed in response to the decreasing oxygen supply. The hepatocyte viability in this platform decreased to approximately 80% along the hypoxia gradient. Simultaneously, a progressive increase in accumulation of reactive oxygen species and expression of hypoxia‐inducible factor 1α was observed with increasing hypoxia. These results demonstrate the induction of distinct metabolic and genetic responses in hepatocytes upon exposure to an oxygen (/hypoxia) gradient. This progressive hypoxia‐on‐a‐chip platform can be used to study the role of oxygen and hypoxia‐associated molecules in modeling healthy and injured liver tissues. Its use can be further expanded to the study of other hypoxic tissues such as tumors as well as the investigation of drug toxicity and efficacy under oxygen‐limited conditions

Brain-specific and systemic inflammatory response following repetitive concussive impact in a mouse model

Concussion is the most common form of mild traumatic brain injury (mTBI). TBI resolution is modulated by neuroinflammation, which is augmented by the infiltration of innate immune cells from the circulation. Peripheral, myeloid immune cells not only invade neural tissues but other organs as well causing local inflammation and tissue damage, known as systemic inflammatory response syndrome. Here, I assessed the temporal and anatomical nature of the neural and systemic cellular inflammatory response to repetitive, mTBI in a 3-hit mouse model of concussion. The results showed significant microglial activity, accumulation of peripheral myeloid cells and prominent axonal damage post-injury. The peripheral immune cells emerged through the brain microvasculature and resided in the parenchyma, along the pia mater and within the ventricles. There was also evidence of systemic inflammation in the lungs as well as in the cervical spinal cords of the mTBI mice

Leading Climate & Environmental Action in the San Diego Region

Leading Climate & Environmental Action in the San Diego Region presents the state of environment-focused nonprofits in the San Diego region and their legacies that position them to continue impactful climate action. Findings in this report are synthesized from quarterly public opinion pollings (San Diego Residents Survey), surveys of 30 local environmental nonprofit leaders (Nonprofit Leaders Survey), the latest nonprofit data from the Internal Revenue Service (IRS), and data on foundation grants awarded to local nonprofits (Candid). The environmental nonprofit sector in the San Diego region is relatively small, but it has worked on the frontlines for many years to strengthen the region’s resilience to climate change through various programmatic focuses. The ongoing climatic threats to the region’s environment and vulnerable populations, concerns of the community, and insights from environmental nonprofit leaders highlight a crucial gap in funding and capacity-building that must be addressed in order to better position the region to meet community needs and protect the quality of life of the San Diego region.https://digital.sandiego.edu/npi-environment/1001/thumbnail.jp

Development of a dental handpiece angle correction device

Background Preparation of a uniform angle of walls is essential for making an ideal convergence angle in fixed prosthodontics. We developed a de novo detachable angle-correction apparatus for dental handpiece drills that could help the ideal tooth preparation. Methods We utilized a gyro sensor to measure the angular velocities to calculate the slope of an object by integrating the values, acceleration sensor to calculate the slope of an object by measuring the acceleration relative to gravity, and Kalman filter algorithm. Converting the angulation of the handpiece body to its drill part could be performed by a specific matrix formulation set on two reference points (2° and 6°). A flexible printed circuit board was used to minimize the size of the device. For convergence angle investigation, 16 volunteers were divided randomly into two groups for performing tooth preparation on a mandibular first molar resin tooth. All abutments were scanned by a 3D scanner (D700®, 3Shape Co., Japan), the convergence angle and tooth axis deviation were analyzed by a CAD program (SolidWorks 2013®, Dassault Systems Co., USA) with statistical analysis by Wilcoxon signed-rank test (α = 0.05) using SPSS statistical software (Version 16.0, SPSS Inc.). Results This device successfully maintained the stable zero point (less than 1° deviation) at different angles (0°, 30°, 60°, 80°) for the first 30 min. In single tooth preparation, without this apparatus, the average bucco-lingual convergence angle was 20.26° (SD 7.85), and the average mesio–distal (MD) convergence angle was 17.88° (SD 7.64). However, the use of this apparatus improved the average BL convergence angle to 13.21° (SD 4.77) and the average MD convergence angle to 10.79° (SD 4.48). The angle correction device showed a statistically significant effect on reducing the convergence angle of both directions regardless of the order of the directions. Conclusions The angle correction device developed in this study is capable of guiding practitioners with high accuracy comparable to that of commercial navigation surgery. The volume of the angle correction device is much smaller than that of any other commercial navigation surgery system. This device is expected to be widely utilized in various fields of orofacial surgery.This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (2017R1D1A1B03036054)

Patient-specific molecular response dynamics can predict the possibility of relapse during the second treatment-free remission attempt in chronic myelogenous leukemia

In chronic myelogenous leukemia (CML), treatment-free remission (TFR) is defined as maintaining a major molecular response (MMR) without a tyrosine kinase inhibitor (TM), such as imatinib (IM). Several studies have investigated the safety of the first TFR (TFR1) attempt and suggested recommendation guidelines for such an attempt. However, the plausibility and predictive factors for a second TFR (TFR2) have yet to be reported. The present study included 21 patients in chronic myeloid leukemia who participated in twice repeated treatment stop attempts. We develop a mathematical model to analyze and explain the outcomes of TFR2. Our mathematical model framework can explain patient-specific molecular response dynamics. Fitting the model to longitudinal BCR ABL1 transcripts from the patients generated patient-specific parameters. Binary tree decision analyses of the model parameters suggested a model based predictive binary classification factor that separated patients into low- and high-risk groups of TFR2 attempts with an overall accuracy of 76.2% (sensitivity of 81.1% and specificity of 69.9%). The low-risk group maintained a median TFR2 of 28.2 months, while the high-risk group relapsed at a median time of 3.25 months. Further, our model predicted a patient-specific optimal IM treatment duration before the second IM stop that could achieve the desired TFR 2 (e.g., 5 years)

Electron microscopic analysis of necrotic bone and failed implant surface in a patient with medication-related osteonecrosis of the jaw

Background Bisphosphonates (BP), a commonly used medication for various bone diseases, have been known to have severe complications such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Failure of dental implants has also been found in patients with medication-related osteonecrosis of the jaw (MRONJ). In this study, we analyzed the necrotic bone tissues and the surface of the failed implants removed from the jaw in patients treated with BPs and antiresorptive agents. Results Chronic inflammatory cells with collagen and fibrous tissues and bone sequestrum were shown at 5.0 × , 10.0 × , 20.0 × , and 40.0 × magnified histologic sections in the bone and fibrotic scar tissues removed from patients with MRONJ due to osteonecrosis. Hardened bone tissues with microcracked bony resorbed lacunae were observed in SEM. Unlike the previously published comparative data where immune cells, such as dendritic cells, were found in the failed implant surface, these immune cells were not identified in the BRONJ-related peri-implantitis tissues through the TEM investigations. Furthermore, EDS revealed that in addition to the main titanium element, gold, carbon, oxygen, calcium, phosphorus, silicon, and sulfur elements were found. Conclusion Hardened bone tissues with microcracked bony resorbed lacunae were observed in the SEM findings, which were considered as the main characteristic of the osteonecrosis of the jaw. Immune cells, such as dendritic cells were not identified in the TEM. EDS showed that in addition to the main titanium element, gold, carbon, oxygen, calcium, phosphorus, and silicon elements were found. Furthermore, it was revealed that sulfur was found, which was considered to be one of the complicated causes of implant failure in patients with BRONJ

A 10-year survival rate of tapered self-tapping bone-level implants from medically compromised Korean patients at a maxillofacial surgical unit

Background The 10-year survival rate of dental implants in healthy subjects is 90–95%. While in healthy individuals, dental implants have become commonplace to solve problems of edentulism, whether dental implant treatment is optimal in patients with systemic disease remains unclear. The purpose of this study is to investigate the clinical outcomes of tapered, sand-blasted, and acid-etched internal submerged dental implants installed in medically compromised patients in our maxillofacial surgical unit. Methods A total of 1019 Luna® dental implants were placed in 333 patients at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Kaplan–Meier survival estimates after 10 years of follow-up were computed for healthy vs. medically compromised patients. Results The 10-year follow-up survival rate of 1019 Luna® dental implants in the Korean maxillofacial surgical unit was 97.0% with a mean follow-up of 41.13 ± 35.13 months (0–120 months). The survival rate was 97.0%, in which 31 implants were failed during the follow-up. Cumulative 10-year implant survival rates were 99.4% in healthy individuals without systemic disease and 95.9% in patients with systemic disease. Conclusions Comparable success and survival rates were achieved with those of implants in healthy patients. Preoperative general health assessments including laboratory test results and checking the previous medication records are essential in diagnosing any unrecognized conditions for improved implant success rates in medically compromised patients