A highly automated, continuous method for developing active controllers of product quality attributes in early phase clinical development

The biotherapeutics industry is aggressively targeting increases in product quality. It has been recently suggested that a 10x increase in robustness of product quality will be required in the next 5-10 years to meet the changing market forces of our industry1. This step-increase in quality will likely only be achieved by actively controlling product quality attributes in bioproduction processes, using techniques like model predictive control (MPC)2. Adoption of MPC of product quality attributes in bioproduction processes has been somewhat sluggish, despite the recent introduction of enabling technologies, such as aseptic auto samplers. One barrier for adoption of MPC is the current difficulty involved in developing MPC controllers. This difficulty stems from the fact that critical to quality process technologies like MPC must be adopted early in the drug development process to achieve consistent clinical material throughout the drug development process. There remains a need for a method to quickly and cheaply develop MPC strategies during early phase development for biomanufacturing processes Please click Additional Files below to see the full abstract

Autonomy Infused Teleoperation with Application to BCI Manipulation

Robot teleoperation systems face a common set of challenges including latency, low-dimensional user commands, and asymmetric control inputs. User control with Brain-Computer Interfaces (BCIs) exacerbates these problems through especially noisy and erratic low-dimensional motion commands due to the difficulty in decoding neural activity. We introduce a general framework to address these challenges through a combination of computer vision, user intent inference, and arbitration between the human input and autonomous control schemes. Adjustable levels of assistance allow the system to balance the operator's capabilities and feelings of comfort and control while compensating for a task's difficulty. We present experimental results demonstrating significant performance improvement using the shared-control assistance framework on adapted rehabilitation benchmarks with two subjects implanted with intracortical brain-computer interfaces controlling a seven degree-of-freedom robotic manipulator as a prosthetic. Our results further indicate that shared assistance mitigates perceived user difficulty and even enables successful performance on previously infeasible tasks. We showcase the extensibility of our architecture with applications to quality-of-life tasks such as opening a door, pouring liquids from containers, and manipulation with novel objects in densely cluttered environments

Data integration methodology that couples novel bioreactor monitoring tools, automated sampling, and applied mathematics to redefine bioproduction processes

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Use of an automated, integrated laboratory environment to enable predictive modeling approaches for identifying critical process parameters and controlling key quality attributes

An essential part of ensuring a high quality medicine is being able to reliably control Critical Quality Attributes (CQA’s). In the cell culture process, bioreactor conditions, feeds, cell state are some of the many variables that affect CQA’s. Out of this very large set of possible variables, the small subset of these (i.e., critical process parameters, or CPP’s) that have a large effect on the CQA’s must be identified and understood such that those CPP’s can be controlled to ensure quality product. Here, we demonstrate the use of predictive modeling techniques to supplement experimental bioreactor studies when defining critical process parameters (CPP’s) and generating process control strategies. Using predictive models to relate culture process conditions to CQA’s has the benefit of enabling both: 1) using model predictions to supplement experimental data when determining critical process parameters (CPP’s) and the resulting control strategy, and 2) active control of CQA’s based on model forecasts to achieve finer control of CQA’s. In order to support this predictive forecasting approach for bioreactor process definition and control, Bend Research has developed a new bioreactor laboratory environment that allows us to run the right experiments, take the right data, and determine which measurements are actually important in determining CQA’s, and to generate model predictions based on those data sets. Here we demonstrate the application of this new laboratory paradigm in practice, using galactosylation, an important product quality attribute, as the “CQA” of interest. We show how through using automated, perfusion-type systems identification experiments, combined with automated data-generation and reduction tools, we can generate a prediction of the effect of galactose feeding on product qualit

Flat Lens Focusing Demonstrated With Left-Handed Metamaterial

Left-handed metamaterials (LHM's) are a new media engineered to possess an effective negative index of refraction over a selected frequency range. This characteristic enables LHM's to exhibit physical properties never before observed. In particular, a negative index of refraction should cause electromagnetic radiation to refract or bend at a negative angle when entering an LHM, as shown in the figure above on the left. The figure on the right shows that this property could be used to bring radiation to a focus with a flat LHM lens. The advantage of a flat lens in comparison to a conventional curved lens is that the focal length could be varied simply by adjusting the distance between the lens and the electromagnetic wave source. In this in-house work, researchers at the NASA Glenn Research Center developed a computational model for LHM's with the three-dimensional electromagnetic commercial code Microwave Studio, constructed an LHM flat lens, and used it to experimentally demonstrate the reversed refraction and flat lens focusing of microwave radiation

Buttressing staples with cholecyst-derived extracellular matrix (CEM) reinforces staple lines in an ex vivo peristaltic inflation model

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer Science + Business Media, LLC 2008Background - Staple line leakage and bleeding are the most common problems associated with the use of surgical staplers for gastrointestinal resection and anastomotic procedures. These complications can be reduced by reinforcing the staple lines with buttressing materials. The current study reports the potential use of cholecyst-derived extracellular matrix (CEM) in non-crosslinked (NCEM) and crosslinked (XCEM) forms, and compares their mechanical performance with clinically available buttress materials [small intestinal submucosa (SIS) and bovine pericardium (BP)] in an ex vivo small intestine model. Methods - Three crosslinked CEM variants (XCEM0005, XCEM001, and XCEM0033) with different degree of crosslinking were produced. An ex vivo peristaltic inflation model was established. Porcine small intestine segments were stapled on one end, using buttressed or non-buttressed surgical staplers. The opened, non-stapled ends were connected to a peristaltic pump and pressure transducer and sealed. The staple lines were then exposed to increased intraluminal pressure in a peristaltic manner. Both the leak and burst pressures of the test specimens were recorded. Results - The leak pressures observed for non-crosslinked NCEM (137.8 ± 22.3 mmHg), crosslinked XCEM0005 (109.1 ± 14.1 mmHg), XCEM001 (150.1 ± 16.0 mmHg), XCEM0033 (98.8 ± 10.5 mmHg) reinforced staple lines were significantly higher when compared to non-buttressed control (28.3 ± 10.8 mmHg) and SIS (one and four layers) (62.6 ± 11.8 and 57.6 ± 12.3 mmHg, respectively) buttressed staple lines. NCEM and XCEM were comparable to that observed for BP buttressed staple lines (138.8 ± 3.6 mmHg). Only specimens with reinforced staple lines were able to achieve high intraluminal pressures (ruptured at the intestinal mesentery), indicating that buttress reinforcements were able to withstand pressure higher than that of natural tissue (physiological failure). Conclusions - These findings suggest that the use of CEM and XCEM as buttressing materials is associated with reinforced staple lines and increased leak pressures when compared to non-buttressed staple lines. CEM and XCEM were found to perform comparably with clinically available buttress materials in this ex vivo model.Enterprise Irelan

The critically ill patient after hepatobiliary surgery

BACKGROUND: We analyzed the causes and results of utilization of critical care services in the special care unit in patients after surgical procedures performed by the hepatobiliary surgical service during a 23-month period. RESULTS: Thirty-two of 537 patients (6.0%) required postoperative admission to the special care unit. Twenty-one patients were admitted directly from operating room or from recovery room because of inability to wean from ventilator (n = 10), hypovolemic shock (n = 4), myocardial ischemia or infarction (n = 2), sepsis (n = 2), upper gastrointestinal bleeding (n = 2), and acute renal failure (n =1). Eleven postoperative patients were admitted from floor care for respiratory failure (n = 4), cardiac dysrhythmia or infarction (n = 4), sepsis (n = 2), and upper gastrointestinal bleeding (n = 1). Thirty-eight per cent of patients (n = 12) admitted to the special care unit after surgery died. By multivariate analysis, total postoperative stay in the special care unit that was greater than median total duration of stay of 4.5 days was the only independent predictor of mortality (P = 0.041). CONCLUSIONS: Respiratory failure was the predominant component of all complications after hepatobiliary surgery. No clinically useful predictors of eventual outcome could be identified

Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus

Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. Cyp

Human alveolar macrophage metabolism is compromised during Mycobacterium tuberculosis infection

Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a virulent strain of Mycobacterium tuberculosis (H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for Mtb survival and that metabolic reprogramming may be a viable host targeted therapy against TB