HemaMax™, a Recombinant Human Interleukin-12, Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates

HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8–9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit–expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD50/30) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12–14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting hematopoiesis and recovery of immune functions and possibly gastrointestinal functions, likely through a network of interactions involving dendritic cells, osteoblasts, and soluble factors such as IL-12, IFN-γ, and cytoprotectant erythropoietin

Using CFD Simulations to Guide the Development of a New Spray Dryer Design

A new spray-drying system has been designed to overcome the limitations caused by existing designs. A key feature of the approach has been the systematic use of Computational Fluid Dynamics (CFD) to guide innovation in the design process. An example of an innovation is the development of a box-shaped transitional feature between the bottom of the main drying chamber and the entrance to the secondary chamber. In physical experiments, the box design performed better in all three representative operating conditions, including the current conditions, a higher feed solids concentration (30% solids rather than 8.8%), and a higher inlet drying temperature (230 &deg;C rather than 170 &deg;C). The current conditions showed a 3% increase in yield (solids recovery) while the 30% feed condition improved the yield by 7.5%, and the higher temperature test increased the yield by 13.5%. Statistical analysis showed that there were significant reductions in the wall flux at the high solids feed concentration. The observed deposition in the box was primarily from the predicted particle impacts by an inertial deposition process on the base of the box, which underwent little degradation due to lower temperatures. There is therefore evidence that the box design is a better design alternative under all operating conditions compared with other traditional designs

Multifilm Mass Transfer and Time Constants for Mass Transfer in Food Digestion: Application to Gut-on-Chip Models

This review highlights the involvement of mass transfer in animal food-digestion processes. There may be several mass-transfer steps during the dissolution of food components, starting from the food itself, moving into the digestive juices, then moving through the walls of the gastrointestinal tract. These steps create a sequence of film resistances to mass transfer, where one film resistance often limits the overall mass-transfer process. Mass-transfer rates, mass-transfer coefficients, and the time scales and time constants for different parts of the food-digestion process are all interlinked, and the connections have been explained. In some parts of the food-digestion process, the time constants for the mass-transfer process are similar to the residence times for food digestion, emphasising the importance of mass transfer in these parts of food digestion, such as the duodenum. The mass-transfer and transport behaviour for in vivo human digestive systems and in vitro guts-on-a-chip may be very similar, suggesting that cells on the intestine walls, whether in vitro (guts-on-a-chip) or in vivo, may see similar transport behaviour for both nutrients towards the cells, and waste products away from them

Using Particle Residence Time Distributions as an Experimental Approach for Evaluating the Performance of Different Designs for a Pilot-Scale Spray Dryer

The performances of four different designs for a pilot-scale spray dryer have been evaluated and compared based on experimentally measured particle residence time distributions (RTD), recovery rates and physical properties of spray-dried fresh skim milk. The RTDs have been measured using a dye pulse injection method, and the measurements have been fitted to models using continuous stirred-tank reactors in series (CSTR-TIS) for quantitative performance evaluation and comparison. Conical drying chambers and a box connection design have been used in the latest dryer design to reduce the amount of wall deposition and provide a smoother gas flow pattern. The particle-to-gas mean residence time ratio for the latest design is significantly closer to unity (1.6 s/s to 1.0 s/s) compared with earlier designs (2.6 s/s to 1.5 s/s). The latest design has a wider spread of RTD (n = 5–8) compared with earlier designs (n = 13–18), which may be linked to the recirculation zone in the box connection. Although the latest design has a wider spread of RTD, the conical design has shown promising results compared with a cylindrical drying chamber in terms of overall wall deposition behaviours

Simulating Tablet Dissolution Using Computational Fluid Dynamics and Experimental Modeling

The study of mass transfer is essential in the food digestion process, especially when gastric acid interacts with food and nutrients dissolve in the gastric system. In this study, a computational fluid dynamics (CFD) model was built based on an in vitro study, which investigated the mass transfer in a tablet dissolution process in a beaker and stirrer system. The predicted mass transfer coefficients from the simulation aligned well with the experimental values. The effect of the type and rotation speed of the stirrers was also investigated. Mass transfer from the tablet was found to be closely related to the tablet Reynolds number of the fluid (ranging from 0 to 938) and the shear stress (0 to 0.167 Pa) acting on the tablet. The relationship between the power number (0.0061 to 0.196) and the Reynolds number for the impeller (719 to 5715) was also derived for different stirrers

Simulating Flow in an Intestinal Peristaltic System: Combining In Vitro and In Silico Approaches

Transport and mixing in the gastric duct occur via peristaltic flow. In vivo data are hard to collect and require strict ethical approval. In contrast, both in vitro and in silico studies allow detailed investigation and can be constructed to answer specific questions. Therefore, the aim of this study was to design a new elastic thermoplastic polyurethane (TPU) intestine model and to compare the flow patterns observed experimentally with those predicted by a Fluid Structure Interaction (FSI) simulation. Here, we present complementary studies that allow feedback to improve both techniques and provide mutual validation. The experimental work provides direct measurement of mixing, and the simulation allows the experimental setup to be studied to determine the impacts of various parameters. We conclude by highlighting the utility of this approach