An experimentally validated cavitation inception model for spring-driven autoinjectors.

Cavitation, the formation and collapse of vapor-filled bubbles, poses a problem in spring-driven autoinjectors (AIs). It occurs when the syringe accelerates abruptly during activation, causing pressure fluctuations within the liquid. These bubbles expand and then collapse, generating shock waves that can harm both the device and the drug molecules. This issue stems from the syringe's sudden acceleration when the driving rod hits the plunger. To better understand cavitation in AIs, we explore how design factors like drive spring force, air gap size, and fluid viscosity affect its likelihood and severity. We use a dynamic model for spring-driven autoinjectors to predict and analyze the factors contributing to cavitation initiation and severity. This model predicts the motion of AI components, such as the displacement and velocity of the syringe barrel, and allows us to investigate pressure wave propagation and the subsequent dynamics of cavitation under various operating conditions. We investigated different air gap heights (from 1 to 4 mm), drive spring forces (from 8 to 30 N), and drug solution viscosities (from 1 to 18 cp) to assess cavitation inception based on operational parameters. Results reveal that AI dynamics and cavitation onset and severity strongly depend upon AI operating parameters, namely drive spring force and air gap height. The maximum syringe acceleration increases with spring stiffness and decreases with air gap height; increases in air gap height prolong the time interval of syringe acceleration but diminish the maximum syringe acceleration. From actuation to injection, air gap pressure peaks twice, first due to impact with the rod/plunger and secondly due to the deacceleration event upon injection. The maximum air gap pressure increases with spring stiffness and decreases with air gap height. Results show that maximum cavitation bubble radii and collapse-driven extension rates occur with higher driver spring forces, smaller air gap heights, and less viscous solutions. A cavitation criterion is developed for cavitation in autoinjectors that concludes that cavitation in autoinjectors depends on the peak syringe acceleration.

A numerical lift force analysis on the inertial migration of a deformable droplet in steady and oscillatory microchannel flows.

Inertial migration of deformable particles has become appealing in recent years due to its numerous applications in microfluidics and biomedicine. The physics underlying the motion of these particles is contingent upon the presence of lift forces in microchannels. Therefore, in this work, we present a lift force analysis for such migration of a deformable droplet in steady and oscillatory flow regimes and identify the effects of varying Capillary number and oscillation frequency on its dynamics. We then propose an expression that mimics the lift force behavior in oscillatory flows accurately. Finally, we introduce a procedure to derive and predict a simple expression for the steady and averaged oscillatory lift for any given combination of Capillary number and oscillation frequency within a continuous range.

Modeling cavitation bubble dynamics in an autoinjector and its implications on drug molecules.

The collapse of cavitation bubbles induced by abrupt acceleration of the syringe in an autoinjector device can lead to protein aggregation. The details of bubble dynamics are investigated using an axisymmetric, three-dimensional simulation with passive tracers to illustrate the transport of protein molecules. When a bubble near the syringe wall collapses, protein molecules are concentrated in the re-entrant jet, pushed towards the syringe wall, and then spread across the wall, potentially leading to protein adsorption on the syringe wall and aggregation. This phenomenon is more prominent for bubbles positioned closer to the bottom wall, growing to a larger maximum radius. The bubble's maximum radius decreases with the bubble's distance from the syringe wall and air gap pressure, and increases with an increase in liquid column height and nucleus size. The strain rate induced by the bubble collapse is not large enough to unfold the proteins. When the re-entrant jet impacts the bubble surface or syringe wall, the bubble breaks up, generating smaller bubbles with high surface concentration of protein molecules, potentially inducing aggregation in the bulk. The bubble dynamics are influenced by dimensionless distance of the nucleus from the wall, normalized by maximum bubble radius (γ). The re-entrant jet velocity increases with γ, while the maximum liquid pressure, typically 100∼1000 bar, first decreases and then increases with γ. For a cloud of cavitation bubbles, i.e., closely clustered bubbles, coalescence of bubbles can occur, leading to a higher peak pressure at collapse.

Monitoring heterogeneity in therapeutic samples using Schlieren.

Antigen, antibodies, and other therapeutic biomolecule solutions are likely to undergo physical and chemical processes during their development, manufacturing, transport, and storage. This can induce internal stresses in the sample, resulting in aggregation, heterogeneities, and an overall reduction in the sample quality, e.g., freeze-thawing of samples for storage. Monitoring mixing is thus crucial to ensure homogeneity and consistency while further optimizing downstream processes. We present a simple and portable all-lens Schlieren setup to detect, visualize, and quantify heterogeneities in the protein/antigen or other pharmaceutical solutions during and after thawing in real-time. We illustrate the capabilities of the proposed method by visualizing and quantifying heterogeneities during the thawing of BSA and IgG in four different formulation buffers. The local concentration gradients in a thawing sample lead to light intensity variations which are captured using the Schlieren technique. The sample heterogeneity can then be quantified by relating these light intensity variations to concentration gradients. To this end, we first measure the refractive index of the sample solutions, which varies linearly with the sample concentration. This linear relation is then used to extract the concentration gradient field from the light intensity data. We establish the validity of the proposed approach by demonstrating its accuracy in measuring the diffusion coefficient of a diffusing interface. The portability of the setup and its applicability to a wide range of pharmaceutical solutions make this Schlieren-based technique suitable for monitoring the mixing, heterogeneity, and stability of pharmaceutical samples.

Inertial migration of a deformable capsule in an oscillatory flow in a microchannel.

Dynamics of a deformable capsule in an oscillatory flow of a Newtonian fluid in a microchannel has been studied numerically. The effects of oscillation frequency, capsule deformability, and channel flow rate have been explored by simulating the capsule within a microchannel. In addition, the simulation captures the effect of the type of imposed pressure oscillations on the migration pattern of the capsule. An oscillatory channel flow enables the focusing of extremely small biological particles by eliminating the need to design impractically long channels. The presented results show that the equilibrium position of the capsule changes not only by the addition of an oscillatory component to the pressure gradient but it also is influenced by the capsule deformability and channel flow rate. Furthermore, it has been shown that the amplitude of oscillation of capsules decreases as the channel flow rate and the rigidity of the capsule increases.

Elasto-inertial migration of deformable capsules in a microchannel.

In this paper, we study the dynamics of deformable cells in a channel flow of Newtonian and polymeric fluids and unravel the effects of deformability, elasticity, inertia, and size on the cell motion. We investigate the role of polymeric fluids on the cell migration behavior and the performance of inertial microfluidic devices. Our results show that the equilibrium position of the cell is on the channel diagonal, in contrast to that of rigid particles, which is on the center of the channel faces for the same range of Reynolds number. A constant-viscosity polymeric fluid, modeled using an Oldroyd-B constitutive equation, drives the cells toward the channel centerline, while a shear-thinning polymeric fluid, modeled using a Giesekus constitutive equation, pushes the cells toward the channel wall. The findings of this paper suggest that the addition of polymers in microfluidic devices can be used to enhance the throughput of cell focusing and separation devices at a low cost. This study provides an insight on the role of rheological properties of the fluid and the ways that they can be tuned to control the focal position of the cells.

Deformation and buckling of microcapsules in a viscoelastic matrix.

In this paper, we numerically study the dynamics of (1) a Newtonian liquid-filled capsule in a viscoelastic matrix and that of (2) a viscoelastic capsule in a Newtonian matrix in a linear shear flow using a front-tracking method. The numerical results for case (1) indicate that the polymeric fluid reduces the capsule deformation and aligns the deformed capsule with the flow direction. It also narrows the range of tension experienced by the deformed capsule for case (1), while the tank-treading period significantly increases. Interestingly, the polymeric fluid has an opposite effect on the tank-treading period and the orientation angle of case (2), but its effect on the deformation is similar to case (1).