Spatially selective delivery of living magnetic microrobots through torque-focusing.

Rotating magnetic fields enable biomedical microrobots to overcome physiological barriers and promote extravasation and accumulation in tumors. Nevertheless, targeting deeply situated tumors requires suppression of off-target actuation in healthy tissue. Here, we investigate a control strategy for applying spatially selective torque density to microrobots by combining rotating fields with magnetostatic selection fields. Taking magnetotactic bacteria as diffuse torque-based actuators, we numerically model off-target torque suppression, indicating the feasibility of centimeter to millimeter resolution for human applications. We study focal torque application in vitro, observing off-target suppression of actuation-dependent effects such as colonization of bacteria in tumor spheroids. We then design and construct a mouse-scale torque-focusing apparatus capable of maneuvering the focal point. Applying this system to a mouse tumor model increased accumulation of intravenously injected bacteria within tumors receiving focused actuation compared to non-actuated or globally actuated groups. This control scheme combines the advantages of torque-based actuation with spatial targeting.

3D magnetically controlled spatiotemporal probing and actuation of collagen networks from a single cell perspective.

Cells continuously sense and react to mechanical cues from their surrounding matrix, which consists of a fibrous network of biopolymers that influences their fate and behavior. Several powerful methods employing magnetic control have been developed to assess the micromechanical properties within extracellular matrix (ECM) models hosting cells. However, many of these are limited to in-plane sensing and actuation, which does not allow the matrix to be probed within its full 3D context. Moreover, little attention has been given to factors specific to the model ECM systems that can profoundly influence the cells contained there. Here we present methods to spatiotemporally probe and manipulate extracellular matrix networks at the scale relevant to cells using magnetic microprobes (µRods). Our techniques leverage 3D magnetic field generation, physical modeling, and image analysis to examine and apply mechanical stimuli to fibrous collagen matrices. We determined shear moduli ranging between hundreds of Pa to tens of kPa and modeled the effects of proximity to rigid surfaces and local fiber densification. We analyzed the spatial extent and dynamics of matrix deformation produced in response to magnetic torques on the order of 10 pNm, deflecting fibers over an area spanning tens of micrometers. Finally, we demonstrate 3D actuation and pose extraction of fluorescently labelled µRods.

A Pulsatile Flow System to Engineer Aneurysm and Atherosclerosis Mimetic Extracellular Matrix.

Alterations of blood flow patterns strongly correlate with arterial wall diseases such as atherosclerosis and aneurysm. Here, a simple, pumpless, close-loop, easy-to-replicate, and miniaturized flow device is introduced to concurrently expose 3D engineered vascular smooth muscle tissues to high-velocity pulsatile flow versus low-velocity disturbed flow conditions. Two flow regimes are distinguished, one that promotes elastin and impairs collagen I assembly, while the other impairs elastin and promotes collagen assembly. This latter extracellular matrix (ECM) composition shares characteristics with aneurysmal or atherosclerotic tissue phenotypes, thus recapitulating crucial hallmarks of flow-induced tissue morphogenesis in vessel walls. It is shown that the mRNA levels of ECM of collagens and elastin are not affected by the differential flow conditions. Instead, the differential gene expression of matrix metalloproteinase (MMP) and their inhibitors (TIMPs) is flow-dependent, and thus drives the alterations in ECM composition. In further support, treatment with doxycycline, an MMP inhibitor and a clinically used drug to treat vascular diseases, halts the effect of low-velocity flow on the ECM remodeling. This illustrates how the platform can be exploited for drug efficacy studies by providing crucial mechanistic insights into how different therapeutic interventions may affect tissue growth and ECM assembly.

Non-Newtonian Blood Flow Simulation of Diastolic Phase in Bileaflet Mechanical Heart Valve Implanted in a Realistic Aortic Root Containing Coronary Arteries.

Coronary arteries, which are branched from the sinuses, have tangible effects on the hemodynamic performance of the bileaflet mechanical heart valve (BMHV), especially in the diastolic phase. To better understand this issue, a computer model of ascending aorta including realistic sinus shapes and coronary arteries has been generated in this study in order to investigate the BMHV performance during diastole. Three-dimensional transient numerical analysis is conducted to simulate the diastolic blood flow through the hinges and in coronary arteries under the assumption of non-Newtonian behavior. Results indicate that as blood flows to the coronary arteries mainly during diastole, leakage flow from the hinge and other gaps will change considering the influence of coronary arteries. In addition, BMHV in the case of aortic replacement will increase blood flow rate into the coronary arteries about 100% as the mechanical valve resistance is higher than a native heart valve. Also, it will change the wall shear stress (WSS) distribution and increase coronary artery disease (CAD) potential. It is found out that although less leakage flow reduces the velocity magnitudes through the gaps, the shear stress acting on blood elements with non-Newtonian assumption will be detrimental in the hinge corner at the ventricular side. High WSS of 1800 Pa is observed at beginning of diastole at this region.

On-X Heart Valve Prosthesis: Numerical Simulation of Hemodynamic Performance in Accelerating Systole.

Numerical simulation of the bileaflet mechanical heart valves (BMHVs) has been of interest for many researchers due to its capability of predicting hemodynamic performance. A lot of studies have tried to simulate this three-dimensional complex flow in order to analyze the effect of different valve designs on the blood flow pattern. However, simplified models and prescribed motion for the leaflets were utilized. In this paper, transient complex blood flow in the location of ascending aorta has been investigated in a realistic model by fully coupled simulation. Geometry model for the aorta and the replaced valve is constructed based on the medical images and extracted point clouds. A 23-mm On-X Medical BMHV as the new generation design has been selected for the flow field analysis. The two-way coupling simulation is conducted throughout the accelerating phase in order to obtain valve dynamics in the opening process. The complex flow field in the hinge recess is captured precisely for all leaflet positions and recirculating zones and elevated shear stress areas have been observed. Results indicate that On-X valve yields relatively less transvalvular pressure gradient which would lower cardiac external work. Furthermore, converging inlet leads to a more uniform flow and consequently less turbulent eddies. However, the leaflets cannot open fully due to middle diffuser-shaped orifice. In addition, asymmetric butterfly-shaped hinge design and converging orifice leads to better hemodynamic performance. With the help of two-way fluid solid interaction simulation, leaflet angle follows the experimental trends more precisely rather than the prescribed motion in previous 3D simulations.