ABSTRACT
Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches. Precise regulation of these cell types can remodel niches and develop new therapeutics. Multiple nanocarriers have been developed to transport drugs into the bone marrow selectively. However, the delivery efficiency of these nanotherapeutics into crucial niche cells is still unknown, and there is no method available for predicting delivery efficiency in these cell types. Here, we constructed a three-dimensional bone marrow niche composed of three crucial cell populations: endothelial cells (ECs), mesenchymal stromal cells (MSCs), and osteoblasts (OBs). Mimetic niches were used to detect the cellular uptake of three typical drug nanocarriers into ECs/MSCs/OBs in vitro. Less than 5% of nanocarriers were taken up by three stromal cell types, and most of them were located in the extracellular matrix. Delivery efficiency in sinusoidal ECs, arteriole ECs, MSCs, and OBs in vivo was analyzed. The correlation analysis showed that the cellular uptake of three nanocarriers in crucial cell types in vitro is positively linear correlated with its delivery efficiency in vivo. The delivery efficiency into MSCs was remarkably higher than that into ECs and OBs, no matter what kind of nanocarrier. The overall efficiency into sinusoidal ECs was greatly lower than that into arteriole ECs. All nanocarriers were hard to be delivered into OBs (<1%). Our findings revealed that cell tropisms of nanocarriers with different compositions and ligand attachments in vivo could be predicted via detecting their cellular uptake in bone marrow niches in vitro. This study provided the methodology for niche-directed nanotherapeutics development.
ABSTRACT
BACKGROUND: Simulation of the emitted acoustic field is crucial to the design of ultrasound transducers. The method based on the spatial impulse response (SIR) and aperture discretization provides a powerful tool to study the acoustic field emitted by a transducer with complex aperture geometry and sophisticated apodization/excitation pattern. METHODS: In this work, a new method based on the dynamically refined sub-elements (SE) is employed to discrete the aperture and generate the SIR. Then, these SIRs are convoluted with the excitation pulse to get the acoustic pressure (AP) signal. When calculating the SIR with this method, the slowly changed time flight from a SE to a field point (FP) is approximated with a step function, and the fast changed length of intersection between a SE and a spherical wave centered at a FP is accurately estimated with the areas of the sub-parts (SP) which are given by the dynamically refined SE. RESULTS: Simulations of the acoustic field created by a focusing transducer array and a hollow structured point focusing transducer indicate that the proposed new method can give similar data accuracy with a sampling frequency 16 times lower than the conventional time tracing SE (TTSE) based method. The computational cost is also reduced by nearly one order of magnitude. CONCLUSIONS: A new method is proposed to simulate the acoustic field emitted by transducers with complex geometrical structure and sophisticated apodization/excitation patterns. The required sampling frequency with the new algorithm is greatly reduced compared to that of the conventional TTSE-based method; thus, the efficiency of the acoustic field calculation is improved significantly.
