High‐Throughput Magnetic Actuation Platform for Evaluating the Effect of Mechanical Force on 3D Tumor Microenvironment

Abstract

Accurately replicating and analyzing cellular responses to mechanical cues is vital for exploring metastatic disease progression. However, many of the existing in vitro platforms for applying mechanical stimulation seed cells on synthetic substrates. To better recapitulate physiological conditions, a novel actuating platform is developed with the ability to apply tensile strain on cells at various amplitudes and frequencies in a high‐throughput multi‐well culture plate using a physiologically relevant substrate. Suspending fibrillar fibronectin across the body of the magnetic actuator provides a matrix representative of early metastasis for 3D cell culture that is not reliant on a synthetic substrate. This platform enables the culturing and analysis of various cell types in an environment that mimics the dynamic stretching of lung tissue during normal respiration. Metabolic activity, YAP activation, and morphology of breast cancer cells are analyzed within one week of cyclic stretching or static culture. Further, matrix degradation is significantly reduced in breast cancer cell lines with metastatic potential after actuation. These new findings demonstrate a clear suppressive cellular response due to cyclic stretching that has implications for a mechanical role in the dormancy and reactivation of disseminated breast cancer cells to macrometastases.

Monitoring and modulation of the tumor microenvironment for enhanced cancer modeling

“…149 One such example uses a magnetic actuating platform to mimic respiration-induced tissue stretching in vitro . 150 Results show actuation of breast cancer cells decreases metabolic activity and inhibits matrix degradation, indicating a potential role in dormancy and reactivation. 150 To improve the structural composition of tumor models, microscale organization of cells, and bioactive materials can be achieved using bioprinting and scaffold technologies.…”

In Vitro Magnetic Techniques for Investigating Cancer Progression

“…For example, Enríquez et al recently used cantilever magnetic actuators to cyclically stretch fibronectin, a glycoprotein with elastic properties, in an effort to mimic the breathing cycle of the lungs as a platform to study changes in disseminated breast cancer cells upon arrival to the common metastatic location. The material experienced uniaxial stretching as the distance from the cantilever edge and the device's outer frame changed due to the out-of-plane deflection [35].…”

“…In vitro, the contactless, but precise, movement attainable with magnetic force can better preserve the sterility of biological samples and simplifies fabrication within the confines of traditional culturing equipment, such as commercial cell culture well plates, Petri dishes, and incubators, as compared to other force-generating apparatuses (e.g., pneumatics, electrostatic, piezoelectric, etc.) [35].…”

“…(c) Fabrication process of fibronectin-coated polydimethylsiloxane (PDMS) cantilever with embedded permanent magnet. The cantilever deflects once exposed to a magnetic field enabling cyclic actuation [35]. (d) Uniaxial stretching platform using magnetic posts to stretch a cell scaffold [121].…”

“…A main advantage of this recent design is the suspended matrix, which does not utilize any polymeric support mesh in the culture region of interest (Figure 2d). It also benefits from a high-throughput design, consisting of an array of permanent magnets in a linearly moving actuating platform that sits beneath a standard multi-well culture plate [35].…”