In Vitro Research with Stretchable MicroElectrode Arrays (sMEAs)

Advantages of in vitro research:

  • tight control of chemical and physical environment

  • cheaper

  • faster

  • fewer animals are needed

However, one of the substantial weaknesses of in vitro experiments is that they fail to replicate the conditions of cells in an organism, e.g., isolated and cultivated primary cells usually differ strongly from the corresponding cell type in an organism, limiting the value of in vitro data to predict in vivo behavior.

BMSEED’s MEASSuRE system addresses this weakness by reproducing the mechanical and electrical environment of cells in vivo in a controlled environment in vitro with the goal to bridge the gap between in vitro and in vivo research.

This capability is enabled by a combination of BMSEED’s stretchable multielectrode array (sMEA), which contains elastically stretchable electrodes embedded in an elastomeric matrix that contact the cell or tissue culture. MEASSuRE contains the hardware to mechanically stretch, optically image, and electrically stimulate/record from the cells/tissue on the stretchable MEA.

In the Past,

researchers had to choose between electrical, mechanical biophysical cues and electrophysiological measurements for in vitro research. No more.

With the MEASSuRE platform,

researchers do NOT need to choose between electrical and mechanical biophysical cues for in vitro research. The cell and tissue cultures are grown on silicone substrates with embedded microelectrodes. These stretchable microelectrode arrays (sMEAs) enable to interface mechanically and electrically with a cell or tissue culture.

Unique Value Proposition and Benefits of MEASSuRE

A.    Concurrent mechanical, optical and electrical interface with a cell culture:

The unique feature of MEASSuRE is that it combines three modes of interaction with a cell or tissue culture: mechanical, optical, and electrical. The following benefits are gained from this capability.

  1. Comparison of pre- and post-stretch: MEASSuRE allows the normalization of post-stretch electrophysiological activity of the cell/tissue to pre-stretch level because the microelectrodes on the stretchable MEA stretch with the cells/tissue, i.e., they remain in contact with the same location on the tissue (or cell culture) before, during, and after stretching. This is a unique value proposition of MEASSuRE that is enabled by our patented stretchable microelectrode technology.

  2. Repeated stretch and relaxation: The microelectrodes of the stretchable MEA elastically stretch with the tissue, allowing for cyclic or repeated stretching. This capability is important for the investigation of the effects of repeated injuries (e.g., concussions), and for Organ-on-a-Chip and regenerative medicine applications.

  3. Tissue strain verification: The strain that the cells experience depends on the strength and uniformity of cell adhesion to the underlying silicone membrane, and is not necessarily the same as the strain on the PDMS substrate of the stretchable MEA, which depends on the displacement over the indenter. It is therefore important to be able to determine exactly by how much the cells have been stretched. MEASSuRE provides this capability. By design, the cells remain in the focal plane of the lens during stretching, i.e., cells can be imaged throughout the stretching process with the built-in high speed camera. BMSEED’s MATLAB-based image analysis software allows to calculate the strain of the cells using these images.

  4. Convenience and time saving: Being able to perform three operations with one tool is convenient, and saves time and space compared to having to use 2 or 3 separate tools.

B.    High reproducibility of strain: A Voice Coil Actuator (VCA) produces the motion to generate the strain on the stretchable MEA and tissue by pulling the stretchable section of the stretchable MEA over a cylindrical indenter. A position sensor that is built into the VCA and a PID controller allow precise closed-loop motion control.

C.    High versatility: Any stretch pattern within the limits of the VCA with respect to acceleration, velocity, and stroke, can be programmed using macros.

D.    High strain: MEASSuRE produces strains of up to 50%.

E.    High strain rate: MEASSuRE is able to produce sufficiently high velocity and acceleration for very high strain rates of >90/s because a low friction voice coil actuator (VCA) is used to produce the stretch motion.

F.    Radial and linear strain: MEASSuRE is able to produce radial and linear strain in the same tool. Only the type of indenter over which the stretchable MEA is pulled needs to be exchanged.

G.    Price: The price for a MEASSuRE system will be lower than the combined purchase price for three systems from different vendors.

How MEASSuRE Works

Morrison et al., Journal of Neuroscience Methods, 150:192, 2006.

The cells are stretched by pulling the silicone membrane with the embedded microelectrodes over the indenter. The electrodes stretch with the tissue, thus being able to record neural activity before and after stretching from the same location.

Assess Cell Health & Maturity with Electrophyiological Measurements

Before Stretching: The electrodes record neural activity prior to cell stretching.

During Stretching: The stretchable electrodes move with the tissue during the stretching motion.

After Stretching: The stretchable electrodes record neural activity from the same location as before the stretching motion.

Cells in the Body are Exposed to Two Types of Mechanical Environments

Physiological stretch, where the cells are stretched within their healthy limits:

The differentiation of stem cells into a specific cell type is regulated by micro-environmental cues, such as chemical factors, mechanical forces, and electrical fields. Existing products to direct the differentiation of stem cells are using chemical factors alone, or in combination with either mechanical forces or electrical fields. MEASSuRE provides the only method for researchers to manipulate these three factors independently, which will allow for the generation of organs and tissue that resemble the mature organs in vivo more closely than current approaches, i.e., they will more closely replicate the complexity of the human body.

Pathological stretch, where cells are stretched beyond their healthy limits, causing a trauma:

MEASSuRE reproduces the biomechanics of a neurotraumatic injury (traumatic brain injury, TBI; spinal cord injury, SCI) or muscle injury in a controlled environment in vitro. The electrodes in the stretchable MEA stretch with the cells/tissue, i.e., they remain in contact with the same location on the tissue before, during, and after stretching. This capability allows for a direct, straightforward assessment of the damage to the injured cells by comparing the electrophysiology (e.g., signal amplitude and frequency) of the cells post-injury to pre-injury level, i.e., MEASSuRE is a screening platform to assess the efficacy of drugs and other treatment strategies for neurotraumatic injuries. The screening is based on the electrophysiology of the injured cells and tissue slices. The electrodes in sMEAs are elastically stretchable, i.e., they also allow the investigation of repeated injuries of the same cells/tissue, e.g., to investigate the cellular and molecular mechanisms of repeated concussions (mild TBI), which is poorly understood.

MEASSuRE serves as a platform to enable fundamentally improved methods to investigate physiological stretch and pathological stretch of cells in a controlled in vitro environment. In addition, MEASSuRE allows optical imaging of the cells throughout the stretching process for verification of the tissue strain and to detect morphological changes in the tissue.