Name: home-based monitor for gait and activity analysis
Uploaded: 2019-08-08T13:30:00
Description: Watch this Scientific Journal Video about Home-Based Monitor for Gait and Activity Analysis at JoVE.com

The authors thank Anne-Ga&#235;lle Le Moing, Am&#233;lie Moreaux, and Eric Dorveaux for their contribution to the development of this wearable magneto-inertial sensor and Jackie Wyatt for the review.

Any use of the device must be carried out in accordance with the rules established by the reference protocol, validated by the ethics committee and the national regulatory agencies of the country. The use of the device and the various elements attached to it must be done within the intended use described in the patient&#39;s manual.
NOTE: To be eligible to use of the WMIS, patient must be over 5 years old, be able to understand and follow the usage rules, provide informed consent, be affiliate...

<ol>
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M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ataluren+in+patients+with+nonsense+mutation+Duchenne+muscular+dystrophy+(ACT+DMD):+a+multicentre,+randomised,+double-blind,+placebo-controlled,+phase+3+trial.">Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.</a> The Lancet. 390 (10101), 1489-1498 (2017).</li><li>Aartsma-Rus, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+Exon+Skipping+Therapies+for+Duchenne+Muscular+Dystrophy:+A+Critical+Review+and+a+Perspective+on+the+Outstanding+Issues.">Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues.</a> Nucleic Acid Therapeutics. 27 (5), 251-259 (2017).</li><li>McDonald, C. 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M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Upper+Limb+Evaluation+and+One-Year+Follow+Up+of+Non-Ambulant+Patients+with+Spinal+Muscular+Atrophy:+An+Observational+Multicenter+Trial.">Upper Limb Evaluation and One-Year Follow Up of Non-Ambulant Patients with Spinal Muscular Atrophy: An Observational Multicenter Trial.</a> PLoS One. 10 (4), e0121799 (2015).</li><li>Servais, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Innovative+methods+to+assess+upper+limb+strength+and+function+in+non-ambulant+Duchenne+patients.">Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients.</a> Neuromuscular Disorders. 23 (2), 139-148 (2013).</li><li>Le Moing, A. 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H. M., Verheyen, C. C. P. M., Zijlstra, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+body-fixed-sensor+based+analysis+of+compensatory+trunk+movements+during+unconstrained+walking.">A body-fixed-sensor based analysis of compensatory trunk movements during unconstrained walking.</a> Gait &amp; Posture. 27 (1), 164-167 (2008).</li><li>Brandes, M., Zijlstra, W., Heikens, S., van Lummel, R., Rosenbaum, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accelerometry+based+assessment+of+gait+parameters+in+children.">Accelerometry based assessment of gait parameters in children.</a> Gait &amp; Posture. 24 (4), 482-486 (2006).</li><li>Liu, K., Liu, T., Shibata, K., Inoue, Y., Zheng, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Novel+approach+to+ambulatory+assessment+of+human+segmental+orientation+on+a+wearable+sensor+system.">Novel approach to ambulatory assessment of human segmental orientation on a wearable sensor system.</a> Journal of Biomechanics. 42 (16), 2747-2752 (2009).</li><li>Itoh, T., Morioka, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Developing+Leg-Motion+Measurement+System+Using+Acceleration+Sensors.">Developing Leg-Motion Measurement System Using Acceleration Sensors.</a> Electrical Engineering in Japan. 204 (1), 59-66 (2018).</li><li>Scott, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+functional+assessment+scale+for+ambulatory+boys+with+Duchenne+muscular+dystrophy.">Development of a functional assessment scale for ambulatory boys with Duchenne muscular dystrophy.</a> Physiotherapy Research International. 17 (2), 101-109 (2012).</li><li>Sonenblum, S. E., Sprigle, S., Caspall, J., Lopez, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Validation+of+an+accelerometer-based+method+to+measure+the+use+of+manual+wheelchairs.">Validation of an accelerometer-based method to measure the use of manual wheelchairs.</a> Medical Engineering &amp; Physics. 34 (6), 781-786 (2012).</li><li>Hiremath, S. V., Ding, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regression+equations+for+RT3+activity+monitors+to+estimate+energy+expenditure+in+manual+wheelchair+users.">Regression equations for RT3 activity monitors to estimate energy expenditure in manual wheelchair users.</a> 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society. , 7348-7351 (2011).</li><li>Ciuti, G., Ricotti, L., Menciassi, A., Dario, P. M. E. M. 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In the past decade, a number of different systems have been developed, such as an activity monitor (Table of Materials [IV]), which uses accelerometric sensors to monitor activities of daily life for energy expenditure quantification13. A triaxial accelerometer (Table of Materials [V]) was used by Tanaka et al.14 to monitor activity of preschool children. Lau et al.15 showed through the combination of a dual-accelero...

A number of potential therapies are in development for treatment of genetic neuromuscular diseases. These diseases include Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) type 3. Subjects with these diseases present initially with proximal lower limb weakness that leads to progressive difficulties in ambulation. The final step in translational research is the demonstration of efficacy of a potential treatment or approach in a clinical trial. Specific, quantifiable, objective, and reliable measures are required. The importance of such measures was recently emphasized by the failure of the phase IIb ataluren trial1 and the phase III Biomarin trial2. One of the likely explanations for these failures was the variability and the nonlinear evolution of the primary outcome measure of these trials, the 6-minute walk test3 (6 MWT). Increasing reliability and sensitivity to the change of outcome measures and the understanding of the factors leading to their variation could contribute to decrease the number of trial failures related to the main outcome measures.
One of the limitations of the current outcomes is the subjectivity of the assessment. To further increase the objectivity of assessments, Heberer et al.4 showed that through a marker set and the use of a gait analysis software, there was a significant increase in stride length in patients treated with steroids compared with the na&#239;ve group. Hip joint kinetics are early markers of proximal weakness in patients with DMD and are responsive to change with steroid intervention, which is the only available treatment for these patients. Gait laboratories are, however, only available in large clinics. Furthermore, laboratory evaluations are point assessments, and a patient&#8217;s condition may greatly vary on a day to day basis due to factors such as fatigue, motivation, and intercurrent illness.
The use of continuous and home-based measurement should achieve both a more objective and a more globally representative assessment. In other fields of neurology, for instance Parkinson5 or multiple sclerosis6, several studies have assessed the feasibility, reliability, and consistency with other measures of different sensors including accelerometers with or without gyrometers or magnetometers, yet none of these devices is currently a gold standard for evaluation of patients during clinical trials. In the field of neuromuscular diseases, there is currently no validated method for continuous home monitoring of patients. In recent years, through a close collaboration between clinicians and engineers, the Institute of Myology in Paris has developed several devices for upper limb assessment to precisely evaluate upper limb strength and function7,8,9. A wearable magneto-inertial sensor (WMIS; i.e., ActiMyo) has been developed in collaboration with a company specialized in navigation systems. Initially a monitoring device dedicated to non-ambulant subjects with neuromuscular disorders such as DMD and SMA10,11, the same device has now been used to monitor ambulant patients in two different configurations: sensors on both ankles or one sensor at the wrist and the other one at the ankle. The configuration for a non-ambulant population is composed of a sensor at the wheelchair and the other one at the wrist.
This WMIS is able to precisely capture and quantify all movements of the limb on which it is placed. The measuring principle is based on the use of microelectromechanical system (MEMS) inertial sensors and magnetometers operated through magneto-inertial equations. Dedicated algorithms allow precise qualification and quantification of patients&#8217; movements in a non-controlled environment.&#160;
The overall goal of the method is to provide identification and quantification of any movement produced by a patient over a pre-defined period of time, and to integrate these measures into disease-specific outcome measures representative of the patient&#8217;s condition over a period of time.
To effectively assess ambulant and non-ambulant patients with movement disorders at home, the device must be provided to the patient by a trained evaluator who is responsible for making sure that the instructions have been understood. An investigator and a patient manual are provided with the device. This WMIS is currently being used as an exploratory outcome measure in a number of clinical trials for neuromuscular and neurologic diseases (NCT03351270, NCT02780492, NCT01385917, NCT03039686, NCT03368742, NCT02500381). Specific procedures adapted to the pathology and/or to the clinical trial design have been developed.

<table>
	<tbody>
		<tr>
			<td>ActiMyo Sensors</td>
			<td>Sysnav</td>
			<td>SF-000080</td>
			<td>Wearable magneto-inertal sensors attached to the patient for movment recording</td>
		</tr>
		<tr>
			<td>Helen Hayes marker set</td>
			<td>Vicon</td>
			<td>NA</td>
			<td>Whole body jumpsuit with predefined Vicon&#39;s spots</td>
		</tr>
		<tr>
			<td>OrthoTrak (Motion Analysis, Santa Rosa, CA, USA)</td>
			<td>Motion Lab Systems</td>
			<td></td>
			<td>Gait analysis software</td>
		</tr>
		<tr>
			<td>ActiGraph</td>
			<td>ActiGraph Corp</td>
			<td>GTM1</td>
			<td>Activity monitor, used by researchers to capture and record continuous, high resolution physical activity and sleep/wake information</td>
		</tr>
		<tr>
			<td>ActivTracer GMS LTD</td>
			<td>GMS Co. Ltd Japan</td>
			<td>AC-301A</td>
			<td>Triaxial accelerometer</td>
		</tr>
		<tr>
			<td>ADXL202E dual-accelerometer</td>
			<td>Analog Devices</td>
			<td>ADXL212AEZ</td>
			<td>High precision, low power, complete dual axis accelerometer with signal conditioned, duty cycle modulated outputs, all on a single monolithic IC.</td>
		</tr>
		<tr>
			<td>ENC-03J gyroscope</td>
			<td>Murata Electronics</td>
			<td>ENC-03J</td>
			<td>Vibration Sensors</td>
		</tr>
		<tr>
			<td>DynaPort MiniMod</td>
			<td>MCROBERTS</td>
			<td></td>
			<td>Small and light case containing a tri-axial accelerometer, a rechargeable battery, an USB connection, and raw data storage on a MicroSD card</td>
		</tr>
		<tr>
			<td>MM-2860 Sunhayato</td>
			<td>Sunhayato</td>
			<td>MM-2860</td>
			<td>3-axis accelerometer</td>
		</tr>
		<tr>
			<td>MicroStone MA3-10Ac</td>
			<td>MA3-04AC</td>
			<td>Microstone Co.</td>
			<td>Acceleration sensors</td>
		</tr>
		<tr>
			<td>RT3 Activity monitor</td>
			<td>Abledata</td>
			<td>NA</td>
			<td>Triaxial accelerometer</td>
		</tr>
		<tr>
			<td>Aparito</td>
			<td>aparito</td>
			<td>NA</td>
			<td>Wearables and disease specific mobile apps to deliver patient monitoring outside of the hospital; Elin Davies, Aparito: https://www.aparito.com/</td>
		</tr>
		<tr>
			<td>Docking station</td>
			<td>Sysnav</td>
			<td>SF-000118</td>
			<td></td>
		</tr>
		<tr>
			<td>Sensor</td>
			<td>Sysnav</td>
			<td>SF-000080</td>
			<td></td>
		</tr>
		<tr>
			<td>Bracelet 
			(black/grey L) 
			(black/grey S) (black/yellow L) (black/yellow S)</td>
			<td>Sysnav</td>
			<td>ZZ-000093 ZZ-000094 ZZ-000247 ZZ-000248</td>
			<td></td>
		</tr>
		<tr>
			<td>Patient manual</td>
			<td>Sysnav</td>
			<td>FD-000086</td>
			<td></td>
		</tr>
		<tr>
			<td>Ethernet cable (2 m max.)</td>
			<td>Sysnav</td>
			<td>IC-000458</td>
			<td></td>
		</tr>
		<tr>
			<td>Power cable 
			(EU) 
			(UK) 
			(US)</td>
			<td>Sysnav</td>
			<td>ZE-000440 ZE-000441 ZE-000442</td>
			<td></td>
		</tr>
		<tr>
			<td>Power supply unit</td>
			<td>Sysnav</td>
			<td>ZE-000443</td>
			<td></td>
		</tr>
		<tr>
			<td>Ankle strap</td>
			<td>Sysnav</td>
			<td>ZZ-000462</td>
			<td></td>
		</tr>
		<tr>
			<td>Small bag</td>
			<td>Sysnav</td>
			<td>ZZ-000033</td>
			<td></td>
		</tr>
	</tbody>
</table>

home-based monitor for gait and activity analysis

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical evaluators. These measures are slightly subjective and are performed during a visit to a clinic or hospital and constitute therefore a point assessment. Point assessments can be influenced by daily patient condition or factors such as fatigue, motivation, and intercurrent illness. To enable home-based monitoring of gait and activity, a wearable magneto-inertial sensor (WMIS) has been developed. This device is a movement monitor composed of two very light watch-like sensors and a docking station. Each sensor contains a tri-axial accelerometer, gyroscope, magnetometer, and a barometer that record linear acceleration, angular velocity, the magnetic field of the movement in all directions, and barometric altitude, respectively. The sensors can be worn on the wrist, ankle, or wheelchair to record the subject&#8217;s movements during the day. The docking station enables data uploading and recharging of sensor batteries during the night. Data are analyzed using proprietary algorithms to compute parameters representative of the type and intensity of the performed movement. This WMIS can record a set of digital biomarkers, including cumulative variables, such as total number of meters walked, and descriptive gait variables, such as the percentage of the most rapid or longest stride that represents the top performance of patient over a predefined period of time.

Data presented here were acquired during clinical trials approved by the ethics committee and the French Regulatory Agency. All patient representatives signed an informed consent.
This WMIS was first used in a clinical study setting in 2012 for controlled and home-based monitoring of upper-limb movements in non-ambulant DMD patients (NCT01611597), which demonstrated the autonomy and feasibility of device use10<...

Watch this Scientific Journal Video about Home-Based Monitor for Gait and Activity Analysis at JoVE.com

Home-Based Monitor for Gait and Activity Analysis

This innovative device uses magneto-inertial sensors to permit gait and activity analysis in uncontrolled environments. Currently in the qualification process as an outcome measure in the European Medical Agency, one of the applications will be to serve as a clinical endpoint in clinical trials in neuromuscular diseases.

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical ...

Our innovative device uses Magneto Inertial sensors to precisely capture movements and dedicated algorithms to precisely qualify and quantify the motor activity of specific subject within a non-controlled environment. The use of a continuous in-home-based activity measurement device, allows an objective, and more globally representative assessment of both ambulant and non-ambulant subjects. This device was initially developed to precisely measure the activity of neuromuscular patients.But, it can be used for a broad variety of pathologies in patients suffering movement, gate, and activity disruptions. Currently, the device is being used as an exploratory outcome measure in clinical trials for neuromuscular and neurologic diseases. Visual demonstration allow an accurate explanation of the main steps of the device set-up, including sense of placement and orientation, according to the required configuration.To prepare for a participant's visit to the clinical center, first check the suitcase contents. The suitcase should contain the docking station to plug in the sensors during the night for data uploading onto a USB key and the battery recharging;The power cord, divided into two pieces, to connect the docking station to a power supply;The ethernet cable to permit interface with a router;the two sensors to permit daily activity recording;one participant manual, and one task reminder, bands for attachment of the sensors depending on the chosen configuration and ambulatory status of the participant;a second participant manual and an investigator manual, a screw driver to enable replacement of the USB key;and blank USB keys. Then print and prepare the assignment form to record the assignment of a device to a participant, to enable data reconciliation with a subject ID.To position the wearable Magneto Inertial sensor on an ambulant participant, fix one sensor on the wrist of the dominant hand using the provided bracelet, so that the waves are pointing towards the fingers.Place the second sensor on the ankle, on the same side as the wrist sensor, above the external malleolus with the waves pointing in the forward direction. For the ankle-ankle configuration, place one shoe sticker on each sensor, following the curve of the wave, and place the appropriate sensor on each ankle above the external malleolus. The sensors are placed appropriately if the stickers are upright and pointing in the forward direction.To position the wearable Magneto Inertial sensor on a non-ambulant participant, place one sensor on the wrist of the participant's dominant hand using the provided bracelet, so that the waves are pointing towards the fingers. Place the second sensor in the provided bag, and attach the bag to a safe place on the wheelchair. The sensor should fit tightly, but not too much to the wrist and/or the ankle to prevent them from spinning around.Also, the participants should not switch the sensors'positions. After explaining the sensor positions to the participant, explain the daily routine for the sensors use. The first evening, the participant should plug the docking station into the power supply, and attach the docking station to the router, if an internet connection is available.Every evening, the participant should insert the sensors into the docking station. The two Light Emitting Diodes, or LEDs on the docking station, should become orange, to indicate that the sensor batteries are charging, and that the data is being downloaded from the sensors to the USB drive. Every morning, the participant should verify that the LEDs are green, indicating that the sensor batteries are fully charged, and the data has been cleared from the sensor memory.The participant should then remove the sensors from the docking station, and put on the sensors in the configuration demonstrated by the evaluator. The participant should keep the sensors on throughout the day, before placing the sensors back on the docking station at the end of the day. The sensor should be removed, and kept on a safe, firm surface during activities involving water, special medical examinations, or any other activity that could be damaging.At the end of the recording period, the participant should place all of the items neatly back into the suitcase and bring the device back to the clinical center. The participant should then complete a dedicated assignment form. If the docking station cannot be connected to the internet, use the screwdriver to remove the USB drive from the docking station, and replace the drive with a blank USB drive at the end of the recording period.Then send the USB drive to the support team for analysis. At selected time points during the study, have the analyst extract the data from the cloud storage, and analyze the data using a dedicated algorithm, adjusting the analysis periods and the monitoring reports based on the clinical study. The wearable Magneto Inertial sensor allows variables, such as the norm of angular velocity, the ratio of the vertical component of the acceleration to the overall acceleration, the elevation rate, and the computed power to be identified for the clinical characterization of the upper limb activity of the participants in a controlled environment.The device also allows the identification and measurement of each single stride of a participant over a long time period, enabling analysis of the distribution of all of the captured strides, as well as the calculation of the centile of stride speed and length. Several parameters measurable by this wearable Magneto Inertial sensor, are less sensitive to change than the 95th centile stride velocity, but are closely related to quality of life, such as the distance walked per hour, and the number of falls per hour. Testing of the precision of the gate trajectory in controlled participants using an optokinetic system confirmed an excellent agreement between the trajectories measured by the optokinetic system, and the Magneto Inertial sensor.Remember to use the device according to the manual and clinical trial requirements, and to make sure each participant meets the eligibility criteria for using the device. Additional applications of our device include the evolution of patients with multiple sclerosis or Parkinson's disease. In these conditions, connected devices have already been tested, but we're still missing validated, sensitive, and reliable outcome measures that could be qualified by the regulators.

home-based-monitor-for-gait-and-activity-analysis

Research

JoVE Journal

Bioengineering

Polymer Microarrays for High Throughput Discovery of Biomaterials

The discovery of novel biomaterials that are optimized for a specific biological application is readily achieved using polymer microarrays, which allows a combinatorial library of materials to be screened in a parallel, high throughput format1. Herein is described the formation and characterization of a polymer microarray using an on-chip photopolymerization technique 2. This involves mixing monomers at varied ratios to produce a library of monomer solutions, transferring the solution to a glass slide format using a robotic printing device and curing with UV irradiation. This format is readily amenable to many biological assays, including stem cell attachment and proliferation, cell sorting and low bacterial adhesion, allowing the ready identification of 'hit' materials that fulfill a specific biological criterion3-5. Furthermore, the use of high throughput surface characterization (HTSC) allows the biological performance to be correlated with physio-chemical properties, hence elucidating the biological-material interaction6. HTSC makes use of water contact angle (WCA) measurements, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In particular, ToF-SIMS provides a chemically rich analysis of the sample that can be used to correlate the cell response with a molecular moiety. In some cases, the biological performance can be predicted from the ToF-SIMS spectra, demonstrating the chemical dependence of a biological-material interaction, and informing the development of hit materials5,3.

A description of the formation of a polymer microarray using an on-chip photopolymerization technique. The high throughput surface characterization using atomic force microscopy, water contact angle measurements, X-ray photoelectron spectroscopy and time of flight secondary ion mass spectrometry and a cell attachment assay is also described.

The discovery of novel biomaterials that are optimized for a specific biological application is readily achieved using polymer microarrays, which allows a ...

Self-reporting Scaffolds for 3-Dimensional Cell Culture

Culturing cells in 3D on appropriate scaffolds is thought to better mimic the in vivo microenvironment and increase cell-cell interactions. The resulting 3D cellular construct can often be more relevant to studying the molecular events and cell-cell interactions than similar experiments studied in 2D. To create effective 3D cultures with high cell viability throughout the scaffold the culture conditions such as oxygen and pH need to be carefully controlled as gradients in analyte concentration can exist throughout the 3D construct. Here we describe the methods of preparing biocompatible pH responsive sol-gel nanosensors and their incorporation into poly(lactic-co-glycolic acid) (PLGA) electrospun scaffolds along with their subsequent preparation for the culture of mammalian cells. The pH responsive scaffolds can be used as tools to determine microenvironmental pH within a 3D cellular construct. Furthermore, we detail the delivery of pH responsive nanosensors to the intracellular environment of mammalian cells whose growth was supported by electrospun PLGA scaffolds. The cytoplasmic location of the pH responsive nanosensors can be utilized to monitor intracellular pH (pHi) during ongoing experimentation.

Biocompatible pH responsive sol-gel nanosensors can be incorporated into poly(lactic-co-glycolic acid) (PLGA) electrospun scaffolds. The produced self-reporting scaffolds can be used for in&#160;situ monitoring of microenvironmental conditions whilst culturing cells upon the scaffold. This is beneficial as the 3D cellular construct can be monitored in real-time without disturbing the experiment.

Culturing cells in 3D on appropriate scaffolds is thought to better mimic the in vivo microenvironment and increase cell-cell interactions. The resulting ...

Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles

In cardiac myocytes a complex network of membrane tubules - the transverse-axial tubule system (TATS) - controls deep intracellular signaling functions. While the outer surface membrane and associated TATS membrane components appear to be continuous, there are substantial differences in lipid and protein content. In ventricular myocytes (VMs), certain TATS components are highly abundant contributing to rectilinear tubule networks and regular branching 3D architectures. It is thought that peripheral TATS components propagate action potentials from the cell surface to thousands of remote intracellular sarcoendoplasmic reticulum (SER) membrane contact domains, thereby activating intracellular Ca2+ release units (CRUs). In contrast to VMs, the organization and functional role of TATS membranes in atrial myocytes (AMs) is significantly different and much less understood. Taken together, quantitative structural characterization of TATS membrane networks in healthy and diseased myocytes is an essential prerequisite towards better understanding of functional plasticity and pathophysiological reorganization. Here, we present a strategic combination of protocols for direct quantitative analysis of TATS membrane networks in living VMs and AMs. For this, we accompany primary cell isolations of mouse VMs and/or AMs with critical quality control steps and direct membrane staining protocols for fluorescence imaging of TATS membranes. Using an optimized workflow for confocal or superresolution TATS image processing, binarized and skeletonized data are generated for quantitative analysis of the TATS network and its components. Unlike previously published indirect regional aggregate image analysis strategies, our protocols enable direct characterization of specific components and derive complex physiological properties of TATS membrane networks in living myocytes with high throughput and open access software tools. In summary, the combined protocol strategy can be readily applied for quantitative TATS network studies during physiological myocyte adaptation or disease changes, comparison of different cardiac or skeletal muscle cell types, phenotyping of transgenic models, and pharmacological or therapeutic interventions.

In cardiac myocytes, tubular membrane structures form intracellular networks. We describe optimized protocols for i) isolation of myocytes from mouse heart including quality control, ii) live cell staining for state-of-the-art fluorescence microscopy, and iii) direct image analysis to quantify the component complexity and the plasticity of intracellular membrane networks.

In cardiac myocytes a complex network of membrane tubules - the transverse-axial tubule system (TATS) - controls deep intracellular signaling functions. ...

Hybrid &#181;CT-FMT imaging and image analysis

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to assess the biodistribution of novel probes and to assess disease progression using established molecular probes or reporter genes. The combination with an anatomical modality, e.g., micro computed tomography (&#181;CT), is beneficial for image analysis and for fluorescence reconstruction. We describe a protocol for multimodal &#181;CT-FMT imaging including the image processing steps necessary to extract quantitative measurements. After preparing the mice and performing the imaging, the multimodal data sets are registered. Subsequently, an improved fluorescence reconstruction is performed, which takes into account the shape of the mouse. For quantitative analysis, organ segmentations are generated based on the anatomical data using our interactive segmentation tool. Finally, the biodistribution curves are generated using a batch-processing feature. We show the applicability of the method by assessing the biodistribution of a well-known probe that binds to bones and joints.

Hybrid  &#181;CT-FMT imaging and image analysis

We describe a protocol for hybrid imaging, combining fluorescence-mediated tomography (FMT) with micro computed tomography (&#181;CT). After fusion and reconstruction, we perform interactive organ segmentation to extract quantitative measurements of the fluorescence distribution.

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to ...

Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry

Increasing evidence supports transcellular propagation of toxic protein aggregates, or proteopathic seeds, as a mechanism for the initiation and progression of pathology in several neurodegenerative diseases, including Alzheimer's disease and the related tauopathies. The potentially critical role of tau seeds in disease progression strongly supports the need for a sensitive assay that readily detects seeding activity in biological samples. 
By combining the specificity of fluorescence resonance energy transfer (FRET), the sensitivity of flow cytometry, and the stability of a monoclonal cell line, an ultra-sensitive seeding assay has been engineered and is compatible with seed detection from recombinant or biological samples, including human and mouse brain homogenates. The assay employs monoclonal HEK 293T cells that stably express the aggregation-prone repeat domain (RD) of tau harboring the disease-associated P301S mutation fused to either CFP or YFP, which produce a FRET signal upon protein aggregation. The uptake of proteopathic tau seeds (but not other proteins) into the biosensor cells stimulates aggregation of RD-CFP and RD-YFP, and flow cytometry sensitively and quantitatively monitors this aggregation-induced FRET. The assay detects femtomolar concentrations (monomer equivalent) of recombinant tau seeds, has a dynamic range spanning three orders of magnitude, and is compatible with brain homogenates from tauopathy transgenic mice and human tauopathy subjects. With slight modifications, the assay can also detect seeding activity of other proteopathic seeds, such as &#945;-synuclein, and is also compatible with primary neuronal cultures. The ease, sensitivity, and broad applicability of FRET flow cytometry makes it useful to study a wide range of protein aggregation disorders.

Cell-to-cell transfer of protein aggregates, or proteopathic seeds, may underlie the progression of pathology in neurodegenerative diseases. Here, a novel FRET flow cytometry assay is described that enables specific and sensitive detection of seeding activity from recombinant or biological samples.

Increasing evidence supports transcellular propagation of toxic protein aggregates, or proteopathic seeds, as a mechanism for the initiation and ...

Optical Control of Living Cells Electrical Activity by Conjugated Polymers

Hybrid interfaces between organic semiconductors and living tissues represent a new tool for in-vitro and in-vivo applications. In particular, conjugated polymers display several optimal properties as substrates for biological systems, such as good biocompatibility, excellent mechanical properties, cheap and easy processing technology, and possibility of deposition on light, thin and flexible substrates. These materials have been employed for cellular interfaces like neural probes, transistors for excitation and recording of neural activity, biosensors and actuators for drug release. Recent experiments have also demonstrated the possibility to use conjugated polymers for all-optical modulation of the electrical activity of cells. Several in-vitro study cases have been reported, including primary neuronal networks, astrocytes and secondary line cells. Moreover, signal photo-transduction mediated by organic polymers has been shown to restore light sensitivity in degenerated retinas, suggesting that these devices may be used for artificial retinal prosthesis in the future. All in all, light sensitive conjugated polymers represent a new approach for optical modulation of cellular activity.
In this work, all the steps required to fabricate a bio-polymer interface for optical excitation of living cells are described. The function of the active interface is to transduce the light stimulus into a modulation of the cell membrane potential. As a study case, useful for in-vitro studies, a polythiophene thin film is used as the functional, light absorbing layer, and Human Embryonic Kidney (HEK-293) cells are employed as the biological component of the interface. Practical examples of successful control of the cell membrane potential upon stimulation with light pulses of different duration are provided. In particular, it is shown that both depolarizing and hyperpolarizing effects on the cell membrane can be achieved depending on the duration of the light stimulus. The reported protocol is of general validity and can be straightforwardly extended to other biological preparations.

A method for stimulation of in-vitro cell cultures electrical activity with visible light, based on the use of organic semiconducting polymers is described.

Hybrid interfaces between organic semiconductors and living tissues represent a new tool for in-vitro and in-vivo applications. In particular, conjugated ...

2D and 3D Matrices to Study Linear Invadosome Formation and Activity

Cell adhesion, migration, and invasion are involved in many physiological and pathological processes. For example, during metastasis formation, tumor cells have to cross anatomical barriers to invade and migrate through the surrounding tissue in order to reach blood or lymphatic vessels. This requires the interaction between cells and the extracellular matrix (ECM). At the cellular level, many cells, including the majority of cancer cells, are able to form invadosomes, which are F-actin-based structures capable of degrading ECM. Invadosomes are protrusive actin structures that recruit and activate matrix metalloproteinases (MMPs). The molecular composition, density, organization, and stiffness of the ECM are crucial in regulating invadosome formation and activation. In vitro, a gelatin assay is the standard assay used to observe and quantify invadosome degradation activity. However, gelatin, which is denatured collagen I, is not a physiological matrix element. A novel assay using type I collagen fibrils was developed and used to demonstrate that this physiological matrix is a potent inducer of invadosomes. Invadosomes that form along the collagen fibrils are known as linear invadosomes due to their linear organization on the fibers. Moreover, molecular analysis of linear invadosomes showed that the discoidin domain receptor 1 (DDR1) is the receptor involved in their formation. These data clearly demonstrate the importance of using a physiologically relevant matrix in order to understand the complex interactions between cells and the ECM.

This protocol describes how to prepare a 2D mixed matrix, consisting of gelatin and collagen I, and a 3D collagen I plug to study linear invadosomes. These protocols allow for the study of linear invadosome formation, matrix degradation activity, and the invasion capabilities of primary cells and cancer cell lines.

Cell adhesion, migration, and invasion are involved in many physiological and pathological processes. For example, during metastasis formation, tumor ...

Nanosensors to Detect Protease Activity In Vivo for Noninvasive Diagnostics

Proteases are multi-functional enzymes that specialize in the hydrolysis of peptide-bonds and control broad biological processes including homeostasis and allostasis. Moreover, dysregulated protease activity drives pathogenesis and is a functional biomarker of diseases such as cancer; therefore, the ability to detect protease activity in vivo may provide clinically relevant information for biomedical diagnostics. The goal of this protocol is to create nanosensors that probe for protease activity in vivo by producing a quantifiable signal in urine. These protease nanosensors consist of two components: a nanoparticle and substrate. The nanoparticle functions to increase circulation half-life and substrate delivery to target disease sites. The substrate is a short peptide sequence (6-8 AA), which is designed to be specific to a target protease or group of proteases. The substrate is conjugated to the surface of the nanoparticle and is terminated by a reporter, such as a fluorescent marker, for detection. As dysregulated proteases cleave the peptide substrate, the reporter is filtered into urine for quantification as a biomarker of protease activity. Herein we describe construction of a nanosensor for matrix metalloproteinase 9 (MMP9), which is associated with tumor progression and metastasis, for detection of colorectal cancer in a mouse model.

Nanosensors to Detect Protease Activity In Vivo for Noninvasive Diagnostics

Proteases are tightly regulated enzymes involved in fundamental biological processes, and dysregulated protease activity drives progression of complex diseases such as cancer. This method&#39;s goal is to create nanosensors that measure protease activity in vivo by producing a cleavage signal that is detectable from host urine and discriminates disease.

Proteases are multi-functional enzymes that specialize in the hydrolysis of peptide-bonds and control broad biological processes including homeostasis and ...

Manufacturing of a Nafion-coated, Reduced Graphene Oxide/Polyaniline Chemiresistive Sensor to Monitor pH in Real-time During Microbial Fermentation

Here, we report the engineering of a solid-state micro pH sensor based on polyaniline-functionalized, electrochemically reduced graphene oxide (ERGO-PA). Electrochemically reduced graphene oxide acts as the conducting layer and polyaniline acts as a pH-sensitive layer. The pH-dependent conductivity of polyaniline occurs by doping of holes during protonation and by the dedoping of holes during deprotonation. We found that an ERGO-PA solid-state electrode was not functional as such in fermentation processes. The electrochemically active species that the bacteria produce during the fermentation process interfere with the electrode response. We successfully applied Nafion as a proton-conducting layer over ERGO-PA. The Nafion-coated electrodes (ERGO-PA-NA) show a good sensitivity of 1.71 &#937;/pH (pH 4 - 9) for chemiresistive sensor measurements. We tested the ERGO-PA-NA electrode in real-time in the fermentation of Lactococcus lactis. During the growth of L. lactis, the pH of the medium changed from pH 7.2 to pH 4.8 and the resistance of the ERGO-PA-NA solid-state electrode changed from 294.5 &#937; to 288.6 &#937; (5.9 &#937; per 2.4 pH unit). The pH response of the ERGO-PA-NA electrode compared with the response of a conventional glass-based pH electrode shows that reference-less solid-state microsensor arrays operate successfully in a microbiological fermentation.

Here, we report the protocol for the fabrication of a Nafion-coated, polyaniline-functionalized, electrochemically reduced graphene oxide chemiresistive micro pH sensor. This chemiresistor-based, solid-state micro pH sensor can detect pH changes in real-time during a Lactococcus lactis fermentation process.

Here, we report the engineering of a solid-state micro pH sensor based on polyaniline-functionalized, electrochemically reduced graphene oxide (ERGO-PA). ...

Colorimetric Analysis of Alkaline Phosphatase Activity in S. aureus Biofilm

Alkaline phosphatase (ALP) is a common enzyme expressed in both prokaryotic and eukaryotic cells. It catalyzes the hydrolysis of phosphate monoesters from many molecules at basic pH and plays an indispensable role in phosphate metabolism. In humans, eukaryotic ALP is one of the most frequently used enzymatic signals in diagnosing various diseases, such as cholestasis and rickets. In S. aureus, ALP is detected exclusively on the cell membrane; it is also expressed as a secretory form as well. Yet, little is known about its function in biofilm formation.
The purpose of this manuscript is to develop a quick and reliable assay to measure ALP activity in S. aureus biofilm that does not require protein isolation. Using p-nitrophenyl phosphate (pNPP) as a substrate, we measured ALP activity in S. aureus biofilm formed in 96-well tissue culture plates. Activity was based on the formation of the soluble reaction product measured by 405 nm absorbance. The high throughput nature of the 96 well tissue culture plate method provides a sensitive and reproducible method for ALP activity assays. The same experimental set up can also be extended to measure other extracellular molecular markers related to biofilm formation.

Colorimetric Analysis of Alkaline Phosphatase Activity in S. aureus Biofilm

In this manuscript, we established a high throughput method to quantify alkaline phosphatase activity in S. aureus biofilm culture from 96-well tissue culture plate

Alkaline phosphatase (ALP) is a common enzyme expressed in both prokaryotic and eukaryotic cells. It catalyzes the hydrolysis of phosphate monoesters from ...