Ex Vivo Monitoring of Rat Heart Wall Motion Using Piezoelectric Cantilevers

Rui Zhang1, Ya Chen2, Wen H. Ko1, David S. Rosenbaum3,4, Xin Yu2,3, Philip X.-L. Feng1
1

Electrical Engineering, 2Biomedical Engineering, Case School of Engineering 3 Physiology and Biophysics, Case School of Medicine, 4MetroHealth System Case Western Reserve University, Cleveland, OH 44106, USA Corresponding Authors; Email: philip.feng@case.edu, xin.yu@case.edu

Abstract We report on an experimental exploration of ex vivo measurements and real-time monitoring of the motions of heart wall for perfused rat hearts, by employing a surface-contact type of electromechanical probes based on piezoelectric transduction. In a hybrid experimental apparatus consisting of a conventional heart perfusion system and external electromechanical probing devices and circuitry, prototyped piezoelectric cantilever devices are calibrated and tested. We demonstrate that the external piezoelectric cantilevers are capable of monitoring the dynamic behavior of the isolated heart ex vivo, by measuring the motions of the heart wall. For typical rat hearts with heart rates in the  range of ~150250bpm (beats per minute), cantilevers with dimensions of t w L | 130m (0.38)mm (119)mm yield electrical signal of ~50400mV. Measured data can also help identify signatures of various regimes (e.g., from healthy to fatigued, to expiring) in the dynamical evolution during the perfused hearts lifetime. Preliminary tests on parallel multichannel monitoring with probes positioned at multiple locations on heart surface prove to be valid and useful in obtaining information of regional displacement of heart wall.

and structures (Figure 1) enabled by soft materials and tissues this causes some of the fundamental issues that are challenging the devices and instruments to be interfaced with heart for diagnosis and treatment. The prevalent electrocardiography (ECG) today is easy to use but only retrieves crude signals of overall heart function. Magnetic resonance imaging (MRI) is a powerful tool for studying heart structural and motional details and disease mechanisms. However todays MRI systems are bulky, highly complicated, and expensive, and often suffer from limitations in speed and resolution. We have been exploring a new, low-cost approach of directly probing heart wall motion by using distributed, surface-mount, and miniaturized (e.g., micro and nanoscale) electromechanical devices for regional strain/stress and motion sensing. Here we report our initial effort toward this goal, and describe our first experimental results.

I. INTRODUCTION Heart is the foundation of advanced lives including human being. Heart health and function monitoring are critical, especially for patients who suffer from heart diseases. Heart diseases are the top one cause of death in the United States and several other countries (e.g., a total death of ~600,000 per year in 20072009 in US means one death due to heart disease every ~50 seconds) [1], and are the top reason for diseasebased deaths throughout the world. This drives researchers to push the limits in advancing heart healthcare technology. We perceive at least the following major challenges: (i) early detection of alarms of heart diseases for apparently healthy people it is desirable to develop devices that are wearable or implanted (with very low pain), especially for old people, athletes, and those who may have family history of heart diseases; (ii) post-surgery chronic heart monitoring for patients who are already receiving surgery and other treatment what is desired includes low-pain implantable solutions that are small, light, enduring, and compatible with telemetry. To date it has been well recognized that regional strain and stress on heart wall are related to development of disease [2], and studying the electromechanical properties and monitoring heart wall motion can help for heart diseases diagnosis [3]. From an engineering perspective, the heart is an amazing electromechanical device with exquisitely elegant functions

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Figure 1. A glance of the heart structures and functions from an engineers viewpoint. (a) Illustration of the anatomy of the heart, showing the heat chambers, vessels and valves. (b) Illustraton of the pacemaker and distal conduction system.

II. HEART WALL MOTION The heart is an electromechanical organ with great structural and functional complexities. Its wall motion is depending upon the compromised coronary arterial supply. Myocardial wall motion defects are essential and sensitive markers for coronary artery disease and myocardial ischemia. The capability of directly probing regional or highly localized heart wall motion may also have critical impact on arrhythmia,

restoring synchronization between asynchronous chambers or regions, early alarm of regional muscle fatigue or failure, etc.
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for a PZE cantilever device to interface with a beating heart: (i) making contact between the free end of the cantilever and regions of interest on the heart wall, while keeping the other end of cantilever clamped on a solid (not moving) substrate; (ii) mounting the base (clamped end) of the cantilever on the beating hearts surface and having the cantilever body free to move and vibrate. The former is suited for ex vivo studies; the latter is attractive for packaged implanted systems. Figure 3 illustrates a generic cantilever device based upon a ~65Pm-thick PZE lead-zirconate-titanate (PZT) thin film sandwiched between two metal electrodes, a bottom ~65Pmthick brass layer, and a top ~15Pm silver coating. We exploit the d31 coupling in such structures transverse (out-of-plane) motion of the cantilever tip (free end) induces in-plane strain in the PZT layer and causes surface charge and electrical potential between the two electrodes which is read out for monitoring of motion. Within the scope of this work cantilever tip in contact with heart wall with quasi-DC movements (beating frequency much lower than the fundamental resonance of the cantilever), the displacement, force, and the voltage signal are in convenient linear relationship, i.e., VPZE v d31G v d31F/keff, in a simple lumped parameter model [8].
TABLE I. Material PZT ZnO AlN PVDF PIEZOELECTRIC MATERIALS OF INTEREST Youngs Modulus [GPa] ~40150 ~30140 ~330410 ~215 Density [g/cm3] ~7.57.8 ~5.6 ~3.26 ~1.76

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Figure 2. Simplified illustration of the complexity of the heart wall muscle structure and organization the basket-weaving arthitecture of cardiac muscle cells and the myrocardial fibers. (a) A perspective view of the weaving fibers in layers at various depth in the heart wall. (b) A simplified model showing the weaving structure and orientation.

There are several types of muscle cells that participate in and coordinate the complex motions in concert. The most important of these include: (i) the cardiac muscle cells making the weaving myocardial fibers (see Figure 2a), (ii) the vascular smooth muscle cells (abundant in the coronary arterial tree), (iii) the conduction system muscle cells (e.g., in the pacemaker region shown in Figure 1b). For this weaved basket, advanced MRI techniques including tagging, harmonic phase, and diffusion tensor MRI (DTMRI) have been developed for regional wall motion and strain assessment [4-7]. This work describes our initial effort and preliminary results toward a convenient electromechanical monitoring and diagnosis system using piezoelectric (PZE) devices, which, with computer aid, can automatically detect and monitor local heart wall motion ex vivo.
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Piezoelectric Coefficients [pm/V or pC/N] d33~100600, d31~50300 d15~100800 d33~10, d31~4, d15~3 d33~5.6, d31~2.6, d15~2.5 d33~2030, d31~20, d15~1040

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Figure 3. Piezoelectric (PZE) cantilever devices for electromechanical signal transduction. (a) Illustration of a prototypical composite cantilever with an active PZT layer sanwiched between two thin electrodes (metallic coating layers). (b) Simplified illustration of cantilever bending upon application of external force at the cantilever tip.

III. PIEZOELECTRIC CANTILEVER SENSORS A. Piezoelectric Cantilevers We explore piezoelectric (PZE) device technology because of the direct electromechanical coupling effect in PZE transducers. A PZE device as simple as a singly-clamped cantilever beam (Figure 3) can be conveniently maneuvered to probe static deflections and dynamic motions of other mechanical systems. We have been exploring two scenarios

Figure 4. The first generation of our prototyped piezoelectric (PZE) devices based upon flexural-mode cantilevers using PZE thin film materials (e.g., PZT and PVDF). (a) A vibration energy converter in plastic package with complementary dual PZT layers, easily generating ~10V level voltage signals from human body movements. (b) A PZT-based device with on-board energy conversion and harvesting circuit. (c) A much thinner PZT-based device. (d) A PZE cantilever based on flexible PVDF material. Scale bars: 1cm. (e) Measured time-domain voltage waveform (peak voltage ~2V) due to ringdown oscillations of a ~30Hz resonanst mode. (f) Voltage (peak voltage ~32V) measured from ~110Hz oscillations. Legend: initial tip deflection.

B. Materials of Choice We choose PZT as the active material for its large PZE coefficient and easy availability for this study. Table I displays a short list of materials that we find interesting for employment in our studies. We have also been exploring devices made of polyvinylidene fluoride (PVDF) because of its attractive and promising properties for implants on flexible substrates. Other

materials of potential interest include zinc oxide (ZnO) and aluminum nitride (AlN), particularly for recent developments in engineering them into micro and nanoscale functional devices that could be integrated and packaged in implanted microsystems. C. Prototyped Devices We first demonstrate several prototyped PZE cantilevers using PZT and PVDF. The prototyped devices (see examples in Figure 4) are first calibrated in DC/static operation, and are

then extensively tested in pulse and resonant modes. Early generations of cantilevers are on the few-mm- to 1cm-scale in size, with fundamental flexural resonance frequencies in the ~0.1kHz to ~1100kHz ranges, and easily generates voltage signals up to ~10V. Our preliminary data and estimation show that these devices and their performance can be suited for both quasi-DC and resonant-mode applications, operating at atmospheric pressure, either in customized macroscopic plastic packages, or in micro polymeric thin film packages.

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Pressure Perfusion System

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Right Atrium Tricuspid Valve Right Ventricle

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Figure 5. The heart perfusion system for ex vivo experimental studies with the isolated live rat heart. (a) Picture of a prototypical perfused rat heart with surfacemount external bulky electrodes for physiological measurements (e.g., see http://vflab.org). (b) Highly simplified schematic of our experimental approach using both the external piezoelectric (PZE) devices on heart wall, and the conventional approach for heart function recording system in a canonical rat heart perfusion system. (c) Illustration of the scheme of using a balloon (i.e., simiar to balloon valvuloplasty) and its associated external perssure sensor for heart function recording. (I) and (II) are two specific options for implanting the balloon; we use option (II) in all the tests presented in this work.

IV. EXPERIMENTAL TECHNIQUES In this early-stage effort of our exploration, as illustrated in Figure 5, we combine the piezoelectric (PZE) cantilever monitoring technique with well-established (commercially available) heart function recording systems. This helps to reliably evaluate the new approach and calibrate the measurements and the devices, both qualitatively and quantitatively, against todays standard protocols. A. Heart Perfusion System and Heart Function Recording The conventional real-time heart function recording is realized in a heart perfusion system, as illustrated and shown in Figure 5 and Figure 6. The system is based on the classical Langendorff technique for isolated heart perfusion [9]. This allows for convenient and prompt ex vivo studies, and many brute-force (e.g., Figure 5a) experiments, on isolated hearts. In the particular case of this study, the perfusion system greatly facilitates the continuous tests with the piezoelectric cantilever probes in a considerably long time (depending on the heart lifetime in the perfusion system, ~1-3 hours typically). It provides not only the live heart, but also a parallel monitoring option as a control experiment. Male Sprague-Dawley rats of 1012 weeks old are heparinized (1000 units/kg, i.p.) and anesthetized by sodium pentobarbital (85 mg/kg. i.p.). The heart is excised, cannulated, and perfused with Krebs-Henseleit (KH) buffer containing (in mM) 118.5 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 KH2PO4, 1.5 CaCl2, 11.1 glucose, and 25 NaHCO3. Isolated hearts are perfused at a

constant pressure in the Langendorff-type perfusion system. The perfusate was maintained at 37C and equilibrated with 95% O2-5% CO2.

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Figure 6. Pictures of the rat heart perfusion system employed in this work. (a) The overall Langendorff perfusion system with rat heart, pump, circulation lines, the implanted balloon sensor and its data acquisition system (vendor: ADInstruments). (b) Close-in view of the rat heart in the perfusion buffer.

Embedded in the heart perfusion system, as shown in Figure 5c, we insert a water-filled latex balloon into the left ventricle (i.e., similar to balloon valvuloplasty). The balloon is connected to an external pressure transducer to record the left ventricular developed pressure (LVDP) and heart rate (HR). The hearts rate-pressure-product (RPP), i.e., the product of LVDP and HR, is then calculated as an index of the workload.

The measured rat heart rate can typically be in the range of ~150250 bpm (beats per minute) at the beginning of the experiment (with a fresh and healthily perfused rat heart). The heart rate decreases gradually as the time elapses. The temperature of the perfusion buffer is a critical factor for keeping the heart alive. When temperature deviates, the heart function could degrade, and the amplitude of heart wall movement may decrease dramatically. Figure 6 demonstrates pictures and details of the rat heart perfusion system we have been implementing in this study. B. Piezoelectric Cantilever Monitoring System We have built a convenient desktop apparatus for interfacing the piezoelectric cantilever probes with the rat heart in the operating perfusion system. Cantilever probes can be positioned and adjusted by moving the arms (to which the cantilevers are clamped) on the stage with control in all three directions. Figure 7 demonstrates a picture of an early generation of the implementation.

(all micropackaged with ~5Pm parylene C thin layer) are immersed in the fluid. Basic parameters of two generations of devices tested in this work are summarized in Table II. V. EXPERIMENTAL RESULTS AND DISCUSSIONS Extensive experimental observations and measurements have been performed. First, the heart function is recorded using the balloon implanted in the left ventricle, which provides a reference and calibration for the performance of the perfused rat heart. Then the piezoelectric cantilevers are applied to make contact to the heart wall for direct electromechanical probing. A. Heart Function Recorded by Balloon in Left Ventricle Without engaging any piezoelectric devices, real-time heat function is recorded by the left ventricular balloon and its associated pressure sensor. Typical data traces of LVDP and left ventricular pressure changing rate dp/dt are recorded for ~12 hours or even longer, throughout the whole lifetime of the perfused heart. Figure 8 shows the measured data in a very short 12s time interval. Table III summarizes the results from a few repeated measurement runs by only using the implanted balloon for monitoring and recording.
LVDP (mmHg)

200 150 100 50

Figure 7. Picture of first-generation exprimental implementation of ex vivo monitoring of rat heart wall motion, by using surface-contacting piezoelectric (PZE) cantilever probes. For each cantilever, its one end is clamped, and the other end (tip) is in contact with the heart wall muscle. In paralle, the perfused rat hearts basic function is also being monitored using the balloon valvuloplasty technique. In this particular picture, the free ends of a pair of cantilevers are gently contacting the left and right ventricle of the heart. TABLE II. Cantilever Device ID (I)-A (I)-B (II)-A1 (II)-A2 (II)-A3 (II)-B1 (II)-B2 (II)-B3 PARAMETERS OF SELECTED TESTED DEVICES Length [mm] 18.0 19.0 1.5 1.3 1.4 1.6 1.5 1.4 Width [mm] 7.0 7.3 0.3 0.4 0.3 0.4 0.3 0.4 Resonance [Hz] 222.0 214.0

0 1000 500 0 -500 -1000

dp/dt (mmHg/s)

6 Time (Sec)

10

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Figure 8. Representative data of the perfused rat heart under healthy condition, measured in real time by only the balloon implanted in left ventricle (no any external cantilever probes touching the heart wall). (a) Left ventricular developed pressure (LVDP, in mmHg) as a fundtion of time. (b) Measured pressure changing rate dp/dt as a function of time. TABLE III. Test Run ID 1 2 3 MEASURED HEART PARAMETERS WITHOUT CANTILEVERS Heart Rate (HR) [beats per minute, bpm] 153 r 3 150 r 3 184 r 5 LVDP [mmHg] 135 r 2 120 r 2 102 r 2 RPP [mmHgbpm] 20655 r 710 18000 r 666 18765 r 890

As we expect these cantilever devices to operate while interfacing with perfused hearts in physiological solutions, we need to package the devices so that their electromechanical performance would not be compromised by any corrosion or contaminants. Prior to testing, every device is coated by a thin layer of parylene C (thickness on the order of ~5Pm). We note that in Figure 7 the liquid solution for nurturing the heart is temporarily moved away. In the present generation of setup, both the heart and all the cantilevers and device arrays

B. Measurements with Piezoelectric (PZE) Cantilevers Prior to using the cantilevers for perfused heart wall motion probing, we first perform a dry-run test by using air-filled balloons to mimic simplified heart motions. Because the fundamental flexural-mode resonance frequencies of the PZT cantilevers in this work are usually in the range of ~200Hz to ~100kHz range, the rat heart motions are well in the close-toDC or quasi-DC range. Because in all our tests, the cantilevers are in contact with the air balloon (i.e., heart model) or perfused heart at the cantilevers tips, the tip motions closely follow the contractions and heart beat cycles. The heart motion does not drive the cantilever into its flexural-mode resonance.

Voltage Signal (Volt)

Such quasi-DC operations of the cantilever probes lead to a simple linear relation between the piezoelectric voltage output and the detected displacement of heart wall motion. The dryrun test (using air balloon to simulate a beating heart) indicates that for the early generations of devices (relatively large), e.g., both (I)-A and (I)-B (listed in Table II), have high conversion responsivity (i.e., gain), ~3V/mm (voltage per unit cantilever deflection at its tip). In both the dry-run with heart models and the perfused heart tests, the output voltage signals are directly recorded and monitored by the oscilloscope using Labview/DAQ software.

Voltage Signal (Volt)

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Figure 10. Voltage signal measured from a pair of smaller cantilever devices with varying the depth of the cantilever tip touching the heart wall. (a) Data from device (II)-B1. (b) Data from device (II)-B2. The data shown are truncated from much longer traces. For each device, data for three contact conditions are taken at three time intervals in series. Throughout these time intervals, the implanted balloon recording ensures that the heart functions are normal and stable. The offsets on the time axes are not adjusted among the different traces.

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Figure 9. Voltage signal measured from a pair of PZT cantilevers touching the heart wall. (a) The free ends (tips) of the two cantilevers touching the heart wall of the left and right ventricle, respectively. (b) The free ends of the cantilevers are touching the base and apex of the heart wall, respectively.

Figure 9 demonstrates the voltage signals representing the local heart wall motions, probed by a pair of PZT cantilevers. In all these cases, the free ends of the cantilevers just barely touch the heart wall. When the cantilevers tips make contact to the left and right ventricles (Figure 9a) respectively, the extracted heart rate is HR~229bpm. Measured voltage signal is Vpp~150mV, and ~350mV, for device (I)-A and (I)-B respectively. The asymmetry in the data amplitude from this pair of devices is due mainly to the fact that one cantilever device has been pre-bent (with a transverse crack developed but not yet broken, at ~1/3 length near the clamped end), and thus has much less strain developed given the same displacement at the tip. When the devices tips are placed against the base and the apex at a later time, the data show a lower HR~43bpm, and lower Vpp~50mV and 150mV, respectively, mostly due to the heart degradation during the time of transition. The effects of probing the heart wall motion by making contacts with different depths and strengths are also explored. A second generation (group (II) listed in Table II), smaller cantilevers, in small parallel fingers-alike arrays, are used. With control of the positioning arms, the devices are first carefully placed to just barely touch the heart wall, and then gradually move toward the heart center to start gently pressing the heart wall. Figure 10 displays the measured data from a pair of small cantilevers, (II)-B1 and (II)-B2, in contact with the heart wall under three different depth/strength conditions.

In case of just touching but not pressing the heart wall, larger devices (group (I) in Table II) yield larger Vpp, which is evident from Figure 9 and Figure 10. As cantilever tips get to press against the heart wall gradually, the signals first increase as expected, and then there is no more appreciable signal increase observed with further pressing of the devices against the heart surface. Such information can help us better understand the strength of the heart wall motion, especially with more advanced future generations of devices. We also note that the data traces from larger devices (gently touching heart wall, Figure 9) appear to be proportional to the dp/dt data in Figure 8, while the voltage signals from the smaller devices (under all contact conditions, see Figure 10) seem to have the shape similar to that of the LVDP curve in Figure 8. We are currently making more effort to investigate this intriguing phenomenon. As we aggressively miniaturize these devices by using micromachining techniques, their apparent signal levels decline. Nonetheless, with significant volume reduction they become better suited with flexible substrates [10,11] and packages that are more amenable to harsh environments for implants in living bodies. We envision that it is also possible for us to take advantage of the resonant operations of the PZE devices, combined with air-cavity packages possible in flexible substrate, cantilever- and membrane-structured micro/nano resonators in various frequency ranges can be exploited for local heart wall motion monitoring. Further, the same types of PZE devices in micropackages can also be employed for energy conversion from heart beats [12], which could be exploited for self powering low-power implants. Moreover, for miniaturized devices and chip-scale implants, the signal transmission could be not only wired but also wireless. As all these technical components are getting ready, the approach of using miniaturized PZE devices explored in this work can lead to both external heart function monitoring systems in research and clinic labs (e.g., supplementing the

conventional implanted balloon recording), and implanted systems for surgery and patients chronic heart monitoring and in all these applications, capable of offering high sensitivity and high spatial and temporal resolutions for parallel readout of heart wall motion at various locations. VI. CONCLUDING REMARKS In summary, we have shown that using external surfacecontact or surface-attached piezoelectric (PZE) cantilevers can probe the rat heart wall motion and the heart function ex vivo. The cantilevers in the present work are made of PZT thin films with strong PZE effect. The d31 coupling effect in the cantilever is exploited to transduce the flexural mechanical motion of the cantilever into electrical signal for readout. The cantilevers have been limited to quasi-DC operation (heart beating rate much lower than cantilevers resonance frequency) with their tips closely following the movements of the regional heart wall. Devices with sizes in the mm-scale and sub-mmscale are tested. The preliminary tests verify the feasibility of monitoring heart wall movements with good resolutions in the time domain, and at different locations on heart surface. The heart wall displacement extracted from the measurement is typically ~0.10.3mm, which is consistent with MRI measurement. The output power level of typical PZE cantilevers we have tested is in the range of ~110 : Combined with advances in PZE materials at micro and nanoscale, implantable and flexible materials, and micropackaging techniques, this approach is expected to have the potential of being implanted, as well as offering very high spatial and temporal resolutions by employing further miniaturized devices. ACKNOWLEDGMENT We thank the Louis Strokes Cleveland Medical Center of the Department of Veterans Affairs and the Case School of Engineering for financial support. We are indebted to C. A. Zorman, M. A. Rogonjic, and K. N. Kortepeter for their administrative support. We are grateful to the IEEE UFFC IFCS/EFTF 2011 for the Student Travel Support Award (for R.Z.). We thank R. C. Roberts and S. B. Lachhman for help on materials and instruments.

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