796IEICE TRANS. COMMUN., VOL.E93–B, NO.4 APRIL 2010

INVITED PAPER Special Section on Information and Communication Technology for Wellness and Medical Applications

Telemetry and Telestimulation via Implanted Devices Necessary inLong-Term Experiments Using Conscious Untethered Animals forthe Development of New Medical Treatments

Masaru SUGIMACHI†a), Toru KAWADA†, and Kazunori UEMURA†, Nonmembers

SUMMARY Effective countermeasures against explosive increase inhealthcare expenditures are urgently needed. A paradigm shift in healthcareis called for, and academics and governments worldwide are working hardon the application of information and communication technologies (ICT) asa feasible and effective measure for reducing medical cost. The more preva-lent the disease and the easier disease outcome can be improved, the moreefficient is medical ICT in reducing healthcare cost. Hypertension and di-abetes mellitus are such examples. Chronic heart failure is another diseasein which patients may benefit from ICT-based medical practice. It is con-ceivable that daily monitoring of hemodynamics together with appropriatetreatments may obviate the expensive hospitalization. ICT potentially per-mit continuous monitoring with wearable or implantable medical devices.ICT may also help accelerate the development of new therapeutic devices.Traditionally effectiveness of treatments is sequentially examined by sac-rificing a number of animals at a given time point. These inefficient andinaccurate methods can be replaced by applying ICT to the devices usedin chronic animal experiments. These devices allow researchers to obtainbiosignals and images from live animals without killing them. They in-clude implantable telemetric devices, implantable telestimulation devices,and imaging devices. Implanted rather than wired monitoring and stimula-tion devices permit experiments to be conducted under even more physio-logical conditions, i.e., untethered, free-moving states. Wireless communi-cation and ICT are indispensible technologies for the development of suchtelemetric and telestimulation devices.key words: sustainable medical system, medical device, preclinical study,chronic disease, implantable device

1. Innovative Role of Information and CommunicationTechnologies in Medical Practice

The primary goal of healthcare is to promote longer andhealthier survival as well as better quality of life for the pop-ulation; thus the healthcare industries may not be as prof-itable or as efficient as other industries. To make up for this,governments in most countries are involved in supportinghealthcare provision for the people by means of public insur-ance systems, especially for those who cannot afford to payfor their own healthcare. Even though health promotion mayultimately help save human resources and productivity thatmay otherwise be lost to diseases, public insurance systemswould, by definition, cost more than gain. As the populationages progressively and as medical practice involves increas-ingly more sophisticated procedures, the deficits continue togrow. The increase in medical expenditures is so great that

Manuscript received November 16, 2009.Manuscript revised December 28, 2009.†The authors are with National Cardiovascular Center Re-

search Institute, Suita-shi, 565-8565 Japan.a) E-mail: su91mach@ri.ncvc.go.jp

DOI: 10.1587/transcom.E93.B.796

this may account for a large proportion of the total nationalexpenditures.

The governments of various countries take differentapproaches to address the healthcare problem, each gov-ernment making continuous attempts to modify its exist-ing healthcare model to make it work for the time being.The representative healthcare models include those of theUnited States, Europe, and Japan. Unfortunately, none ofthese models or their modifications is designed to be sus-tainable in the long term. The government of the UnitedStates tried to privatize medical insurance for as many peo-ple as possible, and the public insurance only covers theaged (Medicare) and low-income people (Medicaid). Unfor-tunately, this model yields a large (> 10%) uninsured pop-ulation. The merit of private insurance is the freedom ofselecting broader coverage of medical procedures by payinga higher premium. At the same time, this system limits theaccess to costly procedures for those people who cannot af-ford a high premium. Hence severe diseases necessitatingexpensive treatments may not be treated properly becausethe available healthcare depends on insurance coverage.

In Europe, conversely, a large public insurance systemcovers advanced treatments for the whole population, at theexpense of a heavy tax burden. However, it is becoming dif-ficult to adjust the system to more advanced treatments orto the aging population by simply imposing heavier taxes.Therefore, this public insurance system is also difficult tosustain in the near future. In Japan, the whole populationis also covered by a statutory health insurance system, butthe optional treatments available to the insured persons areconsiderably limited. One cannot opt to pay a higher pre-mium to be covered for expensive treatments not approvedunder the universal coverage scheme. Such treatments canonly be received on a private, self-paying basis. This systemis also becoming difficult to sustain because of the increas-ing necessity (for medical reasons) and demands (for socialreasons) to cover more advanced treatments.

Effective countermeasures against this explosive in-crease in healthcare expenditures are urgently needed. Aparadigm shift in healthcare is called for, and the traditionalhealthcare delivery methods need to be reexamined. Thatis why academics and governments worldwide are workinghard on the application of information and communicationtechnologies (ICT) as a feasible and effective measure forreducing medical cost. The potential capability of ICT in re-

Copyright c© 2010 The Institute of Electronics, Information and Communication Engineers

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ducing medical cost and human resources are of paramountimportance. At the same time medical ICT, once developed,should be put into practice without delay, so as to save thepresent medical insurance models in US, Europe, and Japanfrom bankruptcy.

2. Medical Device and Information and Communica-tion Technologies

Clinical application of medical ICT requires the devel-opment of medical devices. Most medical ICT involvemeasurement or monitoring of biosignals, which can beachieved with sensors and wearable or implantable devices.Some medical ICT may also serve as a means of tele-diagnosis or tele-treatment under the supervision of medi-cal professionals. Among various technologies, appropri-ate wireless communications between these devices as wellas communication servers would be the key technology thatcontributes to reduce resources needed for patient manage-ment. Continuous real-time monitoring of pertinent biosig-nals is especially useful for the management of patients withmore advanced stages of diseases. In such patients, prompttreatments in response to changes in biosignals or biosystemproperties would prevent disease deterioration or repeatedhospitalization. Even in stable patients, medical ICT maybe useful in decreasing the frequency of visits to clinics.

As is discussed in the previous chapter, ICT-basedmedical practice is best applied to common diseases. Themore prevalent the disease and the easier disease outcomecan be improved, the more efficient is medical ICT in reduc-ing healthcare cost. Hypertension and diabetes mellitus aresuch examples. The former disease has been described asa “silent killer” because of its insidious onset and ultimatefatal outcome. The long-term outcomes of diabetes are alsograve.

Chronic heart failure is another disease in which pa-tients may benefit from ICT-based medical practice. Heartfailure is a syndrome that manifests in the advanced stagesof all heart diseases irrespective of the etiology. This syn-drome is characterized by its progressive nature, high mor-tality rate, frequent and repeated need for hospitalization,and severely deteriorated quality of life. The potentialaggravation of hemodynamics and cardiac function neces-sitates frequent visits to outpatient clinics or emergencyrooms. Despite frequent hospital visits, hospitalization is of-ten unavoidable. Once hospitalized, the quality of life of thepatients is further worsened, and the costs for managementincrease dramatically. It is conceivable that daily monitor-ing of hemodynamics together with appropriate treatmentsmay obviate the expensive hospitalization. ICT potentiallypermit continuous monitoring with wearable or implantablemedical devices.

3. Pathways Needed for Approval of Medical Devices

Thorough and lengthy processes outlined below are requiredto obtain approval of medical devices. After prototyping the

device, the same device that will be sold and manufacturedin a GMP (good manufacturing practice)-certified produc-tion line should be tested in large animals. The safety andeffectiveness (as defined for each device) should be provedstatistically based on experimental data. The data shouldbe obtained under GLP (good laboratory practice) standards(study conducted in an approved laboratory and using ap-proved methods and devices) or equivalent to ensure thequality of data.

These preclinical (animal experiment) data are prereq-uisite for testing of the device in human volunteers. Clini-cal (human) studies can only be started after the preclinicaldata have been officially examined for whether they wereobtained appropriately and whether they proved the safetyand effectiveness of the device. This process should alwaysbe undertaken for any unapproved device and for any off-label use of an approved device. Clinical studies involv-ing the use of an approved device for approved indicationsdo not require the above process but they need the approvalfrom the institutional review boards.

Therefore, the first step for the development of medi-cal devices intended to realize the new ICT technology is touse it in animals to prove its usefulness. Even though thefinal data required for application to conduct clinical stud-ies should normally be obtained from large animals, pilotstudies may be performed in small animals.

4. Another Role of Information and CommunicationTechnologies during Medical Device Development

As discussed in the previous chapter, medical ICT wouldreduce the medical costs most efficiently by combating themost common diseases such as hypertension and diabetes.These diseases are usually chronic in nature. Heart failureis also a chronic disease, affecting patients for years. Thechronic nature of these diseases requires us to plan preclin-ical studies to observe the effectiveness of a new treatmentfor a certain period (this applies to both drugs and devices).In other words, we have to reproduce the equivalent chronicdisease in animals and treat the disease similarly as in pa-tients. This is also true for the development for the ICT-based medical devices.

Traditionally effectiveness of treatments is sequentiallyexamined by sacrificing a number of animals (typicallymore than six to ensure statistical significance) at a giventime point. Biosignals may be obtained under anesthesiajust before euthanasia. Morphological and structural dataare obtained directly by histological examinations. How-ever, this type of approach has a number of limitations. Toraise and to euthanatize a large number of animals is a time-consuming process and is against the animal welfare. Inaddition, biosignals obtained under anesthesia are consider-ably different from those obtained in a conscious state. His-tological examination provides precise but only static (still)images. Dynamic structural images can only be obtainedwhen the animals are alive.

To circumvent these problems, physiological research

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has also been devoted to methodological development forchronic animal experiments. Based on these results andby applying similar technologies of medical devices, sev-eral companies have begun to supply devices that can beused in chronic animal experiments. These devices allow re-searchers to obtain biosignals and images from live animalswithout killing them. They include implantable telemetricdevices, implantable telestimulation devices, and imagingdevices. Implanted rather than wired monitoring and stim-ulation devices permit experiments to be conducted undereven more physiological conditions, i.e., untethered, free-moving states. Wireless communication and ICT are indis-pensible technologies for the development of such telemet-ric and telestimulation devices.

5. Examples of Chronic Animal Experiments Using In-formation and Communication Technologies

In this chapter, we would like to illustrate the importance oftelemetry and telestimulation in the development of medicaldevices using two examples of animal experiments.

5.1 Improved Survival by Chronic Vagal Stimulation inRats with Chronic Heart Failure after Healed Myocar-dial Infarction

As explained previously, patients with extensive or repeatedmyocardial infarction progress to chronic heart failure. Sur-vival of these patients remains poor despite the developmentof various treatment modalities including drugs, medical de-vices, heart transplantation, and artificial hearts. Recently,medical devices have been highlighted due to their ability toprolong life beyond that can be achieved by drugs alone.

We have been developing a device-based treatment ofheart failure by modifying the imbalance in autonomic tone.Excessive activation of sympathetic nerve and withdrawalof vagal nerve activity are known to play a causative rolein aggravating heart failure. Drugs such as beta-adrenergicblockers, angiotensin converting enzyme inhibitors and an-giotensin receptor blockers, which correct the sympatheticarm of the autonomic imbalance, prove to be beneficial.However, vagal tone enhancement has not been used suc-cessfully to treat chronic heart failure. Short-term electricalvagal nerve stimulation has been used only for the preven-tion of fatal arrhythmia during acute ischemia in animals.Therefore, we examined whether chronic (long-term) elec-trical vagal stimulation would delay the progression of heartfailure and improve survival in rats with chronic heart fail-ure after healed myocardial infarction [1]–[3].

Figure 1 illustrates the experimental setup (panels aand b) and study protocol (panel c). Each rat underwenttwo surgeries; in the first surgery we occluded the left coro-nary artery to create myocardial infarction, and in the sec-ond surgery we implanted telemetric and telestimulation de-vices. In the vagal stimulation group, we stimulated theright vagal nerve using bipolar electrodes (0.1–0.13 mA,0.2 msec, 20 Hz-pulses) for 10 sec at intervals of 60 sec.

Fig. 1 Implanted devices and protocol for chronic vagal stimulationexperiments. ((a), reproduced with permission from [1])

This stimulation protocol was administered for 6 weeks. Us-ing 24 rats, we compared the hemodynamics and histologybetween a group with and a group without vagal stimulationat the end of 6-week period. In another 52 rats, we con-ducted right vagal stimulation for 6 weeks and continued tokeep these rats for a further 14 weeks to tabulate 20-weeksurvival. Telemetry and telestimulation were essential toconduct this chronic experiment in conscious free-movinganimals.

Compared to normal rats (serving as control), ratswith heart failure had higher left ventricular filling pressure,lower contractility, and increased biventricular weight. Withvagal stimulation, these changes (i.e., progression of heartfailure) were partially improved (Fig. 2(a)). What is moreimportant is that this novel treatment improved survival dra-matically (Fig. 2(b)).

This novel treatment strategy has now reached the stageof being tested in a small number of patients [4]. De Ferrariet al. have developed an implantable vagal neurostimulator(Cardiofit, BioControl) and the device was tested in a pilotclinical study to obtain data for future approval. In 32 pa-tients with heart failure (baseline ejection fraction ≤35%),the right vagal nerve was stimulated intermittently (4 mA,duty cycle 21%) for 6 months. The preliminary data indi-cated improved quality of life score (48 to 32, p < 0.01);increased 6-min walk distance (410 m to 471 m, p < 0.01),and increased left ventricular ejection fraction (23 to 27%,p < 0.01). More clinically relevant variables such as hos-pitalization frequency and survival will be investigated in alarger patient population.

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Fig. 2 Effects of chronic vagal stimulation on remodeling and survival.((a) and (b), reproduced with permission from [1])

5.2 Precise Evaluation of Cardiovascular System Proper-ties Needed to Combat Cardiovascular Diseases andSolve Circulatory Deconditioning during Space Flight

In establishing a rational treatment strategy, precise evalu-ation of the properties of key elements in the cardiovascu-lar system is a prerequisite. Of these, knowledge of theproperties of the left ventricle, which is the main sourceof energy to expel the blood, is particularly valuable. It isknown that left ventricular properties are best expressed bythe time-varying elastance curve. To obtain elastance weneed to simultaneously measure high-fidelity pressure andvolume waveform. A catheter-tipped micromanometer anda conductance volumetric method are frequently used forthis purpose. The trial of chronic measurement of pressure-volume data is highly significant, as no one has ever mea-sured the changes in ventricular properties during the life-long course of hypertensive heart disease (a consequence oflong-standing hypertension), and during the progression ofheart failure.

We developed the prototype of an implantablepressure-volume telemetric device for this purpose [5], [6].Figure 3 schematically illustrates the components of the de-vice. It consists of a pressure-conductance catheter, an ana-log processor/transmitter, and a battery unit (panels a, d).In animals, the catheter is inserted into the left ventricle,typically from the apex. On the catheter, two sets of elec-trodes are affixed; in each set the outer pair serves as the ex-citation electrodes, and the inner pair as the recording elec-trodes. The set with wider inter-electrode distance is usedto measure ventricular conductance, and the other set withnarrower distance to measure blood resistivity (panels c, d).We applied 2 kHz- and 20 kHz-sinusoidal AC currents with

Fig. 3 Implanted system for pressure-volume telemetry experiments.((a)–(c), reproduced with permission from [5])

known amplitude between excitation electrodes and mea-sured the voltage amplitude to determine the conductance(Panel b). Online measurements of blood resistivity (usingresistivity electrodes) and parallel conductance (using dualexcitation frequency) permit continuous volumetry withoutany external maneuvers for calibration.

We used Bluetooth technology to transmit datafrom the implanted device to an external receiver(CASIRA, CSR, Cambridge, UK). The Bluetooth module(LMBTB027, Murata, Kyoto, Japan) was capable of trans-mitting 4 channel- (pressure, 2 kHz-conductance, 20 kHz-conductance, and electrocardiography), 200 Hz-, 16 bit-datain a real-time manner (data rate 12.8 kbps). For non-real-time analysis with high time resolution, we temporarilystored 2 kHz- signals in an SRAM (HM62 V16256, Hitachi,Tokyo, Japan) for 6 seconds and then transmitted data to thereceiver.

Figure 4(a) is an example of left ventricular pressureand volume waveform measured in a rat by this telemetricdevice. As expected both pressure and volume decreasedwhen the venous return to the left ventricle was decreased.The precision of the volumetry method was judged to begood by comparing stroke volume measured by telemetryagainst that measured by an independent ultrasonic tran-sit time flow probe (Fig. 4(b), flow waveform shown inFig. 4(a)). In a representative rat, the pressure-volume loopsobtained soon after implantation and at 6 days after implan-tation coincided well, as shown in Fig. 4(c).

We had difficulties in monitoring for longer than 2weeks because of the fragility of the pressure transducers.Long-term stability of the pressure transducers that do not

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Fig. 4 Representative results obtained by pressure-volume telemetry.((a)–(c), reproduced with permission from [5])

require external calibration should be improved for chronicmanometry. Notwithstanding this limitation, the develop-ment of this implantable telemetric device opens up the pos-sibility of automatic tele-experiments. We have successfullyperformed a preliminary tele-experiment using an internettelecommunication line, intended for future space experi-ments. We can perform automatic but supervised experi-ments in a spaceship without any intervention by the space-craft crew. This may help uncover the mechanism of circu-latory deconditioning experienced during prolonged stay inmicrogravity in the near future.

6. Proposal for the Future Direction

Both engineers and clinicians should bear in mind that thebenefit of the ICT-based medical system be examined inrather different ways than in conventional ways. The goalshould not be just the better device or the better treatment.The primary goal should be set at reducing the cost, withoutaggravating or more preferably with improving the qualityof medical practice (and ultimately the survival). The devel-opment of such system requires 1) low-cost, accurate, de-pendable methods for diagnosis and treatment even used bynon-medical staff, 2) evidence (large clinical trial)-based al-gorithm to determine the optimal treatment, and 3) the ac-curate global evaluation of the impact on medical expendi-tures. Medical ICT should be developed with the continu-ous intimate interactions among engineers, clinicians, andthe expert of the medical economics.

As discussed in Sect. 2, hypertension, diabetes, and

chronic heart failure are three major candidates to com-bat with, using ICT-based medicine. How to reduce un-detected and/or untreated hypertensive subjects togetherwith improving drug compliance should be the first goalfor hypertension. Effective measures to promote non-pharmacological treatments (i.e., diet, exercise, life-stylemodification, etc.) should be the first goal for diabetes andobesity. Development of more accurate methods to moni-tor daily changes in body weight, intake and output of waterand salt would benefit the long-term management of heartfailure.

7. Conclusion

Use of implantable devices combined with telemetry andtelestimulation in unanesthetized and untethered animalmodels allows long-term observation of and intervention forpathologic changes during the course of common chronicdiseases. More importantly, these devices can be used moreefficiently for understanding disease mechanisms and ratio-nal development of novel treatments. These devices alsoprovide the basis for automatic tele-experiments, even in thespaceship.

Acknowledgments

This work was supported in part by Health and Labour Sci-ences Research Grants (H19-nano-ippan-009, H20-katsudo-shitei-007) from the Ministry of Health Labour and Welfareof Japan.

References

[1] M. Li, C. Zheng, T. Sato, T. Kawada, M. Sugimachi, and K.Sunagawa, “Vagal nerve stimulation markedly improves long-termsurvival after chronic heart failure in rats,” Circulation, vol.109, no.1,pp.120–124, 2004.

[2] M. Li, C. Zheng, M. Inagaki, T. Kawada, K. Sunagawa, and M.Sugimachi, “Chronic vagal stimulation decreased vasopressin secre-tion and sodium ingestion in heart failure rats after myocardial infarc-tion,” Conf. Proc. IEEE Eng. Med. Biol. Soc., vol.4, pp.3962–3965,2005.

[3] C. Zheng, M. Li, M. Inagaki, T. Kawada, K. Sunagawa, and M.Sugimachi, “Vagal stimulation markedly suppresses arrhythmias inconscious rats with chronic heart failure after myocardial infarction,”Conf. Proc. IEEE Eng. Med. Biol. Soc., vol.7, no.1, pp.7072–7075,2005.

[4] G.M. De Ferrari, A. Sanzob, H.J. G.M. Crijns, R. Dennert, G.Milasinovic, S. Raspopovic, M. Borggrefe, C. Wolpert, J. Kuschyk, A.Schoene, H. Klein, J. Smid, A. Gavazzi, M. Zabel, and P.J. Schwartz,“Chronic vagus nerve stimulation: A new treatment modality forcongestive heart failure,” American College of Cardiology, Orland,U.S.A., 2009.

[5] K. Uemura, T. Kawada, M. Sugimachi, C. Zheng, K. Kashihara, T.Sato, and K. Sunagawa, “A self-calibrating telemetry system for mea-surement of ventricular pressure-volume relations in conscious, freelymoving rats,” Am. J. Physiol. Heart Circ. Physiol., vol.287, no.6,pp.H2906–H2913, 2004.

[6] K. Uemura, M. Sugimachi, T. Shishido, T. Kawada, M. Inagaki, C.Zheng, T. Sato, and K. Sunagawa, “Convenient automated conduc-tance volumetric system,” Jpn. J. Physiol., vol.52, no.5, pp.497–503,2002.

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Masaru Sugimachi received his M.D. andhis Ph.D. from Kyushu University in 1984 andin biomedical engineering from Kyushu Univer-sity in 1992, respectively. From 1992, he movedto Department of Cardiovascular Dynamics, Na-tional Cardiovascular Center Research Instituteto develop medical devices and to study clinicalapplication of bionic cardiology.

Toru Kawada received his M.D. and hisPh.D. from Kagawa Medical School in 1988and in biological information and control fromKagawa Medical School in 1992, respectively.From 1993, he moved to Department of Car-diovascular Dynamics, National CardiovascularCenter Research Institute to study cardiovascu-lar regulation using systems analysis.

Kazunori Uemura received his M.D. andhis Ph.D. from Kyushu University in 1992 andfrom Kochi Medical School in 2006, respec-tively. From 2000, he is at the Department ofCardiovascular Dynamics, National Cardiovas-cular Center Research Institute. His main re-search interests are cardiovascular physiologyand biomedical engineering.