“Medicine 4.0”

Abstract

Not only in the technological world (“Industry 4.0”), but also in medicine, a paradigmatic change is taking place: We are already on the threshold of “Medicine 4.0”. Molecular biology has long played a leading role in life sciences. Scientists now realise that, with increasing miniaturisation, microelectronic systems downsized to the dimensions of cellular systems will facilitate new therapeutic approaches. But conventional telecommunications systems can also be equipped with sensors and transformed into intelligent medical monitoring devices that can help patients become part of the diagnostic and therapeutic process. This article illustrates development trends that will lead to modern, electronically supported healthcare concepts.

Full text

Current Directions in Biomedical Engineering 2017; 3(2): 183–186
Bernhard Wolf* and Christian Scholze
“Medicine 4.0”
The role of electronics, information technology and microsystems in modern medicine
Abstract: Not only in the technological world (“Industry
4.0”), but also in medicine, a paradigmatic change is taking
place: We are already on the threshold of “Medicine 4.0”.
Molecular biology has long played a leading role in life
sciences. Scientists now realise that, with increasing
miniaturisation, microelectronic systems downsized to the
dimensions of cellular systems will facilitate new therapeutic
approaches. But conventional telecommunications systems
can also be equipped with sensors and transformed into
intelligent medical monitoring devices that can help patients
become part of the diagnostic and therapeutic process. This
article illustrates development trends that will lead to
modern, electronically supported healthcare concepts.
Keywords: Medicine 4.0, medical electronics, personalised
medicine, telemedicine, tumor therapy
https://doi.org/10.1515/cdbme-2017-0038
1 Introduction
For centuries, medicine was reliant on the knowledge of
highly trained doctors using a modest number of drugs,
mostly based on natural substances. This era of “Medicine
1.0” preceded the discovery of antibiotics and the diagnostic
use of x-rays. These novelties were designed to change
medicine considerably, becoming what we could call
“Medicine 2.0”. In the following decades surgery benefited
from new developments in microsystems technology and
electronics (navigated surgery, image recognition, robotics,
etc.), enabling interventions that previously had been
unthinkable (“Medicine 3.0”). Today we find ourselves on
the threshold of “Medicine 4.0”: The level that information
and communications technologies, electronics and
microstructure technology has reached today could already
facilitate more efficient therapeutic structures than those we
are used to at present. This article provides a few examples to
demonstrate how microelectronics combined with
information systems can enable new forms of treatment that
can, in turn, lead to a better outcome, have fewer or no
adverse effects, and improve the patient's quality of life.
2 Personalised chemotherapy
Personalised chemotherapy is one of the fields of application
for which we have created the “Intelligent Microplate
Reader” (IMR), a fully automated analysis platform. The
IMR consists of a pipetting robot, an air conditioning system,
a fully automated process microscope and an electronic unit
for reading out the data measured by the electrochemical
sensors. The multiparametric sensors are positioned on a
glass substrate at the base of the “intelligent multiwell plate”,
a microtitre plate with 24 reaction chambers (Fig. 1). A
sophisticated three-chamber fluidics system supplies fresh
culture medium at predefined intervals to the cells growing
on the sensors within the chambers.
______
*Corresponding author: Prof. Dr. rer. nat. Bernhard Wolf:
Steinbeis-Transferzentrum Medizinische Elektronik und
Lab on Chip-Systeme, Fendstr. 7, 80802 München, Germany,
e-mail: wolf@stw-med-chip.de
Dipl.-Biol. Christian Scholze: Steinbeis-Transferzentrum
Medizinische Elektronik und Lab on Chip-Systeme, Fendstr. 7,
80802 München, Germany, e-mail: scholze@stw-med-chip.de
Figure 1: Intelligent multiwell plate with sensor system; each of
the 24 chambers contains a sensor for measuring the pH, the
dissolved oxygen concentration and impedance

184
For the purpose of testing, a biopsy sample of tumour
tissue is taken from the patient and cultivated on the sensors
of the intelligent multiwell plate. The pipetting robot of the
IMR permits 24 different active substances or 24 different
concentrations of an active substance to be added to the
24 reaction chambers in a single operation. The sensors then
detect the changes in oxygen concentration, pH and electrical
conductivity around the tissue in each of the chambers. The
microscope automatically detects any morphologic changes
in the cells. The metabolic data thus obtained from the cells
are used to ascertain whether or not there is any significant
sensitivity to certain agents (Fig. 2) [1] [2].
The system permits a large number of these tests to be
conducted within a short period of time and facilitates
extensive test runs. These personalised tests of the
pharmacologic effectiveness of drugs using the IMR enable
physicians to find the ideal combination of drugs for a
particular treatment – for the good of the patient.
3 Personalised telematic
therapy
In the healthcare sector, the sociodemographic situation
means that there is an increasing demand for systems that
support the population's autonomy and empowerment. The
consistent use of microelectronic systems now enables
individuals to independently measure parameters like blood
pressure, pulse, oxygen saturation, hydration, weight and the
intensity of physical activity, and to verify the results via data
exchange. Biomedical sensors are an essential part of these
systems. Impressive cost savings and quality improvements
could also be achieved in the medical field by using clever
combinations of modern sensor systems and state-of-the-art
information and communications technologies [3].
3.1 Telemedical COMES® platform
With the autonomous telemedical COMES® platform (Fig.
3), we have created a system that enables patients with
cardiovascular diseases to measure their vital parameters
themselves and transmit the results automatically to the
database via mobile radiocommunications.
An ideal combination for this purpose is the All-in-One
device shown in Figure 4 comprising a mobile phone with
integrated medical sensor system for pulse oximetry, blood
pressure, temperature, skin resistance (hydration) and
interfaces for measuring body weight, blood glucose
metering and other functional interfaces [5], [6]. The treating
physician can access the data of his/her patients at all times
and will be alerted immediately of any abnormal values so
that the necessary action can be taken. Patients with
cardiovascular diseases feel safer and at the same time more
independent thanks to the constant reassurance offered by the
Figure 2: IMR measurement of chemosensitivity in a tissue
sample of human mammary carcinoma: While one of the
substances tested only has a weak effect on the tumor tissue, the
other almost halts the metabolic activity of the cells [1], [2].
Figure 3: The COMES® overall concept: Cognitive Medical
Systems with intelligent assistance devices that can be used
anywhere, in all walks of life (Comes = Latin for “companion”) [4].
Figure 4: The All-in-One device: Measurements are taken by
slipping a finger (usually the index finger) into the sleeve (right).

sensor system. The patient can manage his or her medical
data via a database and if necessary transmit them to the
doctor, and can also obtain additional information via
database-supported feedback systems. The doctor, on the
other hand, can monitor patients using the COMES® system
and take preventative action as suggested by the data or
arrange for the medical expert system and call centre to
intervene, as necessary, while at the same time remaining in
contact with the patient.
3.2 The intelligent occlusal splint
The general trend towards networked systems can also be
seen in the field of implantable medical devices. Such
implants are being used increasingly to obtain physiological
information important to targeted therapy, or to compensate
for impaired physiological functions. Our approach is to use
closed-loop systems: based on the recorded vital parameters,
an active control unit influences the physiological functions –
e.g. by administering a drug or by delivering targeted
biofeedback to the patient. One example that illustrates the
mode of operation of feedback-driven systems in the human
body is the intelligent occlusal splint developed for the
purpose of diagnosing and treating bruxism (grinding of the
teeth) [7].
The device is very compact and thus can be integrated in a
conventional occlusal splint as shown in Fig. 5. The patient's
chewing activities are measured by means of a piezo-electric
sensor system. A wireless radio transmitter sends the
measured data to a receiver the size of a matchbox which can
be placed at the patient's bedside or may also be worn on the
body. The receiver can store several months’ worth of
incoming data. Via a USB interface, the stored data can be
transmitted to the computer of the treating physician. The
system permits the bruxism activity to be monitored both
during the day and at night. Computer software can be used
to analyse the time, intensity and frequency of teeth grinding.
In addition to using the system diagnostically, it can also
serve treatment purposes by prompting immediate tactile
(vibration) or acoustic biofeedback via the receiver unit in the
occlusal splint. In the long run, such stimulation will help to
condition the patient and reduce the bruxism activity.
3.3 Intelligent implants for cancer
therapy
Feedback and closed-loop systems play an important role in
invasive diagnostic and therapeutic concepts. One example is
our “IntelliTUM” project, funded by the German Federal
Ministry of Education and Research (Bundesministerium für
Bildung und Forschung, BMBF), in which we developed an
implant system for monitoring dissolved oxygen [8].
This system (shown in Fig. 6) is based on the fact that
the saturation of tissues with dissolved oxygen plays a
leading role in invasive processes in malignant tumours: the
oxygen deficiency (hypoxia) found in many solid tumours
correlates with abnormal metabolic profiles and sensitivity to
radiation therapy. A sensor placed in the direct vicinity of
such a tumour can detect increased hypoxia and provide
important information on tumour activity – this may then be
used as the basis for individualising therapy and optimising
the dosage. The implant may be complemented by a drug
metering unit. If the sensor on the outside of the implant
detects a lack of oxygen, which is an indicator of tumour
growth, a chemotherapy agent contained in the drug depot of
the implant could be administered directly to the tumour (see
Fig. 7) [9].
Figure 5: Intelligent occlusal splint with receiver unit (Senso
BiteTM System) for diagnosing and treating buxism.
Figure 6: Prototype of the implant developed in the “IntelliTUM”
project. If the system is used without the drug delivery unit, the
implant size can be reduced to 25 %.

186
These systems are an alternative to conventional, established
treatment methods. They are not limited to oncotherapy, but
also bring considerable improvements above all in the
postsurgical monitoring of cancer patients, since they allow
for minimally invasive and long-term, continuous monitoring
of critical tissue regions in the outpatient setting.
4 Prospects
The few examples discussed in this article indicate to
what extent electronics and microelectronics will change the
fields of diagnosis and therapy in the future and how
immense their additional benefit would be for patients. But
there are still issues with the exemplary results from the
collaborative research projects we have conducted in recent
years which are described in this article: Much valuable time
is lost before such innovations can be marketed and
authorised, and before they may be prescribed by doctors and
used by patients. Too often, political and economic interests,
and the demands of various organisations, associations and
lobbyists, can delay the introduction of new medical
technologies. However, we will continue working on the
research projects discussed here and certain other projects at
our Steinbeis-Transferzentrum – thereby paving the way for
products to go into series production. We would therefore
welcome the support of suitable collaborative partners.
Author’s Statement
Research funding: Our projects were funded by DFG, Heinz
Nixdorf Stiftung, BMBF, Bayerische Forschungsstiftung and
Bayerisches Staatsministerium für Gesundheit und Pflege.
Conflict of interest: Authors state no conflict of interest.
Informed consent: Informed consent is not applicable. Ethical
approval: The conducted research is not related to either
human or animals use.
References
[1] Kleinhans R, Brischwein M, Wang P, Becker B, Demmel F,
Schwarzenberger T, Zottmann M, Wolf P, Niendorf A, Wolf B:
Sensor-Based Cell and Tissue Screening for Personalized
Cancer Chemotherapy. Medical and Biological Engineering
and Computing, 50, 117–126, 2012.
[2] Demmel F, Brischwein M, Wolf P, Huber F, Pfister C, Wolf B:
“Nutrient depletion and metabolic profiles in breast carcinoma
cell lines measured with a label-free platform”. Physiol. Meas.
36 (2015) 1367-1381, 2015.
[3] Friedrich P, Clauss J, Scholz A, Wolf B: Sensorik für
telemedizinische Anwendungen. In: Goss F, Middeke M,
Mendgen T, Smetak N. Praktische Telemedizin in
Kardiologie und Hypertensiologie. Stuttgart: Thieme-Verlag,
6-14, 2009.
[4] Wolf B, Spittler T, Clauss J, Scholz A, Friedrich P, Herzog K:
“Telemedizin - rundum gut betreut”. Bulletin, 4, 33-37, 2014
[5] Gausemeier J, Wolf B, Clauss J, Friedrich P, Herzog K,
Lehner A-C, Placzek M, Schierbaum T, Spittler T,
Westermann T: „Telemedizinische Assistenzsysteme -
Technik, Markt, Geschäftsmodelle“, Heinz Nixdorf Institut
Paderborn und Heinz Nixdorf-Lehrstuhl für Medizinische
Elektronik (ed.), W.V. Westfalia Druck GmbH, 2014.
[6] Wolf B, Grothe H, Herzog K, Demmel F, Wiest J, Wirths W,
Clauss J, Brischwein M, Dormeyer C, Gül M, Hinderer K-U,
Friedrich P: “Von der TUM in den Markt: Mikroelektronik für
Diagnose und Therapie“. Duesberg, F. (ed.): e-Health 2015
Informations- und Kommunikationstechnologien im
Gesundheitswesen. Solingen/Mittweida, medical future
verlag, 120-127, ISBN: 978-3-9814005-9-5, 2014.
[7] Vahle-Hinz K, Clauss J, Seeher W-D, Wolf B, Rybczynski A,
Ahlers M O: Development of a wireless measuring system for
bruxism integrated into occlusal splint. Journal of
Craniomandibular Function 1, No. 2, 125 ff., 2009.
[8] Clauss J, Becker S, Sattler M, Wolf B: In vivo Diagnostik mit
intelligenten Implantaten. In: Bernhard Wolf (ed.):
Bioelektronische Diagnose- und Therapiesysteme. m3:
microelectronic meets medicine, Aachen: Shaker Verlag,
237–246. ISBN: 978-3-8440-0831-9, 2012.
[9] Becker S, Xu T, Ilchmann F, Eisler J, Wolf B: Concept for a
gas-cell-driven drug delivery system for therapeutic
applications, Proceedings of the Institution of Mechanical
Engineers, Part H: Journal of Engineering in Medicine, DOI:
10.1177/0954411911423348, 2010.
Figure 7: Operating principle of a tumor implant as a closed-loop
system.
Figure 8: QR codes linking to videos of our projects:
Personalised chemotherapy (left), Intelligent nano pill (right)