# Magnetic marker monitoring

The Magnetic Marker Monitoring ( english was) designed to movements in closed systems and are difficult to access record, analyze and optimize them. In gastroenterology , magnetic marker monitoring is used to identify specific motility patterns during the gastrointestinal passage of a magnetic marker and thus to be able to diagnose functional diseases of the gastrointestinal tract .

Particular attention in the motility analysis is given to gastric emptying disorders, inflammatory bowel diseases ( Crohn's disease , ulcerative colitis ), gastroparesis , celiac disease and diabetes mellitus . In these diseases, a significant change in motility within the digestive organs is assumed.

## principle

After the patient has been given a bio-inert capsule with a magnetic core (e.g. neodymium-iron-boron , NdFeB), it is placed under a magnetic field-sensitive sensor field (e.g. AMR sensors ). The sensors measure the quasi-static magnetic field that surrounds the marker. The exact alignment and position of the marker is determined by comparing the field distribution resulting from the simulation of the current marker position with the real, measured magnetic field distribution. The data obtained are recorded and analyzed using special software. This exact observation of the marker through the gastrointestinal tract (GI tract) enables the patient's passage time and motility pattern to be examined.

Another application of magnetic marker monitoring is in drug development. Knowledge of the absorption of active ingredients is of central importance for the manufacture of pharmaceutical products . In order to examine the absorption properties in different sections of the intestine, a magnetic capsule is used in the example (MAARS method), which releases the active ingredient in a controlled manner by the user. The capsule consists of individual segments that are held together by magnetic forces. The external magnetic stray field of the capsule is used for localization in the gastrointestinal tract. By means of a controlled demagnetization, the capsule disintegrates into the individual segments and releases the active substance contained in the target volume.

## Physical fundamentals for locating a magnetic marker

### Maxwell's equations

Field distribution for any dipole magnet in the coordinate system

All macroscopic properties of electromagnetic fields can be described with the help of Maxwell's equations . They contain the electric field , the magnetic field and the magnetic flux density in vacuum, the electric charge density ρ, the displacement density D and the current density j. In differential form they are: ${\ displaystyle E}$${\ displaystyle H}$${\ displaystyle B}$

${\ displaystyle {\ mbox {rot}} \, {\ varvec {H}} = {\ frac {\ partial D} {\ partial t}} {\ varvec {B}} + {\ varvec {j}} \ ,, {\ mbox {red}} \, {\ varvec {E}} = - {\ frac {\ partial B} {\ partial t}} \ ,, {\ mbox {div}} \, {\ varvec { D}} = {\ varvec {\ rho}} \ ,, {\ mbox {div}} \, {\ varvec {B}} = 0}$

The description for the field of a magnetic dipole can be derived from these equations:

${\ displaystyle {\ boldsymbol {H}} (r, \ mu) = {\ frac {1} {4 \ pi}} \ left (- {\ frac {\ mu} {\ r ^ {3}}} + {\ frac {3 \ cdot (r, \ mu), r} {r ^ {5}}} \ right) \,}$, with μ = magnetic moment

There are six degrees of freedom for the clear determination of the marker position, five for the position of the dipole in space (X, Y and Z as Cartesian coordinates and φ and θ for describing the orientation of the marker) and the magnetic moment μ as the sixth degree of freedom. If these variables are known, the magnetic field strength can be determined at any point in space. Since the marker localization is an inverse problem , the position of the marker cannot, conversely, be explicitly stated from six independent measurements. For this reason, the problem of determining the position is sensibly solved with the aid of the least squares method.

### The quality function

For a number of n sensors, which is at least equal to the number of degrees of freedom to be determined, the magnetic field H is calculated around a simulated marker and the sensor positions and compared with the measured sensor signals. For this purpose, all squared deviations from simulated and actual magnetic field strengths are added up to form an error or quality function :

${\ displaystyle {\ varvec {Q}} = \ sum _ {n} ^ {i = 1} \, \ {{\ varvec {H}} (r, \ mu) _ {i} ^ {M} - { \ boldsymbol {H}} (r, \ mu) _ {i} ^ {S} \} ^ {2}}$, with M = measurement, S = simulation

The position of the marker to be localized is changed with a suitable strategy ( gradient method or fuzzy methods) until the difference between the sensor signal and the simulated field is minimal. The position determined in this way corresponds to the true position of the marker. To increase the accuracy and to minimize the influence of the static errors in the sensor signals, a large number of sensors is used. In order to minimize the influence of external disturbances, various modifications of the quality function can be created. For example, the sensors can be evaluated with regard to their sensitivity. The quality function is then modified in the following form:

${\ displaystyle {\ varvec {Q}} = \ sum _ {n} ^ {i = 1} {\ frac {\ {{\ varvec {H}} (r, \ mu) _ {i} ^ {M} - {\ boldsymbol {H}} (r, \ mu) _ {i} ^ {S} \} ^ {2}} {\ Delta {\ boldsymbol {H}} _ {i} ^ {2}}}}$, with M = measurement, S = simulation

where Δ H ² i corresponds to the spread of the individual sensor signals. A further increase in accuracy is achieved through the introduction of the gradiometer principle . To do this, various sensor signals are linked to one another in order to eliminate external interference fields. The quality function for a 1st order gradiometer is as follows:

${\ displaystyle {\ varvec {Q}} = \ sum _ {n} ^ {i = 1} \, \ {({\ varvec {H}} (r, \ mu) _ {G} ^ {M} - {\ varvec {H}} (r, \ mu) _ {G} ^ {M}) - ({\ varvec {H}} (r, \ mu) _ {G} ^ {M} - {\ varvec { H}} (r, \ mu) _ {G} ^ {M}) \} ^ {2}}$, with M = measurement, S = simulation, G = gradio

## Used magnetic field sensors

There are various measuring device arrangements and magnetic field sensors, all of which are based on the three-dimensional localization of magnetic markers. “Superconducting Quantum Interference Devices” sensors ( SQUIDs ) enable the detection of the smallest signals up to 10 −15 Tesla. A measurement with these sensors is very complex because the sensors have to be cooled (low-temperature SQUIDs with liquid helium , high-temperature SQUIDs with liquid nitrogen ). Due to the high sensitivity of the sensors to magnetic fields, magnetic shielding is generally required. The application of the SQUIDs is therefore very expensive and remains limited to experimental purposes. Another type of sensor are Hall sensors (named after Edwin Hall ), which have a sensitivity of up to 10 −8 Tesla and are therefore above urban disturbances (magnetic disturbances e.g. from hospital beds, elevators). They don't need magnetic shielding and work at room temperature. In order to achieve a large range, the magnetic markers used in the Hall sensors prove to be very large and are therefore unsuitable for medical applications.

Thus, in clinical practice, v. a. AMR sensors are used. At 10 −10 Tesla, their sensitivity is slightly below urban disturbances. With this type of sensor, measurements can be made at room temperature in a normal examination room with small magnets and with sufficient accuracy. This method is therefore easy to carry out and inexpensive. The position of such a magnet is determined by evaluating the magnetic stray field surrounding it. After it has been ingested by humans, its current location, the respective frequencies , activities and speeds with which it is moved can be determined. The behavior of the magnetic marker corresponds to the indigestible food components in the GI tract e.g. B. that of cherry stones.

## application

Drug release profile with MAARS capsule

A mere monitoring of the passage of a capsule and the motility pattern can provide information about the course of a therapy or illness of all gastrointestinal dysfunctions in which a changed motility of the gastrointestinal tract is part of the symptoms. Particular mention should be made of gastroparesis , celiac disease , Crohn's disease , ulcerative colitis , diabetes mellitus and diarrhea . Changes in motility due to medication, food components and operations can also be assessed very well using magnetic marker monitoring. A targeted release of the active ingredient is of particular importance for the development of medicinal substances, as this enables absorption in different areas of the intestine to be determined and an optimized formulation of the medicinal product to be found. Through a combination of monitoring and controlled drug release , pharmacokinetic data regarding bioavailability and the drug release profile can be recorded. The release profile shown in the picture was generated with the "Magnetic active agent release system" (MAARS).

Probably the most important advantage over other diagnostic methods in gastroenterology, such as endoscopy , is the painless and minimally invasive examination of the patient. In contrast to scintigraphic methods, no radioactive substances are used. For drug research and development, there are advantages primarily from the fact that drug studies can be carried out quickly and easily.

## Individual evidence

1. H. Richert: Development of a magnetic 3-D monitoring system using the example of the non-invasive examination of the human gastrointestinal tract . (Dissertation, Friedrich Schiller University, Jena 2003).
2. Wilfried Andrä, Henri Danan, Klaus Eitner, Michael Hocke, Hans-Helmar Kramer, Henry Parusel, Pieter Saupe, Christoph Werner, Matthias E. Bellemann: A novel magnetic method for examination of bowel motility . In: Medical Physics . tape 32 , 2005, pp. 2942-2944 , doi : 10.1118 / 1.2012788 .
3. Michael Hocke, Ulrike Schöne, Hendryk Richert, Peter Görnert, Jutta Keller, Peter Layer, Andreas Stallmach: Every slow-wave impulse is associated with motor activity of the human stomach . In: American Journal of Physiology-Gastrointestinal and Liver Physiology . tape 296 , 2009, pp. G709-G716 , doi : 10.1152 / ajpgi.90318.2008 , PMID 19095766 .
4. Felber J., Pätzold S., Richert H., Stallmach A .: 3D-MAGMA: A novel way of measuring gastrointestinal motility in patients with infectious diarrhoea . In: Good . tape 60 , 2011, p. 153–154 , doi : 10.1136 / good.2011.239301.325 .
5. a b c Clinical magnetic monitoring system, 3D-MAGMA ( Memento from August 15, 2013 in the Internet Archive ), capsule, measuring system, marker path
6. a b c Release capsule Magnetic drug release, MAARS process ( Memento from March 10, 2013 in the Internet Archive ), Maars process
7. ^ O. Kosch, W. Weitschies, L. Trahms: On-line localization magnetic markers for clinical applications and drug delivery studies . In: Biomag 2004: Proceedings of the 14th International Conference on Biomagnetism: Boston, Massachusetts, USA, August 8-12, 2004 . 2004, p. 261-262 .
8. Werner Weitschies, Olaf Kosch, Hubert Mönnikes, Lutz Trahms: Magnetic Marker Monitoring: An application of biomagnetic measurement instrumentation and principles for the determination of the gastrointestinal behavior of magnetically marked solid dosage forms . In: Advanced Drug Delivery Reviews . tape 57 , no. 8 , 2005, p. 1210-1222 , doi : 10.1016 / j.addr.2005.01.025 .
9. V. Schlageter, B. Thevoz, Y. de Ribaupierre, B. Meyrat, N. Lutz, P. Kucera: Noninvasive examination of gastrointestinal motility by using magneto-detection . In: Neurogastroenterol Motil . No. 10 , 1998, pp. 105 .
10. E. Stathopoulos, V. Schlageter, B. Meyrat, Y. Ribaupierre, P. Kucera: Magnetic pill tracking: a novel non ‐ invasive tool for investigation of human digestive motility . In: Neurogastroenterology & Motility . tape 17 , no. 1 , 2005, p. 148-154 , doi : 10.1111 / j.1365-2982.2004.00587.x .
11. ^ H. Richert, S. Wangemann, O. Surzhenko, J. Heinrich, K. Eitner, M. Hocke, P. Görnert: Magnetic Monitoring of the Human Gastrointestinal Tract . In: Biomedical Engineering . tape 49 , 2004, pp. 718-719 .
12. Hendryk Richert, Olaf Kosch, Peter Görnert: Magnetic Monitoring as a Diagnostic Method for Investigating Motility in the Human Digestive System . In: W. Andrae, H. Nowak (Ed.): Magnetism in Medicine . WILEY-VCH, Weinheim, p. 481-498 , doi : 10.1002 / 9783527610174.ch4b .
13. Biopharmacy and Pharmaceutical Technology ( Memento from January 1, 2009 in the Internet Archive ), example with the Maars method