Systems and methods for detecting magnetic markers for surgical guidance

Abstract

A method of detecting a magnetic marker includes generating a driving magnetic field including a first frequency and a second frequency, and detecting a response magnetic field including a first response component and a second response component. The magnetic marker provides a nonlinear response to the driving signal. A primary portion of the response component is generated by the magnetic marker, and a secondary portion of the response component is generated by a secondary magnetic source. The method includes determining a driving factor representing a ratio of the frequencies in the driving signal, determining a correction factor corresponding to the secondary portion of the second response component based on the first response component and the driving factor, determining a detection signal corresponding to the primary portion of the second response component based on the second response component and the determined correction factor, and generating an output signal based on an intensity of the detection signal.

Description

TECHNICAL FIELD

[0001] The present invention relates generally to the field of surgical guidance, and more particularly to systems and methods for detecting markers and tracers that aid in locating internal sites (e.g., lesions for surgical resection). BACKGROUND

[0002] Markers are used to guide surgeons to areas of interest during surgical procedures, where the site of interest is physically invisible or inaccessible, such as a small tumor that needs to be resected. Markers can be placed at the site of interest in the body, such as a cancerous lesion, during a biopsy or other surgical procedure. Ideally, such markers would be deployable through a narrow gauge needle. The markers are placed under imaging guidance, such as ultrasound or X-ray / mammography. During the subsequent procedure, the markers are detected and located using a hand-held probe that provides auditory, visual, or other feedback to the surgeon to guide the procedure. Typically, the markers are resected along with the surrounding tissue.

[0003] Markers can also be used to mark lymph nodes prior to a course of neoadjuvant therapy. In this way, lymph nodes can be easily identified for resection after neoadjuvant therapy, even if the fibrosis caused by the therapy has affected the lymphatic system such that conventional lymphatic tracers cannot flow to the draining lymph nodes.

[0004] One such method of tumor marking is to use markers containing a radioisotope (e.g., iodine 90), which can be detected using a hand-held gamma detection probe (e.g., a Geiger counter). However, the use of radioactive materials is heavily regulated, which makes it challenging to establish a radioactive seed program at all but the largest academic hospital centers.

[0005] Another method, discussed in earlier published patent applications by the applicant (e.g., WO 2011 / 067576, WO 2014 / 013235, and WO 2014 / 140567), uses magnetic fields and magnetic markers with high magnetic susceptibility. A hand-held probe generates an alternating field that excites the magnetically responsive markers, and detects the response magnetic field.

[0006] Liquid or liquid-borne markers can also be used in surgical procedures, for example for sentinel lymph node detection for biopsies. Such markers can be referred to as "tracers". Sentinel lymph node biopsy is an important technique for staging certain cancers, i.e. assessing the spread of certain cancer types, in particular breast cancer. A tracer can be injected near a cancer tumour. The tracer particles are then taken up by the lymphatic system and flow to and accumulate in draining lymph nodes. The lymph nodes can then be located by visual discoloration of the lymph nodes or using a hand-held probe so that they can be excised for pathological evaluation. Lymph nodes identified in this way are referred to as "sentinel" lymph nodes because they are the ones to which the cancer can spread. The surgical procedure to identify and remove them is called a sentinel lymph node biopsy procedure.

[0007] Typically, both tumour excision and lymph node excision occur in the same procedure. Therefore, tracers and markers can be present in the breast at the same time.

[0008] As mentioned above, one approach is to use a liquid marker containing a radioisotope, for example technetium 99m sulphur colloid. The radio-labelled colloid particles accumulate in the draining lymph nodes which can then be identified for excision using a hand-held gamma probe (Geiger counter). However, technetium 99m has a half-life of only 6 hours, so it must be injected close to the time of the procedure, presenting a scheduling challenge. It can also have a complex supply chain and can not be suitable for remote hospitals. Supply can also be interrupted if the reactor producing the isotope is not operating at a given time.

[0009] Another approach is to use a suspension of superparamagnetic iron oxide nanoparticles. These particles have no half-life, meaning they can be used at any hospital and can be injected several days before the procedure, making scheduling more convenient.

[0010] The nanoparticles can be detected by a magnetic probe, for example the hand-held probe above. However, such a probe can respond to both magnetic markers and the iron oxide nanoparticle suspension. In particular, a portion of the nanoparticle suspension can remain in the area of the injection site near the lesion. It is desirable to perform both the lesion removal procedure and the sentinel lymph node biopsy in one procedure, however, it has proven problematic to provide a detection system that can distinguish between the lesion marker and other magnetically responsive materials. This is illustrated in Figure 1A .

[0011] Other magnetically responsive materials include surgical tools made of metal. It is desirable to develop a magnetic marker or tracer that can be detected in the presence of metal tools. This is illustrated in Figure 1B .

[0012] The human body itself has a magnetic response that interferes with the detection of magnetic markers, because water, which is the main component of human tissue, produces a diamagnetic response. Typically, during a localization procedure, a large amount of human tissue surrounds the injected marker. Therefore, it is advantageous that the marker can be accurately localized with respect to the background signal from the human body. This is described in Figure 1C . .

[0013] Multiple markers can be present at the site of a lesion. For example, a biopsy marker can have been placed previously to monitor the evolution of a tumor mass over time by mammography or ultrasound scanning. Ideally, the probe used for lesion localization during surgery is only sensitive to the marker placed for this purpose. This is described in Figure 1D . .

[0014] If a magnetic marker is used to mark a specific lymph node, and a magnetic tracer is also used to map and identify other sentinel lymph nodes, it is possible that one or more lymph nodes have both a magnetic marker and a magnetic tracer present. It is advantageous to be able to locate and identify which lymph nodes are marked and which contain only a tracer. Also, it can be advantageous to be able to quantify the amount of tracer in a lymph node even in the presence of a marker. Therefore, it is necessary to distinguish between the marker and the tracer within a lymph node. This is described in Figure 1E . .

[0015] One solution to the above problems is to use markers that respond non-linearly to an excitation magnetic field. The complete harmonic response can be analyzed to distinguish the marker from a tracer, a metal tool, the body, or other markers that have a different and usually more linear response at the same field strength. .

[0016] Materials that have a large Barkhausen discontinuity in the magnetization curve, or "Large Barkhausen Jump" (LBJ) materials, undergo a rapid reversal of their magnetic polarization upon excitation by an external magnetic field (also called switching field) of field strength opposite to the instantaneous magnetic polarization of the wire material above a predetermined threshold. The marker thus exhibits bistable behavior, which reverses between two magnetic polarization states. Each magnetization reversal generates a magnetic pulse with harmonic components. The profile and number of harmonics (up to several tens of harmonics) are measured to identify the marker from other materials. .

[0017] It has been shown (e.g. CA3031282A1) that some LBJ materials exhibit strong nonlinear responses even when the marker is shorter than the critical length and / or subjected to excitation below the switching field. Markers formed from such materials are referred to as sub-bistable markers. Other markers with a lesser level or different type of nonlinearity in their magnetic response can also be considered for use to distinguish from more linear secondary signals. For example, the nonlinearity can be a result of including a nonlinear electronic element (such as a diode) in the marker.

[0018] Ideally, the excitation magnetic field (drive field) generated by the magnetic probe should contain only one fundamental frequency component. A strong magnetic field is also required to achieve large detection distances. However, it is challenging to produce an alternating magnetic field around the probe that has both a high field strength and a pure single frequency sinusoidal waveform at the required frequency. When the amplifier is driven with sufficient power to produce a strong field, some distortion or impurities are usually introduced in the sinusoidal waveform, which causes harmonics of the drive frequency to be added in.

[0019] Harmonic components in the drive field can cause responses at the same harmonic frequencies from any linear tracers or markers. This can interfere with the harmonic signals produced by nonlinear markers and can hamper their detection and characterization, as shown in Figure 2

[0020] Low distortion operational amplifiers can provide about -120 dB of harmonic distortion, where the harmonic distortion is the ratio of the rms value of the harmonic of interest (2nd, 3rd, etc.) to the rms signal level. However, such low distortion can only be achieved at a few tenths of a milliamp of current, which is usually too low. Such amplifiers also typically use resistive loads, while magnetic probes typically use inductive loads. Furthermore, the harmonic distortion of operational amplifiers is usually measured by looking at the voltage, not the current. However, in the present application, the harmonic distortion of interest is the magnetic field, which is generated by the current, not the voltage. Therefore, it is not trivial to produce a high purity drive field with off-the-shelf electronic components.

[0021] ​Typically optimised harmonic distortion of the drive field in a magnetic probe such as in WO 2011 / 067576, WO 2014 / 013235 or WO 2014 / 140567 at the frequency of interest can be in the range of -70 dB to -100 dB. This indicates that the harmonic components are 10000-100000 times smaller than the drive signal, which is acceptable for most applications relying on linear detection, even high-end audio systems. However, in the present application, such levels of harmonic distortion in the driver can easily be as large as the signal from a non-linear marker at a distance from the probe when reflected by a linear magnetic material close to the probe. Therefore, there is a need to provide a system that is able to distinguish non-linear markers from other magnetically responsive materials even in the presence of a non-pure drive field. The present invention aims to address this need. SUMMARY

[0022] According to a first aspect of the present invention, there is provided a method of detecting a marker according to claim 1.

[0023] Optional features are as described in the dependent claims. BRIEF DESCRIPTION OF DRAWINGS

[0024] For a better understanding of the present invention and to show how it can be implemented, reference will now be made, purely by way of example, to the accompanying drawings in which:

[0025] Figures 1A to 1E is an exemplifying diagram representing a use scenario of an embodiment;

[0026] Figure 2 is a number of diagrams showing the impact of harmonic components in a drive field;

[0027] Figure 3 is a schematic diagram of a magnetic detection system according to an embodiment;

[0028] Figure 4 is a schematic diagram of a magnetic detection system according to an embodiment;

[0029] Figure 5A is a diagram showing the magnetisation curve of an exemplary marker;

[0030] Figure 5B is a diagram showing the magnetic response in the time domain;

[0031] Figure 5C is a diagram showing the magnetic response in the frequency domain;

[0032] Figure 6A is a diagram showing the magnetisation curve of an exemplary tracer;

[0033] Figure 6B is a diagram showing the magnetic response in the time domain;

[0034] Figure 6C is a graph showing the magnetic response in the frequency domain;

[0035] Figure 7 is a schematic diagram of a magnetic detection system according to an embodiment; and

[0036] Figure 8 is a flowchart showing a method according to an embodiment. DETAILED DESCRIPTION

[0037] The present invention relates to a detection system and method for characterising a marker, and more particularly to a magnetic marker which can be implanted to mark a target site in the body, and to the detection and localisation of the implanted marker using a hand-held probe.

[0038] The marker can be implanted in a site in the body which needs to be marked. This can be, for example, a tumour or other lesion or site of interest in soft tissue. Examples include, but are not limited to, benign lesions, cancerous lesions and lymph nodes. The marker can be placed in or near the lesion, or multiple markers can be placed to mark the edge or perimeter of a surgical site, for example the edge of a tumour or soft tissue sarcoma.

[0039] BRIEF DESCRIPTION OF DRAWINGS Figure 2 A schematic diagram showing an embodiment of a detection system and marker according to the present invention is shown. The detection system 1 comprises a probe 10 connected to a base unit 4. The probe 10 has one or more drive coils which generate an alternating magnetic field to excite the magnetic marker 6. A magnetic tracer 7 can also be present in the vicinity of the marker 6.

[0040] The marker 6 comprises at least one magnetically responsive material and can have a non-linear magnetic susceptibility. The magnetisation of the material can respond to an external magnetic field in a non-linear way. The material can have a large Barkhausen discontinuity in its magnetisation curve and can be referred to as a large Barkhausen jump material, LBJ material, bistable switching material or material having a large degree of non-linearity in its magnetisation curve. For example, when an LBJ material is exposed to such an external magnetic field (switching field H SW ) the magnetic polarisation of the LBJ material undergoes a rapid reversal: the field strength of the external magnetic field which is opposite to the instantaneous magnetic polarisation of the length of material exceeds a predetermined threshold. This magnetisation reversal generates a magnetic pulse with strong harmonic components.

[0041] The tracer 7 comprises a liquid containing a plurality of magnetic nanoparticles. For example, the tracer 7 can comprise a plurality of iron oxide nanoparticles. The nanoparticles can be described as superparamagnetic nanoparticles. The magnetic response can be substantially linear when the tracer 7 is exposed to an external field, i.e. the magnetisation of the tracer 7 is directly proportional to the applied field. The magnetic response of the tracer 7 can be substantially linear when the strength of the external field is within a certain range. When the strength of the external magnetic field is above a certain linear threshold, the magnetisation of the tracer 7 can saturate, resulting in a non-linear magnetic response.

[0042] The probe 10 of the detection system further comprises one or more sense coils arranged to detect changes in the magnetic field caused by changes in the magnetisation of the marker 6 and / or the tracer 7.

[0043] In order to detect the marker 6 in a typical lesion or site of interest, the probe 10 must have a detection depth of at least 30mm, preferably greater than 40mm and more preferably greater than 50mm. Ideally, the marker 6 gives the same magnitude of response regardless of the direction of approach to the marker 6. This is to provide consistent feedback to the surgeon about the location of the marker 6 relative to the probe 10.

[0044] Figure 4 An example probe 10 is illustrated in more detail. The detection probe 10 comprises a drive coil 102 to generate a drive magnetic field and a sense coil to detect a response magnetic field.

[0045] The drive coil 102 is configured to generate a drive magnetic field by an applied current comprising a drive signal. The drive magnetic field is an alternating magnetic field generated to alternate with a fundamental frequency component fi. The drive magnetic field can also comprise one or more additional frequency components f n One or more of the additional frequency components f n may be spurious or unintended frequency components. Some or all of the additional frequency components f n may be harmonic frequencies of the fundamental frequency fi.

[0046] The base unit 4 and the probe 10 can also comprise a sine wave generator and amplifier 100 configured to generate a drive signal at the fundamental frequency fi, and a harmonic filter and drive circuit 101. The sine wave generator and amplifier 100 is configured to generate and amplify an alternating drive signal configured to alternate at the fundamental frequency fi. The drive signal can be generated to have one or more spurious frequency components f n . The additional frequency components can be introduced by amplifying the drive signal. The harmonic filter and drive circuit 101 is configured to filter the drive signal and provide the drive signal to the drive coil 102. The harmonic filter is configured to reduce one or more of the additional frequency components f nThe harmonic filter can be a notch filter tuned to a particular harmonic. The filtered drive signal is provided to the drive coil 102 to generate the drive field.

[0047] The base unit can also comprise one or more processing units, such as a microcontroller and / or a field programmable gate array (FPGA). The base unit can also comprise a memory unit, an analog-to-digital converter (ADC) and a digital-to-analog converter (DAC). The memory unit can be formed from an SD RAM or any suitable volatile or non-volatile storage means, for example. The microcontroller can also control and interact with the computer memory. The microcontroller can be an STM32F769 microcontroller from STM Electronics, for example, or any other suitable microcontroller. The microcontroller and the FPGA can generate a sinusoidal drive signal, which is then converted to an analog signal by the DAC, before being amplified using an operational amplifier, for example.

[0048] The sense coil 104 is configured to generate an electrical sense signal in response to a varying external magnetic field. The sense coil 104 is arranged to detect a response magnetic field generated by the magnetic material in response to the drive magnetic field. In particular, the sense coil 104 is arranged to detect a response magnetic field generated by the marker 6 and / or the tracer 7.

[0049] The detection probe 10 also comprises an electronic filter (such as a notch filter) 106, and a circuit 108 to detect and amplify harmonic content. The electronic filter 106 can be configured to reduce or remove the fundamental frequency f1 from the sense signal to improve sensing of other frequency components f n The circuit 108 to detect and amplify harmonic content can also amplify one or more additional frequency components in the additional frequency components f n corresponding to one or more harmonic frequencies of the fundamental frequency f1, for example. The circuit can also suppress some unwanted frequency components. The operation of the components for processing the sense signal will be described in more detail below.

[0050] Figure 5AA possible magnetization curve of the magnetic marker 6 is shown. The curve shows the level of magnetization of the marker 6 in relation to the strength of the applied external magnetic field. The marker 6 can comprise at least one large Barkhausen jump (LBJ) material. As mentioned above, LBJ materials can produce a non-linear magnetization curve. According to the magnetization curve, an excitation field H below the switching field 25 will result in little or no change in the magnetization B, just the effect of moving from “24” to “25” (small amplitude change), but no change in the polarity of B. Once the switching field indicated by “25” is exceeded, the curve shows a reversal of the magnetization. The curve shows a hysteresis effect, with a further reversal of the magnetization once the switching field indicated by “30” is exceeded. In this way, the reversal occurs regularly in time, with a period in time that is the same as the drive frequency.

[0051] Figure 5B A typical sensing signal corresponding to the magnetization curve of Figure 5A is shown. When the marker 6 is excited by an alternating field with a high enough amplitude, a pulse corresponding to the magnetization reversal is seen in the time domain. If the parasitic drive magnetic field coupled into the sensing coil is not completely filtered out, the pulse can be superimposed on the sinusoidal wave. As will be discussed in more detail below, a material with a linear magnetic response will produce a sinusoidal sensing signal at the same frequency as the drive magnetic field. In contrast, the nonlinear response of the marker 6 produces many harmonic frequency components in the sensing signal, which are superimposed to produce the final pulsed signal.

[0052] Figure 5C The sensing signal corresponding to the magnetization curve of Figure 5A is illustrated in the frequency domain. In response to a drive magnetic field that is substantially at the fundamental frequency (fi), the sensing signal includes at least one additional frequency component at a higher harmonic frequency. As shown, the sensing signal can include significant components in each of the harmonic frequencies of at least the 2ndto 10thharmonic frequencies (f2-f 10 ) relative to the fundamental frequency. Components at higher frequencies can also be present.

[0053] The marker 6 can be configured to provide a significant response at a particular harmonic frequency (f x ). This harmonic frequency f x can be used to distinguish between a portion of the sensing signal generated by the marker 6 and another portion generated by one or more secondary magnetic sources. The harmonic frequency f x can be used to distinguish between the marker 6 and the tracer 7. In some implementations, the third harmonic frequency (f3) can be used to distinguish between the marker 6 and the tracer 7.

[0054] In the response magnetic field generated by the marker 6, the fundamental frequency response is mixed with the particular harmonic frequency f xThe ratio of the change in the signal of the marker to the change in the signal of the reference can be referred to as a marker response factor or a primary response factor. The marker response factor can be about 100 or can be less than 100. In some implementations, the marker response factor can be less than 50, for example, the response factor of the marker can be about 30 before any filters are applied.

[0055] Instead of operating in a bistable mode, the nonlinear marker can operate in a sub-bistable mode. As described above, some LBJ materials can exhibit a nonlinear response (e.g., a third harmonic H3 response) that is almost two orders of magnitude larger than non-LBJ materials at fields that are smaller than the switching field. This can allow for detection of markers that are further away from the probe 10, where the driving field is typically small.

[0056] Figure 6A A typical magnetization curve of the magnetic tracer 7 is shown. The curve shows the relationship between the level of magnetization of the tracer 7 and the strength of the applied external magnetic field. The magnetic response of the tracer 7 is substantially linear at low excitation fields. At higher external magnetic fields, the magnetization of the tracer 7 can saturate as the nanoparticles in the tracer 7 are fully aligned with the external magnetic field. The magnetic response of the tracer 7 is linear at low excitation fields and can become nonlinear in response to higher excitation fields. According to the magnetization curve, a sinusoidal excitation field H with an amplitude below a certain linear threshold will result in a corresponding sinusoidal magnetization M. An excitation field with an amplitude above the linear threshold can result in distortion, i.e., nonlinearity, in the corresponding magnetization. Furthermore, if the central portion of the magnetization curve is not linear (i.e., has a constant slope), further nonlinear distortion can be introduced in the corresponding magnetization.

[0057] Figure 6B A typical sensing signal corresponding to the magnetization curve of Figure 6A is shown. When the tracer 7 is excited by an alternating field with an amplitude below the linear threshold, the sensing signal corresponds linearly to the excitation field. In the case where the alternating field is sinusoidal, the sensing signal has a corresponding sinusoidal form. When the tracer 7 is excited by an alternating field with a sufficiently high amplitude, a pulse corresponding to the saturation of the magnetization of the tracer 7 can be seen in the time domain. The nonlinear response produces one or more harmonic frequency components in the sensing signal, which are superimposed to combine to produce the final pulse signal.

[0058] Figure 6C The sensing signal corresponding to the magnetization curve of Figure 6A is illustrated in the frequency domain. It can be seen that, in response to a low-amplitude driving magnetic field that is substantially at the fundamental frequency (fl), the sensing signal includes primarily the fundamental frequency (fl). In response to a high-amplitude driving magnetic field that is substantially at the fundamental frequency (fl), the sensing signal includes at least one additional frequency component at a higher harmonic frequency. As shown, the sensing signal can include at least the 2ndto 10thharmonic frequencies (f2-f10) relative to the fundamental frequency (fl). The sensing signal can include a plurality of frequency components at the fundamental frequency (fl) and at the higher harmonic frequencies (f2-f10). The plurality of frequency components can be superimposed to combine to produce the final sensing signal. 10Significant components in any of the harmonic frequencies in the sensing signal generated by the tracer 7 can interfere with the detection of the harmonic frequency components generated by the marker 6 and can hinder accurate detection of the marker 6.

[0059] Harmonic frequency components in the sensing signal generated by the tracer 7 can interfere with the detection of the harmonic frequency components generated by the marker 6 and can hinder accurate detection of the marker 6.

[0060] As mentioned above, the marker 6 can be configured to provide a significant response at the harmonic frequency f x The harmonic frequency f x may be used to distinguish between the portion of the sensing signal generated by the marker 6 and the portion generated by the one or more secondary magnetic sources. However, the sensing signal component generated by the tracer 7 at the harmonic frequency f x may hinder accurate detection of the marker 6. Generating a drive magnetic field with an amplitude below the linear threshold of the tracer 7 can reduce the harmonic frequency components generated by the tracer 7. In particular, using a low amplitude drive magnetic field can reduce the third harmonic frequency components generated by the tracer 7.

[0061] The ratio of the fundamental frequency response to the third harmonic frequency in the response magnetic field generated by the tracer 7 can be referred to as the secondary response factor.

[0062] Figure 7 A block diagram of a magnetic detection system 1 according to an embodiment of the application is shown. The magnetic detection system 1 comprises a frequency generator 110. An oscillator or a waveform generator is an example of the frequency generator 110. The frequency generator 110 is configured to generate an alternating signal. The signal can be sinusoidal. The frequency f D of the signal can be in the range 100 Hz to 100 kHz. One example of a frequency generator is a microcontroller that outputs a sinusoidal wave which is then converted to an analogue signal by a digital to analogue converter and filtered by a low pass filter to smooth the signal.

[0063] The generated signal excites one or more drive coils 120. The one or more drive coils generate an alternating magnetic field. The generated field extends into tissue containing a magnetic marker 6 comprising at least one large Barkhausen jump (LBJ) material. The sinusoidal signal can minimise harmonic components in the alternating magnetic field, however, the alternating signal and / or the generated alternating magnetic field can include one or more spurious higher frequency components. The alternating magnetic field can include one or more harmonic components. The ratio of the fundamental frequency to the harmonic frequency f x in the generated alternating magnetic field can be referred to as the drive factor.

[0064] The drive signal generated by the frequency generator 110 can be electronically filtered to attenuate any harmonic components of the drive signal so that the alternating magnetic field is predominantly at the desired excitation or drive frequency. This helps to avoid spurious responses at higher frequencies that can be misinterpreted as harmonic responses. Filtering and processing of the drive signal can reduce the harmonic frequencies f x by several orders of magnitude. The harmonic frequencies f x may be 10 3 or 10 4 times smaller than the fundamental frequency component. That is, the value of the drive factor can be in the range 10 3 to 10 4 or higher. However, even such small components at the harmonic frequencies f x may hinder accurate detection of the marker 6.

[0065] The alternating magnetic field excites the marker 6 and the magnetization of the marker 6 causes generation of harmonic components in the response field. Depending on the arrangement of the marker 6, the harmonics can be odd harmonics (3rd, 5th, 7th, etc.) or even harmonics (2nd, 4th, 6th, etc.) or a combination of odd and even harmonics. The marker 6 can be detected by directly measuring the amplitude of one or more harmonic frequencies or by measuring the ratio of the amplitude of one or more harmonics to the amplitude of other harmonics or to the amplitude of the fundamental frequency.

[0066] The alternating magnetic field can also excite the tracer 7. The tracer distribution in space is generally unknown. However, if the amplitude of the alternating magnetic field is below a linear threshold for any tracer 7 in the volume around the probe 10, the magnetic response of the tracer 7 is linear, independent of the distribution of the tracer in space. The magnetization of the tracer causes generation of a response field with a large fundamental frequency component in response to the large fundamental frequency component of the drive magnetic field. In addition, the linear response of the tracer 7 can cause one or more higher frequency components in response to spurious higher frequency components in the drive magnetic field. Thus, the response field generated by the tracer 7 can include one or more harmonic frequency components due to the harmonic frequency components in the drive magnetic field.

[0067] The response field from the marker 6 and the tracer 7 is detected by one or more sense coils 130 to generate a sense voltage or current. The sense coils 130 can be disposed in a handheld or robotic probe, such as the probe 10. An electronic filter 140 can be disposed to filter out or at least attenuate components of the sense signal at the drive frequency, so that the resulting signal has minimal content at the drive frequency and includes higher harmonic components of the signal, such as second, third, fourth, fifth, or seventh harmonics or a combination of these. The filter 140 can take the form of a passive LCR type filter including known arrangements of capacitors, inductors, and resistors or an active filter including known arrangements based on one or more operational amplifiers.

[0068] The filtered signal can be fed to a harmonic detection circuit 150 that improves the signal-to-noise ratio of one or more harmonic components of the signal and converts the signal to a measure of the distance from the probe 10 to the marker 6. The harmonic detection circuit 150 can be configured to filter the parasitic harmonic response generated by the tracer 7. The harmonic detection circuit 150 can perform a number of operational steps. As described above, the functions of the harmonic detection circuit 150 can be performed by a microcontroller and an FPGA.

[0069] The harmonic detection circuit 150 can be configured to perform a cross-correlation 151 for noise reduction. The harmonic detection circuit 150 can be configured to separate the signal into a plurality of frequency components by the cross-correlation 151. For example, the cross-correlation 151 can separate the signal into a fundamental harmonic signal 152 and at least one n-th harmonic signal 153.

[0070] The harmonic detection circuit 150 can determine a correction factor 154. The correction factor 154 can correspond to the sense signal generated by the tracer 7. The correction factor 154 can correspond to a selected n-th harmonic frequency component generated by the tracer 7. By removing the correction factor 154 from the n-th harmonic signal 153, the harmonic detection circuit 150 can isolate a signal 155 from the nonlinear marker. In particular, the harmonic detection circuit 150 can isolate an n-th frequency signal generated by the marker 6.

[0071] The correction factor 154 can be determined based on the fundamental harmonic signal 152. The correction factor 154 can also be based on a drive factor representing the ratio of the fundamental frequency to the n-th harmonic frequency component in the drive magnetic field. In some implementations, the correction factor 154 can also be based on characteristic spectral responses of the linear tracer and the nonlinear marker. The harmonic detection circuit 150 can reduce the fundamental harmonic signal 152 by the drive factor to determine the correction factor 154. This is a practical approximation that is particularly effective as long as the tracer is about 10 times more linear than the marker. This linearity can be assessed by the corresponding harmonic distortion.

[0072] The correction factor 154 corresponding to the n-th harmonic frequency component generated by the tracer 7 can be expressed using the above-described minor response factor in terms of the fundamental frequency component generated by the tracer 7. Furthermore, the fundamental frequency component generated by the tracer 7 and the fundamental frequency component generated by the marker 6 together constitute the entire fundamental harmonic signal 152. Thus, a portion of the n-th harmonic frequency component generated by the tracer 7 can be related to the fundamental harmonic signal 152 based on the minor response factor. Another portion of the n-th harmonic frequency component generated by the tracer 7 can be related to the n-th harmonic frequency component generated by the marker 6 based on the minor response factor and the marker response factor.

[0073] Insofar as the magnetic response of the tracer 7 is linear, the minor response factor is substantially the same as the drive factor, independent of the spatial variation of the drive field and the spatial distribution of the tracer around the probe 10. That is, the value of the minor response factor can be in the range of 10 3 to 10 4 or higher. Due to the large difference between the minor response factor and the marker response factor, it can be determined that the portion of the n-th harmonic frequency component generated by the tracer 7 that is based on the minor response factor and the marker response factor can be negligible.

[0074] As a result, the correction factor 154 can be determined with high accuracy based on only the fundamental harmonic signal 152 and the drive factor of the drive signal.

[0075] The harmonic detection circuit 150 can be configured to remove the correction factor 154 from the n-th harmonic signal 153 to isolate the signal from the nonlinear marker 155. The signal from the nonlinear marker 155 can be referred to as the detection signal. Similar methods can be applied to reject spurious signals from different sources other than the tracer 7. For example, linear signals can come from metal objects near the probe 10 during surgery, from the patient’s body, from the surgeon’s hand, or from the biopsy marker. The harmonic detection circuit 150 can reject any such signals that are small enough so that they do not saturate the electronic components in the sensing circuit.

[0076] In some implementations, the frequency generator 110 can be configured to vary the amplitude of the drive signal over time. The amplitude of the alternating magnetic field generated by the drive coil 120 can vary over time. In this way, different volume portions around the probe 10 can be magnetically excited at different times. The harmonic detection circuit 150 can be configured to calculate multiple correction factors 154 corresponding to different amplitudes of the drive signal at different times. The calculated multiple correction factors 154 can be arranged in a correction factor array. The signal from the nonlinear marker 155 can be isolated based on the correction factor array. In this way, the system can more accurately reject spurious signals from minor sources that are not uniformly distributed around the probe 10.

[0077] Harmonic detection circuit 150 can also be configured to perform a signal transformation 156 on the n-th harmonic marker signal 155 to generate a measure of the distance from the probe 10 to the marker 6. A user display and sound generator 160 provides visual and audio output to the user indicative of, for example, the proximity of the marker 6 or the amplitude of the magnetic signal. The system can indicate the proximity, size, distance / direction, or orientation of the marker 6, or a combination of these.

[0078] By generating a correction factor corresponding to the n-th harmonic frequency component generated by the tracer 7, and isolating the n-th harmonic frequency component generated by the marker 6, the magnetic detection system 1 can provide a significantly improved indication of the proximity, size, etc. of the marker 6. The magnetic detection system 1 can accurately distinguish between the marker 6 and the tracer 7 even in the case where the drive signal does not have a pure single frequency sinusoidal waveform. The magnetic detection system 1 can improve the accuracy of locating the marker 6 and allow for more accurate removal of the corresponding lesion. Thus, the magnetic detection system 1 can reduce the occurrence of excessive tissue removal by allowing the surgeon to more accurately determine the extent of the lesion, thereby improving recovery time and better surgical outcomes.

[0079] In other cases, the magnetic detection system 1 can provide a more accurate indication of the size or number of magnetic markers, where the magnetic markers can correspond to a sample of any material that provides a non-linear magnetic response. The magnetic detection system 1 can improve the determination of the size or number even in the case where the drive signal includes spurious frequency components in addition to the desired fundamental frequency component.

[0080] Furthermore, extracting the n-th harmonic frequency component generated by the marker 6, along with knowledge of its spectral response, is equivalent to extracting the harmonic frequency component generated by the tracer 7. This can be used to quantify the amount of tracer 7 near the probe 10, or the distance of the tracer 7 from the probe 10, even in the case where there is a marker 6 that produces both the n-th harmonic frequency and the fundamental frequency components.

[0081] The markers of the detection system described above can each include one or more lengths of material that give a harmonic or non-linear response to an alternating magnetic field, the response resulting from a large Barkhausen discontinuity in the magnetization curve (“magnetic marker material”). Examples of such materials include glass-coated amorphous microwires that are iron-rich, cobalt-rich, and nickel-rich, iron-silicon-boron-based amorphous microwires, iron-cobalt-based amorphous microwires, and bulk metallic glass wires.

[0082] In some embodiments, one or more lengths of magnetic marker material (formed from a material having a large Barkhausen discontinuity in its magnetization curve) can include a solid wire of diameter < 2 mm (< 10 mm long) such that the marker can be delivered through a small needle; a glass-coated micro-wire having, for example, a core diameter between 5 and 100 microns and a coating thickness between, for example, 0.5 and 40 microns; a bundle of 2 or more lengths of solid wire or glass-coated micro-wire; or a hollow tube.

[0083] Any of the markers can include more than one magnetic marker material, along with additional materials for joining or surrounding the magnetic marker material and forming the final shape of the marker. The marker can include a tube, multiple tubes, or a complete or partial shell of another material, the interior of which houses multiple lengths of magnetic material of the marker. The marker can include electronic components (e.g., coils, diodes, and transistors), for example, an LC circuit (combination of a capacitor and an inductor) with a diode can produce a non-linear response. The magnetic material can also be coated or surrounded within another biocompatible material. For example, a tube or shell containing the magnetic marker material includes a biocompatible malleable material, such as 316 stainless steel, titanium, nitinol, titanium alloy, or similar materials.

[0084] In some embodiments, the drive unit can include one or more drive coils. Alternatively, the alternating magnetic field can be generated by, for example, a rotating permanent magnet. The sense unit can include one or more sense coils, or alternatively, a solid-state magnetometer. In some implementations, the sense unit can include any suitable magnetic sensor, such as a Hall effect sensor, a mems sensor, a magnetic transistor / diode, a SQUID magnetometer, an AMR sensor, or a GMR sensor.

[0085] The drive frequency can be in the range of 100 Hz to 100 kHz. Higher frequencies near 100 kHz can be advantageous to maximize the sense signal. Higher frequencies can also allow more cycles per second to be averaged during detection to improve noise rejection, while still providing a "real-time" output to the user, i.e., updating the output signal at least 10 times per second. Thus, for noise rejection, a frequency of at least 1000 Hz and preferably at least 10 kHz can be desirable. For example, to give the user a perceptible "real-time" response, the output can need to be updated at least once every 0.1 seconds. A frequency of 1 kHz allows 100 cycles to be averaged between each update to the user, while 10 kHz allows 1000 cycles to be averaged between each update to the user.

[0086] Lower driving frequencies can also bring advantages, including reduced eddy current losses in the marker (in cases where the marker is prone to eddy currents, for example if it has high electrical conductivity) and from surrounding tissue, and stronger magnetic switching in the marker. To reduce eddy current losses, frequencies less than 50 kHz and preferably less than 30 kHz can be advantageous. In a surgical room environment, frequencies higher than 100 kHz can more frequently experience electromagnetic interference signals, so it can be beneficial to select a driving frequency such that the harmonics of interest are less than 100 kHz.

[0087] The drawings Figure 8 A flowchart representing a method of detecting a magnetic marker according to an embodiment is shown. The method starts at step S01.

[0088] At step S02, a driving magnetic field is generated. The driving magnetic field is generated by a driving unit. The driving magnetic field comprises a first driving component (DH1) at a first frequency and a second driving component (DH n ) at a second frequency. The first frequency can be a first fundamental frequency and the second frequency can be an nth harmonic of the first frequency.

[0089] At step S03, a response magnetic field is detected. The response magnetic field is detected by a magnetic field sensor. The response magnetic field comprises a first response component (SH1) at the first frequency and a second response component (SH n ) at the second frequency.

[0090] SH1 comprises two sub-components: a marker sub-component (MH1) and a secondary sub-component (TH1). SH n Also comprises two sub-components: a marker sub-component (MH n ) and a secondary sub-component (TH n ).

[0091] The marker sub-component can be referred to as the primary sub-component or primary part. The secondary sub-component (or secondary part) can be from a magnetic tracer or other magnetic signal source. MH n is the desired signal from the marker, while TH n is an unwanted interference signal from the tracer or other secondary source.

[0092] At step S04, a driving factor DF = DH1 / DH n is generated. The driving factor represents the ratio of the first driving component to the second driving component in the driving signal. The driving factor is generated by a processor.

[0093] At step S05, a correction factor is determined for compensating TH n . That is, the correction factor corresponds to SH na secondary sub-component of the first response component. The correction factor is determined by the processor. The correction factor is determined based on the first response component (SH1) and a driving factor (DF).

[0094] At step S06, a detection signal corresponding to the marker portion of the second response component is determined. The detection signal is determined by the processor. The detection signal is determined based on the second response component (SH n ) and the determined correction factor.

[0095] At step S07, an output signal is generated. The output signal is generated by the processor for output. The output signal is based on the intensity of the detection signal.

[0096] The method completes at step S08.

[0097] While aspects of the application herein have been described with reference to particular embodiments, it is to be understood that the embodiments are illustrative of the principles and application of the application. It should therefore be understood that numerous modifications can be made to the illustrative embodiments and that other arrangements can be devised without departing from the scope of the application as defined by the appended claims.

Claims

1. A method for detecting magnetic markers, the method comprising the following steps: A driving magnetic field is generated by a driving unit, the driving magnetic field including a first driving component at a first frequency and a second driving component at a second frequency, the second frequency being the nth harmonic of the first frequency; A magnetic field sensor detects a response magnetic field, the response magnetic field including a first response component at the first frequency and a second response component at the second frequency. Wherein, the principal portions of the first response component and the principal portions of the second response component are generated by the magnetic marker in response to the driving magnetic field; the magnetic marker has a nonlinear response to the driving magnetic field, and The secondary portions of the first response component and the second response component are generated by at least one secondary magnetic source in response to the driving magnetic field; the secondary magnetic source has a linear response to the driving magnetic field. The processor determines a driving factor, which represents the ratio of the first driving component to the second driving component in the driving magnetic field; the driving factor is approximately equal to the ratio of the minor portion of the first response component to the minor portion of the second response component. The processor determines a correction factor corresponding to a minor portion of the second response component from the first response component and the driving factor. The processor determines a detection signal corresponding to the marker portion of the second response component, wherein the detection signal is determined from the second response component and the correction factor; and The processor generates an output signal based on the intensity of the detected signal.

2. The method according to claim 1, wherein, The magnetic marker is formed from a material that exhibits the Big Buckhausen Jump LBJ pattern in its magnetization curve.

3. The method according to claim 1 or 2, wherein, The magnetic marker is configured to exhibit bistable behavior by oscillating between two magnetic polarization states in response to a sinusoidal drive signal.

4. The method according to claim 1 or 2, wherein, The driving magnetic field is generated with an amplitude below a threshold amplitude level. Above the threshold amplitude level, the response of the secondary magnetic source to the driving magnetic field becomes nonlinear.

5. The method according to claim 1 or 2, wherein, The marker response factor, which represents the ratio of the marker portion of the first response component to the marker portion of the second response component, is less than the minor response factor, which represents the ratio of the minor portion of the first response component to the minor portion of the second response component.

6. The method according to claim 1 or 2, wherein, The step of determining the correction factor is also based on the second response component, the spectral response of the secondary magnetic source, and the spectral response of the marker.

7. The method according to claim 1 or 2, wherein, The magnetic marker is formed of a magnetically responsive material configured to provide a marker response factor having a value less than 300, representing the ratio of the marker portion of the first response component to the marker portion of the second response component.

8. The method according to claim 1 or 2, wherein, The secondary magnetic source is formed of a paramagnetic material.

9. The method according to claim 8, wherein, The secondary magnetic source comprises multiple superparamagnetic iron oxide nanoparticles.

10. The method according to claim 1 or 2, wherein, The second frequency is the third harmonic frequency of the first frequency.

11. The method according to claim 1 or 2, further comprising the step of: The processor determines the secondary detection signal based on the secondary portion of the first response component and the secondary portion of the second response component; as well as The processor generates a secondary output signal based on the strength of the secondary detection signal for output.

12. The method according to claim 1 or 2, wherein, The secondary magnetic source can be any of surgical instruments, biopsy markers, or the human body.

13. The method according to claim 1 or 2, wherein, The amplitude of the output signal is related to the proximity of the magnetic marker to the magnetic field sensor.

14. The method according to claim 11, wherein, The amplitude of the output signal is related to the amount of magnetic material in the magnetic marker or the secondary magnetic source.

15. The method according to claim 1 or 2, further comprising the step of: The amplitude of the driving magnetic field is changed by the driving unit over time, and The processor determines multiple additional correction factors based on the corresponding multiple driving magnetic field amplitudes and generates a correction factor array, and The detection signal is determined based on the second response component and the generated correction factor array.

16. The method according to claim 1 or 2, wherein, The driving factor is in 10 3 Up to 10 4 Within or higher ranges.

17. A detection system for detecting magnetic markers, the detection system comprising: A driving unit configured to generate a driving magnetic field, the driving magnetic field including a first driving component at a first frequency and a second driving component at a second frequency; A magnetic field sensor configured to detect a response magnetic field, the response magnetic field including a first response component at a first frequency and a second response component at a second frequency, the second frequency being the nth harmonic of the first frequency. Wherein, the principal portions of the first response component and the principal portions of the second response component are generated by the magnetic marker in response to the driving magnetic field; the magnetic marker has a nonlinear response to the driving magnetic field, and Wherein, a secondary portion of the first response component and a secondary portion of the second response component are generated by at least one secondary magnetic source in response to the driving magnetic field; the secondary magnetic source is configured to have a linear response to the driving magnetic field; and Processor, the processor being configured to: A driving factor is determined, which represents the ratio of the first driving component to the second driving component in the driving magnetic field; the driving factor is approximately equal to the ratio of the minor portion of the first response component to the minor portion of the second response component. A correction factor corresponding to a minor portion of the second response component is determined from the first response component and the driving factor, wherein the correction factor is determined based on the first response component and the driving factor; Determine a detection signal corresponding to the marker portion of the second response component, wherein the detection signal is determined from the second response component and the correction factor; and An output signal is generated for the user based on the strength of the detected signal.

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